Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2013 Article ID 408681 12 pageshttpdxdoiorg1011552013408681
Review ArticleRedox Regulation in Amyotrophic Lateral Sclerosis
Sonam Parakh1 Damian M Spencer1 Mark A Halloran2 Kai Y Soo1 and Julie D Atkin13
1 Department of Biochemistry La Trobe Institute for Molecular Science La Trobe University Vic 3086 Australia2 School of Psychological Science La Trobe University Vic 3086 Australia3 Florey Department of Neuroscience University of Melbourne Parkville Vic 3010 Australia
Correspondence should be addressed to Julie D Atkin jatkinlatrobeeduau
Received 17 October 2012 Revised 7 January 2013 Accepted 10 January 2013
Academic Editor Jeannette Vasquez-Vivar
Copyright copy 2013 Sonam Parakh et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results from the death of upper and lower motor neuronsDue to a lack of effective treatment it is imperative to understand the underlying mechanisms and processes involved in diseaseprogression Regulations in cellular reductionoxidation (redox) processes are being increasingly implicated in disease Here wediscuss the possible involvement of redox dysregulation in the pathophysiology of ALS either as a cause of cellular abnormalitiesor a consequence We focus on its possible role in oxidative stress protein misfolding glutamate excitotoxicity lipid peroxidationand cholesterol esterification mitochondrial dysfunction impaired axonal transport and neurofilament aggregation autophagicstress and endoplasmic reticulum (ER) stress We also speculate that an ER chaperone protein disulphide isomerase (PDI) couldplay a key role in this dysregulation PDI is essential for normal protein folding by oxidation and reduction of disulphide bondsand hence any disruption to this process may have consequences for motor neurons Addressing the mechanism underlying redoxregulation and dysregulation may therefore help to unravel the molecular mechanism involved in ALS
1 Introduction
Cellular oxidationreduction (redox) states regulate variousaspects of cellular function and maintain homeostasis [1]Moderate levels of reactive oxygen speciesreactive nitro-gen species (ROSRNS) function as signals to promote cellproliferation regulation and survival [2] whereas increasedlevels of ROSRNS can induce cell death [1 2] Under normalphysiological conditions cells maintain redox homeostasisthrough generation of ROS which include free radical speciessuch as superoxide (O
2
minus) hydroxyl radicals (OHminus) and non-radical species such as hydrogen peroxide (H
2O2) and RNS
which includes nitric oxide (NO) nitronium ion (NO2
+)nitrogen dioxide (NO
2
∙) and peroxynitrite (ONOOminus) [3ndash5] RNS are by-products of nitric oxide synthase (NOS)and NADPH oxidase [6] Increased levels of NOS havebeen observed in the motor neurons of amyotrophic lateralsclerosis (ALS) patients suggesting a role of RNS in pathology[7] Higher levels of RNS can react with other free radicalssuch as superoxide and undergo complex reactions to formthe strong oxidant ONOOminus which causes cellular damage [8ndash10]
Cells are equipped with antioxidant systems to eliminateROSRNS and maintain redox homeostasis which includeenzymatic antioxidants such as superoxide dismutase (SOD)peroxidase oxidase catalase and nonenzymatic oxidantssuch as glutathione [3 11] Glutaredoxin and thioredoxin areredox active molecules which undergo cysteine dependentmodifications also making them preferential targets fordirect oxidation [12]
Redox regulation is a fundamental cellular process involv-ing enzymes that maintain the appropriate environment formetabolic activities and proper functioning of the cell [13]Normally redox homeostasis ensures that cells respond tostressors such as oxidative or nitrative stress efficiently butwhen it is disturbed neurodegeneration and apoptosis canoccur [11 14] Neurons are particularly susceptible to degen-eration via redox dysregulation as the high consumption ofoxygen by the brain results in a significant production ofROS [15] Disruption in redox regulation is implicated inthe pathogenesis of neurodegeneration disorders includingALS Interestingly several pathogenic mechanisms linkedto ALS involve redox-sensitive proteins such as SOD1 andproteins with active-site cysteine residues including protein
2 Oxidative Medicine and Cellular Longevity
disulphide isomerase (PDI) thioredoxin and glutathione[16ndash20] These proteins contain a thiol group which ishighly sensitive to changes in redox conditions [12 21] Evenslight modulations in redox state are capable of producingneurotoxic species such as NO
2
+ NO2
∙ and ONOOminus [14]suggesting that redox stress could be of importance in disease[9]
2 Amyotrophic Lateral Sclerosis (ALS)
ALS also known asCharcotrsquos or LouGehrigrsquos disease is a fatalneurodegenerative disorder that affects the upper and lowermotor neurons of the primary cortex brainstem and spinalcord [22 23] The symptoms include muscle weakness andmuscle spasticity eventually resulting in paralysis [24] withALS patients generally dying from respiratory failure within3ndash5 years of diagnosis Approximately 2 per 100000 peopleworldwide are affected by ALS every year [22] Riluzole isthe only FDA-approved drug currently available for ALSRiluzole has modest efficacy It slows disease progressionand a dose of 100mg per day also improves limb functionand muscle strength although it increases life span by anaverage of only 2-3 months [25 26] Therefore a greaterunderstanding of the molecular mechanisms causing ALS isimportant in order to develop better therapeutic solutions
Approximately 90 of ALS cases have no genetic asso-ciation and are known as sporadic ALS (SALS) Howevermutations in genes such as copperzinc superoxide dis-mutase (SOD1) fused in sarcoma (FUS) and TAR DNAbinding protein (TARDBP) have also been described in SALSpatients also environmental causes such as smoking andviral infection are linked to ALS [24 27ndash31] Studies haveshown higher prevalence of ALS in people with a historyof trauma [32] and involvement in physical activities suchas soccer has also been observed in ALS patients [33 34]however the exact aetiology is unknown The remaining 10of ALS cases known as familial ALS (FALS) are linkedto mutations in specific genes [35] including SOD1 TDP-43 FUS vesicle associated membrane protein-B (VAPB)optineurin alsin and ubiquilin-2 [18 36ndash43] Recently anoncoding mutation in C9ORF72 was shown to cause thegreatest proportion of FALS cases [44] SOD1 causes 15ndash20 of all FALS cases and was the first described and hencemost widely researched gene linked to ALS [18] Transgenicmice overexpressing ALS-associated mutant SOD1 proteinshave been used extensively as diseasemodels [45ndash47] Similarto other protein disorders the pathological hallmark ofALS is the presence of intracellular protein inclusions [48]Misfolded wild-type and mutant forms of SOD1 FUS andTDP-43 [41 49 50] are present on the inclusions found inaffected tissues of ALS patients [41 51ndash53] SALS and FALShave similar symptoms and are clinically and pathologicallyindistinguishable
Wild-type SOD1 is a highly stable homodimeric proteinexplained in part by the presence of an intrasubunit disul-phide bond between cysteine 57 and cysteine 146 [54] Itcontains both copper and zinc ions which are essential forthe catalytic activity and stability respectively [55] Reduction
of the disulphide bond results in dissociation of the dimerand the resulting protein is highly unstable and prone toaggregation [56 57]
Dysfunction in multiple cellular mechanisms is linkedto ALS pathology reviewed recently by Cozzolino andcoworkers [58] Many of these events are linked to redoxregulation including oxidative stress protein misfolding andaggregation excitotoxicity lipid peroxidation and cholesterolesterification mitochondrial dysfunction impaired axonaltransport and neurofilament aggregation autophagy and ERstress [46 59ndash68] However there is a complex interplaybetween these processes and the exact aetiology of the diseaseis unclear It is debatable whether redox dysregulation is aprimary effect or a secondary consequence of other patholo-gies and the association of redox regulation and cysteine richredox regulated proteins with these mechanisms is unclearThis paper discusses the main redox linked mechanismswhich are involved in ALS and their association with redoxor cysteine dependent proteins
3 Possible Redox Regulated CellularMechanisms Involved in ALS
31 Oxidative Stress Oxidative stress arises when the levelsof ROSRNS exceed the amounts required for normal redoxsignalling While oxidative stress has been implicated as apathological mechanism in ALS the exact role of ROSRNSin disease processes is unclear [9 69] ROS causes permanentoxidative damage to major cellular components such asproteins DNA lipids and cell membranes [70ndash72] ROS hasbeen detected in the spinal cord and cerebrospinal fluid (CSF)of SALS patients [17] Increased levels of H
2O2and oxidative
damage to protein andDNAhave also been observed in SOD1transgenicmice [73] Defects in the RacNox pathway leadingto redox dysregulation are also linked to SOD1G93A mice [74]Furthermore dysregulation of redox regulated-tumour pro-tein 1 ubiquitin carboxyl-terminal hydrolase isoenzyme L1and 120572B crystallin has been observed in transgenic SOD1G93Amice [75]
Altered redox homeostasis regulates gene expression oftranscriptional factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-120581B) activator protein1 (AP-1) and hypoxia inducible factor 1120572 (HIF-1120572) [76]These transcriptional factors help inmaintaining homeostasisby regulating gene expression They have a redox regulatedcysteine residue at their DNA binding site [76] which canbe affected due to thiol oxidation and could be influencedby ROS [77] A direct relation between the transcriptionfactors and redox regulation in ALS is unknown neverthelessdysregulation in the levels of NF-120581B and HIF-1120572 has beenobserved in SALS patients and activation of AP-1 in mutantSOD1 expressing cells suggesting potential involvement ofredox regulation in ALS pathology [78 79]
SOD1 and its antioxidant properties have been studiedextensively from the perspective of redox regulation in ALS[80 81] SOD1 catalyses the conversion of superoxide intohydrogen peroxide and oxygen and it undergoes cyclicreduction and oxidation of its copper ions [82] Initially it
Oxidative Medicine and Cellular Longevity 3
was proposed that ALSmutations in SOD1 result in the loss ofits ability to act as an antioxidant but further research showedthat disease is not associated with its enzymatic activity[83] However mutations in SOD1 could produce ONOOminusor OHminus and lower its ability to catalyse superoxide [84] byreacting with nitric oxide [85] These intermediate productsare highly unstable and have been detected with other aminoacids such as tyrosine Nitrated proteins and high levelsof nitrotyrosine have been detected in the CSF of bothSALS and FALS patients suggesting that posttranslationalmodification via free radical production is present in ALS[17 86ndash88] Oxidised wild-type SOD1 in the lymphoblastsof SALS patients associates with mitochondrial Bcl-2 whichcauses mitochondrial damage [89] Oxidative damage is animportant phenomenon however treatment with antioxi-dants has not been very successful [90]
32 Protein Aggregation andMisfolding Redox dysregulationmay not only increase the production of ROSRNS but alsoaffect protein conformation and structure Posttranslationalmodification of SOD1 such as oxidation has an adverseeffect on the conformational arrangement of SOD1 [91]Glutathionylation a posttranslational modification of the 111cysteine residue causes destabilisation of SOD1 structure[92] Wild-type SOD1 has been shown in inclusions of SALSpatients suggesting its involvement in causing neurotoxicity[93] Evidence suggests that oxidised wild-type SOD1 hasthe ability to misfold and form aggregates and gain similarconformation as the mutant and has toxic functions in vitro[89 94] SOD1 depleted zinc and copper have altered redoxactivity and are more prone to oxidation [95]
An oxidising environment also causes abnormal disul-phide linkages and protein aggregation in ALS [80 96]SOD1 containing aberrant disulphide bonds involves thenormally unpaired cysteine residues cysteine 6 and cysteine111 in the spinal cord of ALS transgenic mice models [96]Studies show that mutant TDP-43 aggregation is causeddue to increased disulphide bonds [97] Similarly oxidativestress causes aberrant disulphide cross-linking and subcel-lular localisation of TDP-43 [97] as well as accumulation ofFUS into the cytoplasm [98] Mutant SOD1 readily formsmonomers oligomers or inclusions which are insoluble [55]It is unclear how conformational changes cause misfoldingbut one possible explanation could be the modification andalteration of protein structure by ROS through oxidisation ofthe thiol group forming aberrant disulphide bonds
33 Glutamate Excitotoxicity The levels of glutamate presentinmammalian CNS aremuch higher than those of other neu-rotransmitters (5ndash10mmolkg) indicating the importance ofglutamate in neuronal function [99] However excitotoxicityoccurs when the levels of glutamate are increased in neuronsresulting in increased calcium intake and neuronal injury[100 101] Motor neurons are particularly susceptible to highlevels of glutamate [102] Glutamate uptake from the synapseis controlled by glutamate transporters astroglial GLASTGLT1 and neuronal EAAC1 which possess a redox regulatedcysteine residue [103] N-methyl-D aspartic acid (NMDA)
glutamate receptors are also redox regulated suggesting thatredox dysfunction may further affect glutamate regulationIncreased levels of intracellular glutamate and decreaseduptake of glutamate from the synapse have been observedin ALS patients [104 105] Indeed Rothstein and coworkersshowed an absence of GLT1 transporter in ALS patients[106] ROS can reduce the uptake of glutamate in mammals[107] however increased calcium levels in the mitochondriadue to dysfunctional glutamate regulation can result inoverproduction of ROS and cause oxidative stress [108] Thequestion remains whether oxidative stress causes glutamatedysregulation or vice versa
34 Lipid Peroxidation and Cholesterol Esterification TheER is also the main site of lipid and sterol synthesis [109]Lipids are major targets of oxidative stress resulting in lipidperoxidation via a chain-reaction process [11] Sphingolipidsare localised in the plasma membrane and ER membranesand with cholesterol are processed into domains knownas lipid rafts [68] Lipid rafts can form macroplatformsfor redox signalling providing critical mediation for cel-lular functioning [110] Lipid peroxidation and cholesterolesterification have been implicated in the pathogenesis ofALS [68 69 111] Excitotoxicity and oxidative stress altersphingolipid metabolism resulting in the accumulation oflong-chain ceramides sphingomyelin and cholesterol estersin the spinal cords of ALS patients and CuZn SOD1 miceThis occurs at the early presymptomatic stage of disease in theSOD1mice [68] thus implicating aberrant lipidmetabolism inthe pathophysiology of ALS Further evidence of lipid dysreg-ulation in ALS comes from studies which reported that ALSpatients demonstrated a tendency towards hyperlipidemiaAdditionally correlational studies have shown that ALSpatients with the highest low density lipoprotein (LDL) highdensity lipoprotein (HDL) ratio have a significant increasein survival time and respiratory function [112 113] Fur-thermore recently an interaction between SOD1 aggregateswith lipid was found to alter lipid membrane permeability[114]
Lipid peroxidation products such as 4-hydroxynonenalhave been detected at higher levels in ALS patients spinalcord than controls and this has been linked to modificationof astrocytic glutamate transporter EAAT2 and excitotoxicity[111] Excitotoxicity was also linked to upregulation of sterolregulatory binding element 1 (SREBP1) in the spinal cordsof FALS and SALS patients and SOD1G93A transgenic micesuggesting cholesterol depletion [115] Furthermore the linkbetween ALS and statins a class of drug which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reduc-tase may suggest that suppressing cholesterol synthesisincreases the incidence [116 117] progression and severityof ALS [118] although this has been questioned [119] Lipidraft alteration has also been linked to the pathogenesis ofALS Endogenous wild-type and mutant SOD1G93A proteinswere recruited into lipid rafts isolated from spinal cords oftransgenic SOD1mice [120] Hence together the data suggestthat oxidative stress may alter sphingolipid and cholesterolmetabolism and deregulate lipid raft redox signalling leading
4 Oxidative Medicine and Cellular Longevity
to the accumulation of toxic ceramides and cholesterol esterswhich may ultimately result in motor neuron death [68]
35 Mitochondrial Dysfunction Mitochondria are impor-tant players in redox regulation and oxidative stress hasthe potential to cause mitochondrial dysfunction [70 121]Indeed damaged mitochondria are observed in the spinalcord cells of SALS patients [122ndash124] The mitochondrialgenome is particularly susceptible to oxidative damage [125]hence any increase in cellular ROS would potentially per-turb mitochondrial functions Mitochondria participate inneuronal apoptotic signalling pathways through the releaseof mitochondrial proteins including cytochrome c into thecytoplasm [126] There is substantial evidence that molecularcomponents of mitochondrial apoptosis play a role in neu-rodegeneration in both SOD1 rodents and in mutant SOD1overexpressed in cell culture [127] The enzymatic activityof cytochrome c oxidase (COX) in mitochondria is alsoreduced in the spinal cord cells of SALS patients [122ndash124128 129] Mitochondria have been well studied in relation toALS pathogenesis Degenerating or abnormal mitochondriahave been described in mouse models [62 130] culturedneuronal cellular models [131 132] and ALS patients [133134] although how nonfunctioning mitochondria relate toALS is unclear Possible explanations include inhibition ofaxonal transport dysregulation of calcium buffering [135] oractivation of mitochondrial-dependent apoptosis [128 136]Recent studies have shown that overexpression of TDP-43causes mitochondrial dysfunction and induces mitophagy incell culture [137]The presence of ROS and impairment of themitochondrial respiratory chain have also been observed inTDP-43 models [138 139]
Mutant SOD1 has also been implicated in mitochondrialrespiratory complex impairment [140] and a shift in the redoxstate of mitochondria towards oxidation [141] How SOD1functions in the mitochondria is still not clear althoughsome data suggests that SOD1 is crucial for maintenanceof the mitochondrial redox state [142 143] and that ALSmutations affect the localisation or function of SOD1 inmitochondria [135] However mutant misfolded SOD1 hasbeen found localised with various compartments of themitochondria [144] Significantly any pathological changesin regulation of the electron transport chain would result inmore oxidative stress [145] triggering further cellular redoxdysregulation leading to a potential vicious cycle of damageand degeneration
36 Impaired Axonal Transport Axonal transport is a keymechanism required for cellular viability in neuronal cellsMost proteins required in the axon and in synaptic terminalsmust be transported along the axon after synthesis in the cellbody Similarly RNA and organelles also need to be trans-ported over long distances and these transport processesrequire molecular motors such as kinesins dyneins andmyosins that operate along the cellular cytoskeleton Dys-function of axonal transport has now been well documentedin ALS [61] Whilst many of these studies implicate dyneinin this process [146] several also highlight the importance
of kinesin in ALS particularly kinesin heavy chains KIF5Aand KIF1B120573 which transport mitochondria synaptic vesi-cles and macromolecular complexes Interestingly a recentstudy demonstrated that oxidised wild-type SOD1 immuno-purified from SALS patient tissues inhibited kinesin-basedaxonal transport in amanner similar tomutant SOD1 in FALSproviding evidence for common pathogenic mechanisms inboth SALS and FALS [94]
Neurofilaments (NF) accumulation in motor neuronsis another histopathological hallmark of ALS [147 148]Also transgenic mice that overexpress NF subunits in motorneurons develop a motor neuron disease with impairedaxonal flow as axonal defects cause delay in transportationof components required for the maintenance of axon [149]However ONOOminus formed during oxidative stress fromnitrooxide and superoxide can affect NF assembly and causeNF accumulation in motor neurons [8] Chou and coworkersshowed NF aggregations are associated with SOD1 and nitricoxide synthase activities leading to nitrotyrosine formationon NF [150] Nitrotyrosine can inhibit phosphorylation ofheavy or light NF subunits and may alter axonal transportand trigger motor neuron death [150] Taken together thesefindings suggest a relation between redox regulation andaxonal transport dysfunctions in ALS
37 Autophagy Autophagy is a normal homeostatic mecha-nism to dispose large protein aggregates damaged organellesand long-lived proteins Autophagic stress results when thenumber of autophagosomes increases relative to the pro-portion of degradable proteins The presence of high levelsof superoxide and hydrogen peroxide species can induceautophagy in vitro [151] but consequently autophagy canfurther induce oxidative or nitrative stress thus creating avicious cycle [152] Dysregulated redox activity also influ-ences autophagy Cathepsin a class of proteases which havehighly regulated thiol groups [152] and other key regulatoryautophagic complexes such as Beclin 1 and Rubicon alsohave the presence of cysteine residues [152] The presence ofcysteine residues suggests that they are redox regulated andlikely to be affected by ROS ATG 4 another protease is atarget of oxidation by hydrogen peroxide However directassociation of these with ALS has not yet been identifiedAltered autophagic levels have been observed in SOD1G93Amice and sporadic and familial patients but whether theincreased levels are protective or not is still questionable [153ndash156]
38 ER Stress and Protein Disulphide Isomerase (PDI) in ALSThe ER is redox regulated and another important locationfor the production of ROS It plays key roles in protein andlipid synthesis and protein folding Proteinmisfolding withinthe ER triggers ER stress which induces the unfolded proteinresponse (UPR) a distinct signalling pathway which aims torelieve stress [157] While initially protective prolonged UPRcauses apoptosis [158 159] Recent studies suggest that ERstress is an early and important pathogenic mechanism inALS [66 158 160] ER stress is induced in animal modelsof SOD1 in cells expressing mutant FUS and in patients
Oxidative Medicine and Cellular Longevity 5
CGHC CGHC KDEL
119886 119887 119888119909119887998400
119886998400
Figure 1 Schematic diagram showing domain structure of PDIThioredoxin-like 119886 domain (orange) and 1198861015840 domain (purple) pos-sessing the catalyticmotif catalytically inactive 119887 domain (blue) and1198871015840 domain (red) Green represents the linker region 119909 which allowsflexibility between domainsTheC terminal domain is shown in greyfollowed by the ER retrieval signal KDEL
[20 161] Oxidative stress driven by changes in fatty acidcomposition mitochondrial function andor proteosomeactivity leads to oxidative stress and contributes to ER stressin SALS patients [162 163] PDI is an ER chaperone whichis induced during UPR and has been implicated in severalneurodegenerative disorders including ALS [164ndash166]
PDI is a member of an extended family of foldasesand chaperones which are responsible for the formationand isomerisation of protein disulphide bonds [167] ThePDI family comprises 21 members which have structuralsimilarities but different functions [168] and all have asimilar active site to thioredoxin [169] Thioredoxin is anintracellular protein which regulates redox conditions andwhich is effective against oxidative stress [170] PDI is mostabundant in the ER but it is also found in other subcellularlocations such as the nucleus and extracellular matrix [171]and it constitutes 08 of the total cellular protein [172]The yeast PDI crystal structure was recently solved [173]which suggests that 119886 and 1198861015840 domains are responsible forthe formation of disulphide bonds (Figure 1) These domainscontain a redox active CGHCmotif which isomerases proteindisulphide bonds and is involved in redox regulation [173]PDI also contains 119887 and 1198871015840 domains which are responsiblefor substrate binding [174 175] Misfolded proteins attach tothe hydrophobic region of an inverted U shape structure [173176] The C-terminal region also aids in polypeptide bindingand contributes chaperone activity [177] Compared to otherfamilymembers PDI has broad substrate specificities and caninteract with glycosylated as well as nonglycosylated proteins[178]
4 PDI and Redox Regulation
PDI forms protein disulphide bonds by the oxidation ofthiols within the PDI active site cysteine residues [179 180]When PDI is in an oxidised state it transfers a disulphide tothe substrates thereby oxidising the substrate and becomingreduced itself Conversely substrates which need disulphidebond rearrangement are reduced by PDI in the reduced statethus oxidising PDI in the process [168 181] This continualcycling regulates redox conditions within the ER A thiolcontaining tripeptide protein and glutathione also maintainsER redox homeostasis by similar shuffling between oxidizedand reduced cysteine residues Glutathione is also requiredfor the isomerisation and rearrangement of disulphide bonds[182] The redox potential of PDI (minus110mV) is lower than
other family members [183] due to intervening residuespresent between the reactive cysteines thus facilitating disul-phide bonds [183] ERO1 oxidises PDI also aiding disulphidebond formations [184] but PDI is also oxidised throughperoxiredoxin 4 vitamin K glutathione peroxidase andquiescin sulfhydryl oxidase [181] During ER stress highlevels of ERO1 have been observed which accelerates proteinoxidation suggesting interplay between oxidative stress andER stress The transfer of electrons from the thiol groupof PDI to ERO1 results in the production of excess ROSdecreasing the levels of glutathione available for reductionand increasing ERO1 thus altering the redox conditions [185186] Hence imbalance in the redox state of the ERmay resultin dysregulation of thiol containing proteins and triggers
41 The Role of PDI in ALS Due to its function in preventingprotein misfolding PDI is important in protein quality con-trol [166] also deletion of PDI is embryonically lethal [187]Hence regulated expression of PDI is critical for normalcellular functionThere is now growing evidence for a role ofPDI in ALS PDI levels are upregulated in transgenic modelsof ALS and spinal cord tissues of ALS patients [66 158]Overexpression of PDI is also protective againstmutant SOD1mediated aggregation and reduces cell death in vitro [20] PDIcoimmunoprecipitates with both SOD1 and FUS [158 161] italso colocalises with SOD1 TDP-43 and FUS in ALS patientssuggesting a physical interaction exists between PDI andother key misfolded proteins in ALS [66 161 188] SimilarlyPDI also colocalises with TDP-43 in ALS tissues and withVAPB inclusions in a Drosophila melanogaster model ofALS [188 189] A small mimic of the active site of PDIdithiol (plusmn)-trans-12-bis (mercaptoacetamido) cyclohexane(BMC) is also protective in cell culture and it reduces mutantSOD1 aggregation in a dose dependent manner [20] Furtherevidences for a role for disulphide interchange activity in ALScomes from studies showing that another PDI familymemberERp57 is also upregulated in transgenic SOD1 mice and ALSpatients [66] Furthermore thioredoxin is also upregulated inthe erythrocytes of FALS patients [19]
The upregulation of these thiol containing proteins inALS suggests a cellular defensive mechanism is triggeredin disease as a defence against oxidative stress Howeverthere is evidence that normal protective function of PDI isinhibited in disease [20] Modifications of active site thiolgroups through direct oxidation S-glutathiolation and S-nitrosylation can lead to inactivation of the normal enzy-matic activity of PDI [13 190 191] PDI was recently shownto be S-nitrosylated in ALS [20 192] as in other neurodegen-erative disorders such as Parkinsonrsquos and Alzheimerrsquos disease[191] S-nitrosylation occurs when there is an increased pro-duction of RNS during oxidative stress resulting in additionof a nitrogen monoxide group to the thiol side of PDI[20 164] Experiments performed by Chen and coworkerssuggested that in the presence of S-nitrosylated PDI theformation of mutant SOD1 aggregates increases in vitro [192]It is also likely that inactivation of PDI could lead to activationof the UPR as observed in other neurodegenerative disorders[191] The loss of PDI functional activity can directly lead to
6 Oxidative Medicine and Cellular Longevity
Impaired axonaltransport
AutophagyMitochondrialdysfunction
ER stress Proteinmisfolding
Redox dysregulation
PDI dysfunction Oxidative stress
Figure 2 Redox dysfunction and its relationship to other patholo-gies in ALS Alteration in the enzymatic activity of PDI due toredox dysregulation and oxidative stress can further increase theload of misfolded proteins ER stress oxidative stress autophagymitochondrial dysfunction and axonal impairment leading toneuronal cell death
apoptosis or indirectly to a range of cellular abnormalitiessuch as oxidative stress and protein misfolding which againlead to cell death [164 166] Hence the redox regulationof PDI is a crucial component in the maintenance of abalanced redox environment and inhibition of its enzymaticactivity will lead to important consequences for the cell(Figure 2)
Neurons are highly susceptible to redox dysregulationdue to their high metabolic requirements large size andlower ability to maintain the balance between antioxidantsand ROS [15] In disease states such as ALS oxidativestress and altered enzymatic activity of PDI which normallyreduces ROS and the burden of misfolded protein can causeserious damage to the neuron Since multiple mechanismsare involved in neurodegeneration any imbalance in redoxregulation can lead to an imbalance in the production offree radical species which consequently cause mitochondrialdamage and excitotoxicity thus elevating the levels of freeradicals [193] Furthermore an excess of free radicals canalso lead to DNA damage and may also result in aggregationof NF [194] and structural destabilization of other proteinsthus inducing ER stress and apoptosis Since ALS is a slowprogressive disorder it could be hypothesised that these cyclicevents due to loss of functional activity of PDImay graduallylead to neuronal degradation In such a scenario the redoxregulatory function of PDI may therefore have an importantprotective effect
5 Conclusion
Redox regulation is an important mechanism of homeostasisin eukaryotic cells especially neuronal cells where oxygen
levels are high [15] Many cellular processes rely on it includ-ing proper functioning of the mitochondria and ER calciumregulation axonal transport regulated autophagy and pro-tein folding Links between redox dysregulation and ALSare becoming well documented in the literature althoughthe directionality of these links and their underlying causeare still quite unknown One possible key player in redox reg-ulation in ALS is PDI whose role in ALS pathogenesis is thetopic of much new research As the critical protein involvedin thiol reduction any dysregulation of PDI activity can leadto oxidative stress and redox dysregulation Due to its activityPDI itself also contains an active site thiol group suggestingthat it can also be affected by oxidative stress leading to anescalating cycle that perpetuates redox dysregulation HowPDI becomes nonfunctional in the first place is still unclearalthough somepapers point to S-nitrosylation as having a role[20] Regardless of its exact role any mechanism to improvethe catalytic activity of PDI should have a reductive effect onoxidative stress levels in neurons It is therefore tempting tospeculate about PDI as a possible therapeutic target in thetreatment of ALS
Acknowledgments
This work was supported by the National Health and Med-ical Research Council of Australia (project Grants 4547491006141 and 1030513) Amyotrophic Lateral Sclerosis Asso-ciation (USA) MND Research Institute of Australia Beth-lehem Griffiths Research Council Henry H Roth CharitableFoundation Grant for MND Research Australian RotaryHealth and the Brain Foundation S Parakh holds a La TrobeUniversity Post Graduate Research Scholarship
References
[1] H Kamata and H Hirata ldquoRedox regulation of cellular sig-nallingrdquo Cellular Signalling vol 11 no 1 pp 1ndash14 1999
[2] A R Cross and O T G Jones ldquoEnzymic mechanisms ofsuperoxide productionrdquoBiochimica et BiophysicaActa vol 1057no 3 pp 281ndash298 1991
[3] VAdler Z YinKD Tew andZRonai ldquoRole of redox potentialand reactive oxygen species in stress signalingrdquo Oncogene vol18 no 45 pp 6104ndash6111 1999
[4] J Nordberg and E S J Arner ldquoReactive oxygen speciesantioxidants and the mammalian thioredoxin systemrdquo FreeRadical Biology andMedicine vol 31 no 11 pp 1287ndash1312 2001
[5] M G Espey K M Miranda D D Thomas et al ldquoA chemicalperspective on the interplay between NO reactive oxygenspecies and Reactive Nitrogen Oxide Speciesrdquo Annals of theNew York Academy of Sciences vol 962 pp 195ndash206 2002
[6] W A Pryor and G L Squadrito ldquoThe chemistry of per-oxynitrite a product from the reaction of nitric oxide withsuperoxiderdquo American Journal of Physiology-Lung Cellular andMolecular Physiology vol 268 no 5 pp L699ndashL722 1995
[7] K Abe L H Pan M Watanabe H Konno T Kato andY Itoyama ldquoUpregulation of protein-tyrosine nitration in theanterior horn cells of amyotrophic lateral sclerosisrdquo Neurologi-cal Research vol 19 no 2 pp 124ndash128 1997
Oxidative Medicine and Cellular Longevity 7
[8] J S Beckman M Carson C D Smith and W H KoppenolldquoALS SOD and peroxynitriterdquoNature vol 364 no 6438 p 5841993
[9] S C Barber and P J Shaw ldquoOxidative stress in ALS key rolein motor neuron injury and therapeutic targetrdquo Free RadicalBiology and Medicine vol 48 no 5 pp 629ndash641 2010
[10] M C Martınez and R Andriantsitohaina ldquoReactive nitrogenspecies molecular mechanisms and potential significance inhealth and diseaserdquo Antioxidants and Redox Signaling vol 11no 3 pp 669ndash702 2009
[11] D Trachootham W Lu M A Ogasawara N R D Valle andP Huang ldquoRedox regulation of cell survivalrdquo Antioxidants andRedox Signaling vol 10 no 8 pp 1343ndash1374 2008
[12] C E Cooper R P Patel P S Brookes and VM Darley-UsmarldquoNanotransducers in cellular redox signaling modification ofthiols by reactive oxygen and nitrogen speciesrdquo Trends inBiochemical Sciences vol 27 no 10 pp 489ndash492 2002
[13] H Nakamura K Nakamura and J Yodoi ldquoRedox regulation ofcellular activationrdquo Annual Review of Immunology vol 15 pp351ndash369 1997
[14] S A Lipton Y B Choi Z H Pan et al ldquoA redox-based mech-anism for the neuroprotective and neurodestructive effects ofnitric oxide and related nitroso-compoundsrdquo Nature vol 364no 6438 pp 626ndash632 1993
[15] B Halliwell ldquoOxidative stress and neurodegeneration whereare we nowrdquo Journal of Neurochemistry vol 97 no 6 pp 1634ndash1658 2006
[16] R P Guttmann and T J Powell ldquoRedox regulation of cysteine-dependent enzymes in neurodegenerationrdquo International Jour-nal of Cell Biology vol 2012 Article ID 703164 8 pages 2012
[17] H Tohgi T Abe K Yamazaki T Murata E Ishizaki and CIsobe ldquoIncrease in oxidized NO products and reduction inoxidized glutathione in cerebrospinal fluid from patients withsporadic form of amyotrophic lateral sclerosisrdquo NeuroscienceLetters vol 260 no 3 pp 204ndash206 1999
[18] D R Rosen T Siddique D Patterson et al ldquoMutations inCuZn superoxide dismutase gene are associated with familialamyotrophic lateral sclerosisrdquoNature vol 362 no 6415 pp 59ndash62 1993
[19] Y Ogawa H Kosaka T Nakanishi et al ldquoStability of mutantsuperoxide dismutase-1 associated with familial amyotrophiclateral sclerosis determines the manner of copper release andinduction of thioredoxin in erythrocytesrdquo Biochemical andBiophysical Research Communications vol 241 no 2 pp 251ndash257 1997
[20] A KWalker M A Farg C R Bye C AMcLeanM K Horneand J D Atkin ldquoProtein disulphide isomerase protects againstprotein aggregation and is S-nitrosylated in amyotrophic lateralsclerosisrdquo Brain vol 133 no 1 pp 105ndash116 2010
[21] M W Akhtar C R Sunico T Nakamura and S A Lip-ton ldquoRedox regulation of protein function via cysteine S-nitrosylation and its relevance to neurodegenerative diseasesrdquoInternational Journal of Cell Biology vol 2012 Article ID463756 9 pages 2012
[22] J D Rothstein ldquoCurrent hypotheses for the underlying biologyof amyotrophic lateral sclerosisrdquo Annals of Neurology vol 65no 1 pp S3ndashS9 2009
[23] J Mitchell and G Borasio ldquoAmyotrophic lateral sclerosisrdquoLancet vol 369 no 9578 pp 2031ndash2041 2007
[24] L CWijesekera and PN Leigh ldquoAmyotrophic lateral sclerosisrdquoOrphanet Journal of Rare Diseases vol 4 no 1 p 3 2009
[25] G Bensimon L Lacomblez and V Meininger ldquoA controlledtrial of riluzole in amyotrophic lateral sclerosisrdquo New EnglandJournal of Medicine vol 330 no 9 pp 585ndash591 1994
[26] R G Miller J D Mitchell M Lyon and D HMoore ldquoRiluzolefor amyotrophic lateral sclerosis (ALS)motor neuron disease(MND)rdquoCochraneDatabase of Systematic Reviews no 1 ArticleID CD001447 2007
[27] A Alonso G Logroscino S S Jick and M A HernanldquoAssociation of smoking with amyotrophic lateral sclerosis riskand survival in men and women a prospective studyrdquo BMCNeurology vol 10 no 1 p 6 2010
[28] A Verma and J R Berger ldquoALS syndrome in patients withHIV-1 infectionrdquo Journal of the Neurological Sciences vol 240 no 1-2pp 59ndash64 2006
[29] A Chio B J Traynor F Lombardo et al ldquoPrevalence of SOD1mutations in the Italian ALS populationrdquoNeurology vol 70 no7 pp 533ndash537 2008
[30] L Corrado R Del Bo B Castellotti et al ldquoMutations ofFUS gene in sporadic amyotrophic lateral sclerosisrdquo Journal ofMedical Genetics vol 47 no 3 pp 190ndash194 2010
[31] J Sreedharan I P Blair V B Tripathi et al ldquoTDP-43mutationsin familial and sporadic amyotrophic lateral sclerosisrdquo Sciencevol 319 no 5870 pp 1668ndash1672 2008
[32] E Pupillo P Messina G Logroscino et al ldquoTrauma andamyotrophic lateral sclerosis a case-control study from apopulation-based registryrdquo European Journal of Neurology vol19 no 12 pp 1509ndash1517 2012
[33] S Beretta M T Carrı E Beghi A Chio and C Ferrarese ldquoThesinister side of Italian soccerrdquo Lancet Neurology vol 2 no 11pp 656ndash657 2003
[34] M R Turner C Wotton K Talbot and M J GoldacreldquoCardiovascular fitness as a risk factor for amyotrophic lateralsclerosis indirect evidence from record linkage studyrdquo Journalof Neurology Neurosurgery amp Psychiatry vol 83 pp 395ndash3982012
[35] P A Dion H Daoud and G A Rouleau ldquoGenetics of motorneuron disorders new insights into pathogenic mechanismsrdquoNature Reviews Genetics vol 10 no 11 pp 769ndash782 2009
[36] T Arai M Hasegawa H Akiyama et al ldquoTDP-43 is a compo-nent of ubiquitin-positive tau-negative inclusions in frontotem-poral lobar degeneration and amyotrophic lateral sclerosisrdquoBiochemical and Biophysical Research Communications vol 351no 3 pp 602ndash611 2006
[37] M Neumann D M Sampathu L K Kwong et al ldquoUbiq-uitinated TDP-43 in frontotemporal lobar degeneration andamyotrophic lateral sclerosisrdquo Science vol 314 no 5796 pp130ndash133 2006
[38] C Vance B Rogelj T Hortobagyi et al ldquoMutations in FUSan RNA processing protein cause familial amyotrophic lateralsclerosis type 6rdquo Science vol 323 no 5918 pp 1208ndash1211 2009
[39] Y Yang A Hentati H X Deng et al ldquoThe gene encodingalsin a protein with three guanine-nucleotide exchange factordomains is mutated in a form of recessive amyotrophic lateralsclerosisrdquo Nature Genetics vol 29 pp 160ndash165 2001
[40] A L Nishimura M Mitne-Neto H C A Silva et al ldquoAmutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclero-sisrdquoAmerican Journal of HumanGenetics vol 75 no 5 pp 822ndash831 2004
8 Oxidative Medicine and Cellular Longevity
[41] T J Kwiatkowski Jr D A Bosco A L LeClerc et al ldquoMutationsin the FUSTLS gene on chromosome 16 cause familial amy-otrophic lateral sclerosisrdquo Science vol 323 no 5918 pp 1205ndash1208 2009
[42] HMaruyamaHMorinoH Ito et al ldquoMutations of optineurinin amyotrophic lateral sclerosisrdquo Nature vol 465 no 7295 pp223ndash226 2010
[43] H X Deng W Chen S T Hong et al ldquoMutations in UBQLN2cause dominant X-linked juvenile and adult-onset ALS andALSdementiardquo Nature vol 477 pp 211ndash215 2011
[44] M DeJesus-Hernandez I R Mackenzie B F Boeve et alldquoExpanded GGGGCC hexanucleotide repeat in noncodingregion of C9ORF72 causes chromosome 9p-linked FTD andALSrdquo Neuron vol 72 no 2 pp 245ndash256 2011
[45] L I Bruijn T M Miller and D W Cleveland ldquoUnraveling themechanisms involved in motor neuron degeneration in ALSrdquoAnnual Review of Neuroscience vol 27 pp 723ndash749 2004
[46] H D Durham J Roy L Dong and D A Figlewicz ldquoAggrega-tion of mutant CuZn superoxide dismutase proteins in a cul-turemodel ofALSrdquo Journal ofNeuropathology andExperimentalNeurology vol 56 no 5 pp 523ndash530 1997
[47] M Watanabe M Dykes-Hoberg V Cizewski Culotta D LPrice P C Wong and J D Rothstein ldquoHistological evidenceof protein aggregation in mutant SOD1 transgenic mice andin amyotrophic lateral sclerosis neural tissuesrdquo Neurobiology ofDisease vol 8 no 6 pp 933ndash941 2001
[48] C Soto ldquoUnfolding the role of protein misfolding in neurode-generative diseasesrdquo Nature Reviews Neuroscience vol 4 no 1pp 49ndash60 2003
[49] J Wang G Xu and D R Borchelt ldquoMapping superoxidedismutase 1 domains of non-native interaction roles of intra-and intermolecular disulfide bonding in aggregationrdquo Journalof Neurochemistry vol 96 no 5 pp 1277ndash1288 2006
[50] B S Johnson D Snead J J Lee J M McCaffery J Shorterand A D Gitler ldquoTDP-43 is intrinsically aggregation-proneand amyotrophic lateral sclerosis-linked mutations accelerateaggregation and increase toxicityrdquo Journal of Biological Chem-istry vol 284 pp 20329ndash20339 2009
[51] C Vance B Rogelj T Hortobagyi et al ldquoMutations in FUSan RNA processing protein cause familial amyotrophic lateralsclerosis type 6rdquo Science vol 323 no 5918 pp 1208ndash1211 2009
[52] T Arai M Hasegawa H Akiyama et al ldquoTDP-43 is a compo-nent of ubiquitin-positive tau-negative inclusions in frontotem-poral lobar degeneration and amyotrophic lateral sclerosisrdquoBiochemical and Biophysical Research Communications vol 351no 3 pp 602ndash611 2006
[53] N Shibata A Hirano M Kobayashi et al ldquoIntense super-oxide dismutase-1 immunoreactivity in intracytoplasmic hya-line inclusions of familial amyotrophic lateral sclerosis withposterior column involvementrdquo Journal of Neuropathology andExperimental Neurology vol 55 no 4 pp 481ndash490 1996
[54] J S Valentine P A Doucette and S Z Potter ldquoCopper-zinc superoxide dismutase and amyotrophic lateral sclerosisrdquoAnnual Review of Biochemistry vol 74 pp 563ndash593 2005
[55] F Arnesano L Banci I BertiniMMartinelli Y Furukawa andT V OrsquoHalloran ldquoThe unusually stable quaternary structureof human CuZn-superoxide dismutase 1 is controlled by bothmetal occupancy and disulfide statusrdquo Journal of BiologicalChemistry vol 279 no 46 pp 47998ndash48003 2004
[56] C Kayatekin J A Zitzewitz and C R Matthews ldquoDisulfide-Reduced ALS Variants of Cu Zn Superoxide Dismutase Exhibit
Increased Populations of Unfolded Speciesrdquo Journal of Molecu-lar Biology vol 398 no 2 pp 320ndash331 2010
[57] A E Svensson O Bilsel C Kayatekin J A Adefusika J AZitzewitz and C Robert Matthews ldquoMetal-free ALS variantsof dimeric human CuZn-superoxide dismutase have enhancedpopulations of monomeric speciesrdquo PLoS ONE vol 5 no 4Article ID e10064 2010
[58] M Cozzolino M G Pesaresi V Gerbino J Grosskreutzand M T Carr ldquoAmyotrophic lateral sclerosis new insightsinto underlying molecular mechanisms and opportunities fortherapeutic interventionrdquo Antioxidants amp Redox Signaling vol17 no 9 pp 1277ndash1330 2012
[59] O Spreux-Varoquaux G Bensimon L Lacomblez et al ldquoGlu-tamate levels in cerebrospinal fluid in amyotrophic lateralsclerosis a reappraisal using a new HPLC method with coulo-metric detection in a large cohort of patientsrdquo Journal of theNeurological Sciences vol 193 no 2 pp 73ndash78 2002
[60] I Puls C Jonnakuty B H LaMonte et al ldquoMutant dynactin inmotor neuron diseaserdquo Nature Genetics vol 33 no 4 pp 455ndash456 2003
[61] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[62] J Kong and Z Xu ldquoMassive mitochondrial degeneration inmotor neurons triggers the onset of amyotrophic lateral sclero-sis in mice expressing a mutant SOD1rdquo Journal of Neurosciencevol 18 no 9 pp 3241ndash3250 1998
[63] F R Wiedemann K Winkler A V Kuznetsov et al ldquoImpair-ment of mitochondrial function in skeletal muscle of patientswith amyotrophic lateral sclerosisrdquo Journal of the NeurologicalSciences vol 156 no 1 pp 65ndash72 1998
[64] AHiranoHDonnenfeld S Sasaki and I Nakano ldquoFine struc-tural observations of neurofilamentous changes in amyotrophiclateral sclerosisrdquo Journal of Neuropathology and ExperimentalNeurology vol 43 no 5 pp 461ndash470 1984
[65] J D Wood T P Beaujeux and P J Shaw ldquoProtein aggregationin motor neurone disordersrdquo Neuropathology and AppliedNeurobiology vol 29 no 6 pp 529ndash545 2003
[66] J D Atkin M A Farg A KWalker C McLean D Tomas andM K Horne ldquoEndoplasmic reticulum stress and induction ofthe unfolded protein response in human sporadic amyotrophiclateral sclerosisrdquoNeurobiology of Disease vol 30 no 3 pp 400ndash407 2008
[67] S Chen X Zhang L Song and W Le ldquoAutophagy dysregula-tion in amyotrophic lateral sclerosisrdquo Brain Pathology vol 22no 1 pp 110ndash116 2012
[68] R G Cutler W A Pedersen S Camandola J D Rothsteinand M P Mattson ldquoEvidence that accumulation of ceramidesand cholesterol esters mediates oxidative stress-induced deathof motor neurons in amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 52 no 4 pp 448ndash457 2002
[69] R J Ferrante S E Browne L A Shinobu et al ldquoEvidenceof increased oxidative damage in both sporadic and familialamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol69 no 5 pp 2064ndash2074 1997
[70] M Bogdanov R H Brown W Matson et al ldquoIncreasedoxidative damage to DNA in ALS patientsrdquo Free Radical Biologyand Medicine vol 29 no 7 pp 652ndash658 2000
[71] A W Girotti ldquoLipid hydroperoxide generation turnover andeffector action in biological systemsrdquo Journal of Lipid Researchvol 39 no 8 pp 1529ndash1542 1998
Oxidative Medicine and Cellular Longevity 9
[72] P J Shaw P G Ince G Falkous and D Mantle ldquoOxidativedamage to protein in sporadic motor neuron disease spinalcordrdquo Annals of Neurology vol 38 no 4 pp 691ndash695 1995
[73] D Liu J Wen J Liu and L Li ldquoThe roles of free radicalsin amyotrophic lateral sclerosis reactive oxygen species andelevated oxidation of protein DNA and membrane phospho-lipidsrdquo FASEB Journal vol 13 no 15 pp 2318ndash2328 1999
[74] B J Carter P Anklesaria S Choi and J F Engelhardt ldquoRedoxmodifier genes and pathways in amyotrophic lateral sclerosisrdquoAntioxidants and Redox Signaling vol 11 no 7 pp 1569ndash15862009
[75] H F Poon K Hensley V Thongboonkerd et al ldquoRedoxproteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice-a model of familial amyotrophic lateralsclerosisrdquo Free Radical Biology and Medicine vol 39 no 4 pp453ndash462 2005
[76] J J Haddad ldquoAntioxidant and prooxidant mechanisms in theregulation of redox(y)-sensitive transcription factorsrdquo CellularSignalling vol 14 no 11 pp 879ndash897 2002
[77] K T Turpaev ldquoReactive oxygen species and regulation of geneexpressionrdquo Biochemistry vol 67 no 3 pp 281ndash292 2002
[78] C Iaccarino M E Mura S Esposito et al ldquoBcl2-A1 interactswith pro-caspase-3 implications for amyotrophic lateral scle-rosisrdquo Neurobiology of Disease vol 43 no 3 pp 642ndash650 2011
[79] C Moreau P Gosset J Kluza et al ldquoDeregulation of thehypoxia inducible factor-1120572 pathway in monocytes from spo-radic amyotrophic lateral sclerosis patientsrdquo Neuroscience vol172 pp 110ndash117 2011
[80] C M Karch M Prudencio D D Winkler P J Hart andD R Borchelt ldquoRole of mutant SOD1 disulfide oxidation andaggregation in the pathogenesis of familial ALSrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 106 no 19 pp 7774ndash7779 2009
[81] J B ProescherM Son J L Elliott andV C Culotta ldquoBiologicaleffects of CCS in the absence of SOD1 enzyme activationimplications for disease in a mouse model for ALSrdquo HumanMolecular Genetics vol 17 no 12 pp 1728ndash1737 2008
[82] J M McCord and I Fridovich ldquoSuperoxide dismutase Anenzymic function for erythrocuprein (hemocuprein)rdquo Journalof Biological Chemistry vol 244 no 22 pp 6049ndash6055 1969
[83] D Sau S De Biasi L Vitellaro-Zuccarello et al ldquoMutation ofSOD1 in ALS a gain of a loss of functionrdquo Human MolecularGenetics vol 16 no 13 pp 1604ndash1618 2007
[84] J S Beckman M Carson C D Smith and W H KoppenolldquoALS SOD and peroxynitriterdquoNature vol 364 no 6438 p 5841993
[85] N V Blough and O C Zafiriou ldquoReaction of superoxide withnitric oxide to form peroxonitrite in alkaline aqueous solutionrdquoInorganic Chemistry vol 24 no 22 pp 3502ndash3504 1985
[86] M F Beal R J Ferrante S E Browne Jr R T Matthews NW Kowall and R H Brown ldquoIncreased 3-nitrotyrosine in bothsporadic and familial amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 42 no 4 pp 644ndash654 1997
[87] H Tohgi T Abe K Yamazaki T Murata E Ishizaki andC Isobe ldquoRemarkable increase in cerebrospinal fluid 3-nitrotyrosine in patients with sporadic amyotrophic lateralsclerosisrdquo Annals of Neurology vol 46 pp 129ndash131 1999
[88] F Casoni M Basso T Massignan et al ldquoProtein nitration in amouse model of familial amyotrophic lateral sclerosis possiblemultifunctional role in the pathogenesisrdquo Journal of BiologicalChemistry vol 280 no 16 pp 16295ndash16304 2005
[89] S Guareschi E Cova C Cereda et al ldquoAn over-oxidizedform of superoxide dismutase found in sporadic amyotrophiclateral sclerosiswith bulbar onset shares a toxicmechanismwithmutant SOD1rdquo Proceedings of the National Academy of Sciencesvol 109 no 13 pp 5074ndash5079 2012
[90] RW Orrell R J M Lane andM Ross ldquoA systematic review ofantioxidant treatment for amyotrophic lateral sclerosismotorneuron diseaserdquo Amyotrophic Lateral Sclerosis vol 9 no 4 pp195ndash211 2008
[91] S A Ezzi M Urushitani and J P Julien ldquoWild-type superoxidedismutase acquires binding and toxic properties of ALS-linkedmutant forms through oxidationrdquo Journal of Neurochemistryvol 102 no 1 pp 170ndash178 2007
[92] R L Redler K C Wilcox E A Proctor L Fee M Caplowand N V Dokholyan ldquoGlutathionylation at Cys-111 inducesdissociation of wild type and FALS mutant SOD1 dimersrdquoBiochemistry vol 50 no 32 pp 7057ndash7066 2011
[93] K Forsberg P A Jonsson P M Andersen et al ldquoNovelantibodies reveal inclusions containing non-native SOD1 insporadic ALS patientsrdquo PloS One vol 5 no 7 Article ID e115522010
[94] D A Bosco G Morfini N M Karabacak et al ldquoWild-type andmutant SOD1 share an aberrant conformation and a commonpathogenic pathway in ALSrdquo Nature Neuroscience vol 13 no11 pp 1396ndash1403 2010
[95] A C Estevez J P Crow J B Sampson et al ldquoInduction of nitricoxide-dependent apoptosis in motor neurons by zinc- deficientsuperoxide dismutaserdquo Science vol 286 no 5449 pp 2498ndash2500 1999
[96] Y Furukawa R Fu H X Deng T Siddique and T VOrsquoHalloran ldquoDisulfide cross-linked protein represents a signif-icant fraction of ALS-associated Cu Zn-superoxide dismutaseaggregates in spinal cords of model micerdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 18 pp 7148ndash7153 2006
[97] T J Cohen AWHwang T Unger J Q Trojanowski and VMY Lee ldquoRedox signalling directly regulates TDP-43 via cysteineoxidation and disulphide cross-linkingrdquo The EMBO Journalvol 31 no 5 pp 1241ndash1252 2011
[98] DDormann R Rodde D Edbauer et al ldquoALS-associated fusedin sarcoma (FUS) mutations disrupt transportin-mediatednuclear importrdquo EMBO Journal vol 29 no 16 pp 2841ndash28572010
[99] S P Butcher andAHamberger ldquoIn vivo studies on the extracel-lular and veratrine-releasable pools of endogenous amino acidsin the rat striatum effects of corticostriatal deafferentiation andkainic acid lesionrdquo Journal of Neurochemistry vol 48 no 3 pp713ndash721 1987
[100] I Sen A Nalini N B Joshi and P G Joshi ldquoCerebrospinalfluid from amyotrophic lateral sclerosis patients preferentiallyelevates intracellular calcium and toxicity in motor neurons viaAMPAkainate receptorrdquo Journal of the Neurological Sciencesvol 235 no 1-2 pp 45ndash54 2005
[101] A Plaitakis and J T Caroscio ldquoAbnormal glutamatemetabolism in amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 22 no 5 pp 575ndash579 1987
[102] L Van Den Bosch and W Robberecht ldquoDifferent receptorsmediate motor neuron death induced by short and long expo-sures to excitotoxicityrdquo Brain Research Bulletin vol 53 no 4 pp383ndash388 2000
10 Oxidative Medicine and Cellular Longevity
[103] D Trotti ldquoNeuronal and glial glutamate transporters possessan SH-based redox regulatory mechanismrdquo European Journalof Neuroscience vol 9 no 6 pp 1236ndash1243 1997
[104] A Plaitakis and E Constantakakis ldquoAlteredmetabolism of exci-tatory amino acids N-acetyl-aspartate and N- acetyl-aspartyl-glutamate in amyotrophic lateral sclerosisrdquo Brain ResearchBulletin vol 30 no 3-4 pp 381ndash386 1993
[105] J D Rothstein L J Martin and R W Kuncl ldquoDecreasedglutamate transport by the brain and spinal cord in amyotrophiclateral sclerosisrdquo New England Journal of Medicine vol 326 no22 pp 1464ndash1468 1992
[106] J D Rothstein M Van Kammen A I Levey L J Martin andRW Kuncl ldquoSelective loss of glial glutamate transporter GLT-1amyotrophic lateral sclerosisrdquo Annals of Neurology vol 38 no1 pp 73ndash84 1995
[107] A Volterra D Trotti C Tromba S Floridi and G RacagnildquoGlutamate uptake inhibition by oxygen free radicals in ratcortical astrocytesrdquo Journal of Neuroscience vol 14 no 5 pp2924ndash2932 1994
[108] P J Shaw ldquoGlutamate excitotoxicity and amyotrophic lateralsclerosisrdquo Journal of Neurology vol 244 no 2 pp S3ndashS14 1997
[109] W L Miller ldquoMinireview regulation of steroidogenesis byelectron transferrdquo Endocrinology vol 146 no 6 pp 2544ndash25502005
[110] S Jin F Zhou F Katirai and P L Li ldquoLipid raft redox signalingmolecular mechanisms in health and diseaserdquoAntioxidants andRedox Signaling vol 15 no 4 pp 1043ndash1083 2011
[111] W A Pedersen W Fu J N Keller et al ldquoProtein modificationby the lipid peroxidation product 4-hydroxynonenal in thespinal cords of amyotrophic lateral sclerosis patientsrdquo Annals ofNeurology vol 44 no 5 pp 819ndash824 1998
[112] L Dupuis P Corcia A Fergani et al ldquoDyslipidemia is aprotective factor in amyotrophic lateral sclerosisrdquo Neurologyvol 70 no 13 pp 1004ndash1009 2008
[113] L Dupuis and J P Loeffler ldquoNeuromuscular junction destruc-tion during amyotrophic lateral sclerosis insights from trans-genic modelsrdquo Current Opinion in Pharmacology vol 9 no 3pp 341ndash346 2009
[114] I Choi H D Song S Lee et al ldquoDirect observation ofdefects and increased ion permeability of a membrane inducedby structurally disordered CuZn-superoxide dismutase aggre-gatesrdquo PloS One vol 6 no 12 pp e28982ndashe28982 2011
[115] C Taghibiglou J Lu I R Mackenzie Y T Wang and NR Cashman ldquoSterol regulatory element binding protein-1(SREBP1) activation in motor neurons in excitotoxicity andamyotrophic lateral sclerosis (ALS) indip a potential therapeu-tic peptiderdquo Biochemical and Biophysical Research Communica-tions vol 413 no 2 pp 159ndash163 2011
[116] E Colman A Szarfman J Wyeth et al ldquoAn evaluation of adata mining signal for amyotrophic lateral sclerosis and statinsdetected in FDArsquos spontaneous adverse event reporting systemrdquoPharmacoepidemiology and Drug Safety vol 17 no 11 pp 1068ndash1076 2008
[117] I R Edwards K Star and A Kiuru ldquoStatins neuromusculardegenerative disease and an amyotrophic lateral sclerosis-likesyndrome an analysis of individual case safety reports fromvigibaserdquo Drug Safety vol 30 no 6 pp 515ndash525 2007
[118] L Zinman R Sadeghi M Gawel D Patton and A Kiss ldquoArestatin medications safe in patients with ALSrdquo AmyotrophicLateral Sclerosis vol 9 no 4 pp 223ndash228 2008
[119] HToftSoslashrensen andT L Lash ldquoStatins and amyotrophic lateralsclerosis-the level of evidence for an associationrdquo Journal ofInternal Medicine vol 266 no 6 pp 520ndash526 2009
[120] J Zhai A L Strom R Kilty et al ldquoProteomic characterizationof lipid raft proteins in amyotrophic lateral sclerosis mousespinal cordrdquo FEBS Journal vol 276 no 12 pp 3308ndash3323 2009
[121] M F Beal ldquoAging energy and oxidative stress in neurodegen-erative diseasesrdquoAnnals of Neurology vol 38 no 3 pp 357ndash3661995
[122] F RWiedemann GManfredi CMawrinM Flint Beal and EA Schon ldquoMitochondrial DNA and respiratory chain functionin spinal cords of ALS patientsrdquo Journal of Neurochemistry vol80 no 4 pp 616ndash625 2002
[123] G M Borthwick M A Johnson P G Ince P J Shaw and DM Turnbull ldquoMitochondrial enzyme activity in amyotrophiclateral sclerosis implications for the role of mitochondria inneuronal cell deathrdquoAnnals of Neurology vol 46 no 5 pp 787ndash790 2001
[124] P M Keeney and J P Bennett ldquoALS spinal neurons show variedand reducedmtDNAgene copy numbers and increasedmtDNAgene deletionsrdquoMolecular Neurodegeneration vol 5 no 1 p 212010
[125] M B Graeber E Grasbon-Frodl U V Eitzen and S K KoselldquoNeurodegeneration and aging role of the second genomerdquoJournal of Neuroscience Research vol 52 no 1 pp 1ndash6 1998
[126] K C Zimmermann C Bonzon andD R Green ldquoThemachin-ery of programmed cell deathrdquo Pharmacology andTherapeuticsvol 92 no 1 pp 57ndash70 2001
[127] P Nagley G C Higgins J D Atkin and P M Beart ldquoMul-tifaceted deaths orchestrated by mitochondria in neuronesrdquoBiochimica et Biophysica Acta vol 1802 no 1 pp 167ndash185 2010
[128] C GueganM Vila G Rosoklija A P Hays and S PrzedborskildquoRecruitment of the mitochondria-dependent apoptotic path-way in amyotrophic lateral sclerosisrdquo Journal of Neurosciencevol 21 no 17 pp 6569ndash6576 2001
[129] L J Martin Z Liu K Chen et al ldquoMotor neuron degenerationin amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice mechanisms of mitochondriopathy and celldeathrdquo Journal of Comparative Neurology vol 500 no 1 pp 20ndash46 2007
[130] P C Wong C A Pardo D R Borchelt et al ldquoAn adverseproperty of a familial ALS-linked SOD1 mutation causes motorneuron disease characterized by vacuolar degeneration ofmito-chondriardquo Neuron vol 14 no 6 pp 1105ndash1116 1995
[131] F M Menzies M R Cookson R W Taylor et al ldquoMitochon-drial dysfunction in a cell culturemodel of familial amyotrophiclateral sclerosisrdquo Brain vol 125 no 7 pp 1522ndash1533 2002
[132] M T Carrı A Ferri A Battistoni et al ldquoExpression of aCuZn superoxide dismutase typical of familial amyotrophiclateral sclerosis induces mitochondrial alteration and increaseof cytosolic Ca2+ concentration in transfected neuroblastomaSH-SY5Y cellsrdquo FEBS Letters vol 414 no 2 pp 365ndash368 1997
[133] S Sasaki and M Iwata ldquoUltrastructural study of synapses inthe anterior horn neurons of patients with amyotrophic lateralsclerosisrdquoNeuroscience Letters vol 204 no 1-2 pp 53ndash56 1996
[134] L Siklos J Engelhardt Y Harati R G Smith F Joo andS H Appel ldquoUltrastructural evidence for altered calcium inmotor nerve terminals in amyotrophic lateral sclerosisrdquo Annalsof Neurology vol 39 no 2 pp 203ndash216 1996
[135] M Cozzolino and M T Carrı ldquoMitochondrial dysfunction inALSrdquo Progress in Neurobiology vol 97 no 2 pp 54ndash66 2012
Oxidative Medicine and Cellular Longevity 11
[136] K Y Soo J D Atkin M Farg A K Walker M K Horne andP Nagley ldquoBim links ER stress and apoptosis in cells expressingmutant SOD1 associated with amyotrophic lateral sclerosisrdquoPloS One vol 7 no 4 Article ID e35413 2012
[137] K Hong Y Li W Duan et al ldquoFull-length TDP-43 and itsC-terminal fragments activate mitophagy in NSC34 cell linerdquoNeuroscience Letters vol 530 no 2 pp 144ndash149 2012
[138] R J Braun and B Westermann ldquoMitochondrial dynamics inyeast cell death and agingrdquo Biochemical Society Transactionsvol 39 pp 1520ndash1526 2011
[139] W Duan X Li J Shi Y Guo Z Li and C Li ldquoMutant TARDNA-binding protein-43 induces oxidative injury in motorneuron-like cellrdquo Neuroscience vol 169 no 4 pp 1621ndash16292010
[140] C Jung C M J Higgins and Z Xu ldquoMitochondrial electrontransport chain complex dysfunction in a transgenic mousemodel for amyotrophic lateral sclerosisrdquo Journal of Neurochem-istry vol 83 no 3 pp 535ndash545 2002
[141] A Ferri M Cozzolino C Crosio et al ldquoFamilial ALS-superoxide dismutases associate with mitochondria and shifttheir redox potentialsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 37 pp13860ndash13865 2006
[142] K Aquilano P Vigilanza G Rotilio and M R CiriololdquoMitochondrial damage due to SOD1 deficiency in SH-SY5Yneuroblastoma cells a rationale for the redundancy of SOD1rdquoThe FASEB Journal vol 20 no 10 pp 1683ndash1685 2006
[143] E M OrsquoBrien R Dirmeier M Engle and R O PoytonldquoMitochondrial protein oxidation in yeast mutants lackingmanganese- (MnSOD) or copper- and zinc-containing super-oxide dismutase (CuZnSOD) evidence that mnsod and cuzn-sod have both unique and overlapping functions in protectingmitochondrial proteins from oxidative damagerdquo Journal ofBiological Chemistry vol 279 no 50 pp 51817ndash51827 2004
[144] S Pickles and C V Velde ldquoMisfolded SOD1 and ALS zeroingin on mitochondriardquo Amyotrophic Lateral Sclerosis vol 13 pp333ndash340 2012
[145] B Bandy and A J Davison ldquoMitochondrial mutations mayincrease oxidative stress implications for carcinogenesis andagingrdquo Free Radical Biology andMedicine vol 8 no 6 pp 523ndash539 1990
[146] F Zhang A L Strom K Fukada S Lee L J Hayward andH Zhu ldquoInteraction between familial Amyotrophic LateralSclerosis (ALS)-linked SOD1mutants and the dynein complexrdquoJournal of Biological Chemistry vol 282 no 22 pp 16691ndash166992007
[147] S Sasaki and S Maruyama ldquoUltrastructutal study of skein-like inclusions in anterior horn neurons of patients with motorneuron diseaserdquoNeuroscience Letters vol 147 no 2 pp 121ndash1241992
[148] D A Figlewicz A Krizus M G Martinoli et al ldquoVariantsof the heavy neurofilament subunit are associated with thedevelopment of amyotrophic lateral sclerosisrdquo Human Molec-ular Genetics vol 3 no 10 pp 1757ndash1761 1994
[149] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[150] S M Chou H S Wang and K Komai ldquoColocalization of NOSand SOD1 in neurofilament accumulation within motor neu-rons of amyotrophic lateral sclerosis an immunohistochemicalstudyrdquo Journal of Chemical Neuroanatomy vol 10 no 3-4 pp249ndash258 1996
[151] H Zhang X Kong J Kang et al ldquoOxidative stress inducesparallel autophagy and mitochondria dysfunction in humangliomaU251 cellsrdquoToxicological Sciences vol 110 no 2 pp 376ndash388 2009
[152] J Lee S Giordano and J Zhang ldquoAutophagymitochondria andoxidative stress cross-talk and redox signallingrdquo BiochemicalJournal vol 441 pp 523ndash540 2012
[153] A Li X Zhang and W Le ldquoAltered macroautophagy in thespinal cord of SOD1 mutant micerdquo Autophagy vol 4 no 3 pp290ndash293 2008
[154] Y Zhong Q J Wang X Li et al ldquoDistinct regulation ofautophagic activity by Atg14L and Rubicon associated withBeclin 1-phosphatidylinositol-3-kinase complexrdquo Nature CellBiology vol 11 no 4 pp 468ndash476 2009
[155] S Sasaki ldquoAutophagy in spinal cord motor neurons in sporadicamyotrophic lateral sclerosisrdquo Journal of Neuropathology andExperimental Neurology vol 70 no 5 pp 349ndash359 2011
[156] N Morimoto M Nagai Y Ohta et al ldquoIncreased autophagyin transgenic mice with a G93A mutant SOD1 generdquo BrainResearch vol 1167 no 1 pp 112ndash117 2007
[157] M Schroder ldquoEndoplasmic reticulum stress responsesrdquo Cellu-lar andMolecular Life Sciences vol 65 no 6 pp 862ndash894 2008
[158] J D Atkin M A Farg B J Turner et al ldquoInduction ofthe unfolded protein response in familial amyotrophic lateralsclerosis and association of protein-disulfide isomerase withsuperoxide dismutase 1rdquo Journal of Biological Chemistry vol281 no 40 pp 30152ndash30165 2006
[159] C M Haynes E A Titus and A A Cooper ldquoDegradation ofmisfolded proteins prevents ER-derived oxidative stress and celldeathrdquoMolecular Cell vol 15 no 5 pp 767ndash776 2004
[160] K Kanekura H Suzuki S Aiso and M Matsuoka ldquoER stressand unfolded protein response in amyotrophic lateral sclerosisrdquoMolecular Neurobiology vol 39 no 2 pp 81ndash89 2009
[161] M A Farg K Y Soo A K Walker et al ldquoMutant FUS inducesendoplasmic reticulum stress in amyotrophic lateral sclerosisand interacts with protein disulfide-isomeraserdquoNeurobiology ofAging vol 33 no 12 pp 2855ndash2868 2012
[162] E V Ilieva V Ayala M Jove et al ldquoOxidative and endoplas-mic reticulum stress interplay in sporadic amyotrophic lateralsclerosisrdquo Brain vol 130 no 12 pp 3111ndash3123 2007
[163] J D Malhotra and R J Kaufman ldquoEndoplasmic reticulumstress and oxidative stress a vicious cycle or a double-edgedswordrdquo Antioxidants and Redox Signaling vol 9 no 12 pp2277ndash2293 2007
[164] A K Walker and J D Atkin ldquoMechanisms of neuroprotectionby protein disulphide isomerase in amyotrophic lateral scle-rosisrdquo Neurology Research International vol 2011 Article ID317340 7 pages 2011
[165] R B Freedman T R Hirst andM F Tuite ldquoProtein disulphideisomerase building bridges in protein foldingrdquo Trends inBiochemical Sciences vol 19 no 8 pp 331ndash336 1994
[166] C I Andreu U Woehlbier M Torres and C Hetz ldquoProteindisulfide isomerases in neurodegeneration from disease mech-anisms to biomedical applicationsrdquo FEBS Letters vol 586 no18 pp 2826ndash2834 2012
[167] J J Galligan and D R Petersen ldquoThe human protein disulfideisomerase gene familyrdquoHuman Genomics vol 6 no 1 pp 1ndash152012
[168] L Ellgaard and L W Ruddock ldquoThe human protein disulphideisomerase family substrate interactions and functional proper-tiesrdquo EMBO Reports vol 6 no 1 pp 28ndash32 2005
12 Oxidative Medicine and Cellular Longevity
[169] B Wilkinson and H F Gilbert ldquoProtein disulfide isomeraserdquoBiochimica et Biophysica Acta vol 1699 no 1-2 pp 35ndash44 2004
[170] T Tanaka H Nakamura A Nishiyama et al ldquoRedox regulationby thioredoxin superfamily protection against oxidative stressand agingrdquo Free Radical Research vol 33 no 6 pp 851ndash8552000
[171] C Turano S Coppari F Altieri and A Ferraro ldquoProteins ofthe PDI family unpredicted non-ER locations and functionsrdquoJournal of Cellular Physiology vol 193 no 2 pp 154ndash163 2002
[172] D M Ferrari and H D Soling ldquoThe protein disulphide-isomerase family unravelling a string of foldsrdquo BiochemicalJournal vol 339 no 1 pp 1ndash10 1999
[173] G Tian S Xiang R Noiva W J Lennarz and H SchindelinldquoThe crystal structure of yeast protein disulfide isomerasesuggests cooperativity between its active sitesrdquo Cell vol 124 no1 pp 61ndash73 2006
[174] P Klappa LW Ruddock N J Darby and R B Freedman ldquoThebrsquo domain provides the principal peptide-binding site of proteindisulfide isomerase but all domains contribute to binding ofmisfolded proteinsrdquo EMBO Journal vol 17 no 4 pp 927ndash9351998
[175] A Pirneskoski P Klappa M Lobell et al ldquoMolecular char-acterization of the principal substrate binding site of theubiquitous folding catalyst protein disulfide isomeraserdquo Journalof Biological Chemistry vol 279 no 11 pp 10374ndash10381 2004
[176] G Kozlov P Maattanen D Y Thomas and K Gehring ldquoAstructural overview of the PDI family of proteinsrdquo FEBS Journalvol 277 no 19 pp 3924ndash3936 2010
[177] Y Dai and C C Wang ldquoA mutant truncated protein disulfideisomerase with no chaperone activityrdquo Journal of BiologicalChemistry vol 272 no 44 pp 27572ndash27576 1997
[178] C E Jessop R H Watkins J J Simmons M Tasab andN J Bulleid ldquoProtein disulphide isomerase family membersshow distinct substrate specificity P5 is targeted to BiP clientproteinsrdquo Journal of Cell Science vol 122 no 23 pp 4287ndash42952009
[179] C Appenzeller-Herzog J Riemer E Zito et al ldquoDisulphideproduction by Ero1120572-PDI relay is rapid and effectively regu-latedrdquo EMBO Journal vol 29 no 19 pp 3318ndash3329 2010
[180] F Hatahet and L W Ruddock ldquoProtein disulfide isomerase acritical evaluation of its function in disulfide bond formationrdquoAntioxidants and Redox Signaling vol 11 no 11 pp 2807ndash28502009
[181] N J Bulleid and L Ellgaard ldquoMultiple ways to make disulfidesrdquoTrends in Biochemical Sciences 2011
[182] S Chakravarthi C E Jessop and N J Bulleid ldquoThe role ofglutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stressrdquo EMBOReports vol 7 no3 pp 271ndash275 2006
[183] J Lundstrom and A Holmgren ldquoDetermination of thereduction-oxidation potential of the thioredoxin-like domainsof protein disulfide-isomerase from the equilibrium with glu-tathione and thioredoxinrdquo Biochemistry vol 32 no 26 pp6649ndash6655 1993
[184] E Gross C S Sevier N Heldman et al ldquoGenerating disulfidesenzymatically reaction products and electron acceptors of theendoplasmic reticulum thiol oxidase Ero1prdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 2 pp 299ndash304 2006
[185] P I Merksamer A Trusina and F R Papa ldquoReal-time redoxmeasurements during endoplasmic reticulum stress reveal
interlinked protein folding functionsrdquo Cell vol 135 no 5 pp933ndash947 2008
[186] J W Cuozzo and C A Kaiser ldquoCompetition between glu-tathione and protein thiols for disulphide-bond formationrdquoNature Cell Biology vol 1 no 3 pp 130ndash135 1999
[187] L A Rutkevich M F Cohen-Doyle U Brockmeier and DB Williams ldquoFunctional relationship between protein disulfideisomerase family members during the oxidative folding ofhuman secretory proteinsrdquoMolecular Biology of the Cell vol 21no 18 pp 3093ndash3105 2010
[188] Y Honjo S Kaneko H Ito et al ldquoProtein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateralsclerosisrdquo Amyotrophic Lateral Sclerosis vol 12 no 6 pp 444ndash450 2011
[189] H Tsuda S M Han Y Yang et al ldquoThe amyotrophic lateralsclerosis 8 proteinVAPB is cleaved secreted and acts as a ligandfor Eph receptorsrdquo Cell vol 133 no 6 pp 963ndash977 2008
[190] D M Townsend Y Manevich H Lin et al ldquoNitrosative stress-induced S-glutathionylation of protein disulfide isomerase leadsto activation of the unfolded protein responserdquoCancer Researchvol 69 no 19 pp 7626ndash7634 2009
[191] T Uehara T Nakamura D Yao et al ldquoS-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegen-erationrdquo Nature vol 441 no 7092 pp 513ndash517 2006
[192] X Chen C Li T Guan et al ldquoS-nitrosylated protein disul-phide isomerase contributes to mutant SOD1 aggregates inamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol124 no 1 pp 45ndash58 2012
[193] J D Rothstein ldquoTherapeutic horizons for amyotrophic lateralsclerosisrdquo Current Opinion in Neurobiology vol 6 no 5 pp679ndash687 1996
[194] D W Cleveland ldquoNeuronal growth and death order anddisorder in the axoplasmrdquoCell vol 84 no 5 pp 663ndash666 1996
disulphide isomerase (PDI) thioredoxin and glutathione[16ndash20] These proteins contain a thiol group which ishighly sensitive to changes in redox conditions [12 21] Evenslight modulations in redox state are capable of producingneurotoxic species such as NO
2
+ NO2
∙ and ONOOminus [14]suggesting that redox stress could be of importance in disease[9]
2 Amyotrophic Lateral Sclerosis (ALS)
ALS also known asCharcotrsquos or LouGehrigrsquos disease is a fatalneurodegenerative disorder that affects the upper and lowermotor neurons of the primary cortex brainstem and spinalcord [22 23] The symptoms include muscle weakness andmuscle spasticity eventually resulting in paralysis [24] withALS patients generally dying from respiratory failure within3ndash5 years of diagnosis Approximately 2 per 100000 peopleworldwide are affected by ALS every year [22] Riluzole isthe only FDA-approved drug currently available for ALSRiluzole has modest efficacy It slows disease progressionand a dose of 100mg per day also improves limb functionand muscle strength although it increases life span by anaverage of only 2-3 months [25 26] Therefore a greaterunderstanding of the molecular mechanisms causing ALS isimportant in order to develop better therapeutic solutions
Approximately 90 of ALS cases have no genetic asso-ciation and are known as sporadic ALS (SALS) Howevermutations in genes such as copperzinc superoxide dis-mutase (SOD1) fused in sarcoma (FUS) and TAR DNAbinding protein (TARDBP) have also been described in SALSpatients also environmental causes such as smoking andviral infection are linked to ALS [24 27ndash31] Studies haveshown higher prevalence of ALS in people with a historyof trauma [32] and involvement in physical activities suchas soccer has also been observed in ALS patients [33 34]however the exact aetiology is unknown The remaining 10of ALS cases known as familial ALS (FALS) are linkedto mutations in specific genes [35] including SOD1 TDP-43 FUS vesicle associated membrane protein-B (VAPB)optineurin alsin and ubiquilin-2 [18 36ndash43] Recently anoncoding mutation in C9ORF72 was shown to cause thegreatest proportion of FALS cases [44] SOD1 causes 15ndash20 of all FALS cases and was the first described and hencemost widely researched gene linked to ALS [18] Transgenicmice overexpressing ALS-associated mutant SOD1 proteinshave been used extensively as diseasemodels [45ndash47] Similarto other protein disorders the pathological hallmark ofALS is the presence of intracellular protein inclusions [48]Misfolded wild-type and mutant forms of SOD1 FUS andTDP-43 [41 49 50] are present on the inclusions found inaffected tissues of ALS patients [41 51ndash53] SALS and FALShave similar symptoms and are clinically and pathologicallyindistinguishable
Wild-type SOD1 is a highly stable homodimeric proteinexplained in part by the presence of an intrasubunit disul-phide bond between cysteine 57 and cysteine 146 [54] Itcontains both copper and zinc ions which are essential forthe catalytic activity and stability respectively [55] Reduction
of the disulphide bond results in dissociation of the dimerand the resulting protein is highly unstable and prone toaggregation [56 57]
Dysfunction in multiple cellular mechanisms is linkedto ALS pathology reviewed recently by Cozzolino andcoworkers [58] Many of these events are linked to redoxregulation including oxidative stress protein misfolding andaggregation excitotoxicity lipid peroxidation and cholesterolesterification mitochondrial dysfunction impaired axonaltransport and neurofilament aggregation autophagy and ERstress [46 59ndash68] However there is a complex interplaybetween these processes and the exact aetiology of the diseaseis unclear It is debatable whether redox dysregulation is aprimary effect or a secondary consequence of other patholo-gies and the association of redox regulation and cysteine richredox regulated proteins with these mechanisms is unclearThis paper discusses the main redox linked mechanismswhich are involved in ALS and their association with redoxor cysteine dependent proteins
3 Possible Redox Regulated CellularMechanisms Involved in ALS
31 Oxidative Stress Oxidative stress arises when the levelsof ROSRNS exceed the amounts required for normal redoxsignalling While oxidative stress has been implicated as apathological mechanism in ALS the exact role of ROSRNSin disease processes is unclear [9 69] ROS causes permanentoxidative damage to major cellular components such asproteins DNA lipids and cell membranes [70ndash72] ROS hasbeen detected in the spinal cord and cerebrospinal fluid (CSF)of SALS patients [17] Increased levels of H
2O2and oxidative
damage to protein andDNAhave also been observed in SOD1transgenicmice [73] Defects in the RacNox pathway leadingto redox dysregulation are also linked to SOD1G93A mice [74]Furthermore dysregulation of redox regulated-tumour pro-tein 1 ubiquitin carboxyl-terminal hydrolase isoenzyme L1and 120572B crystallin has been observed in transgenic SOD1G93Amice [75]
Altered redox homeostasis regulates gene expression oftranscriptional factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-120581B) activator protein1 (AP-1) and hypoxia inducible factor 1120572 (HIF-1120572) [76]These transcriptional factors help inmaintaining homeostasisby regulating gene expression They have a redox regulatedcysteine residue at their DNA binding site [76] which canbe affected due to thiol oxidation and could be influencedby ROS [77] A direct relation between the transcriptionfactors and redox regulation in ALS is unknown neverthelessdysregulation in the levels of NF-120581B and HIF-1120572 has beenobserved in SALS patients and activation of AP-1 in mutantSOD1 expressing cells suggesting potential involvement ofredox regulation in ALS pathology [78 79]
SOD1 and its antioxidant properties have been studiedextensively from the perspective of redox regulation in ALS[80 81] SOD1 catalyses the conversion of superoxide intohydrogen peroxide and oxygen and it undergoes cyclicreduction and oxidation of its copper ions [82] Initially it
Oxidative Medicine and Cellular Longevity 3
was proposed that ALSmutations in SOD1 result in the loss ofits ability to act as an antioxidant but further research showedthat disease is not associated with its enzymatic activity[83] However mutations in SOD1 could produce ONOOminusor OHminus and lower its ability to catalyse superoxide [84] byreacting with nitric oxide [85] These intermediate productsare highly unstable and have been detected with other aminoacids such as tyrosine Nitrated proteins and high levelsof nitrotyrosine have been detected in the CSF of bothSALS and FALS patients suggesting that posttranslationalmodification via free radical production is present in ALS[17 86ndash88] Oxidised wild-type SOD1 in the lymphoblastsof SALS patients associates with mitochondrial Bcl-2 whichcauses mitochondrial damage [89] Oxidative damage is animportant phenomenon however treatment with antioxi-dants has not been very successful [90]
32 Protein Aggregation andMisfolding Redox dysregulationmay not only increase the production of ROSRNS but alsoaffect protein conformation and structure Posttranslationalmodification of SOD1 such as oxidation has an adverseeffect on the conformational arrangement of SOD1 [91]Glutathionylation a posttranslational modification of the 111cysteine residue causes destabilisation of SOD1 structure[92] Wild-type SOD1 has been shown in inclusions of SALSpatients suggesting its involvement in causing neurotoxicity[93] Evidence suggests that oxidised wild-type SOD1 hasthe ability to misfold and form aggregates and gain similarconformation as the mutant and has toxic functions in vitro[89 94] SOD1 depleted zinc and copper have altered redoxactivity and are more prone to oxidation [95]
An oxidising environment also causes abnormal disul-phide linkages and protein aggregation in ALS [80 96]SOD1 containing aberrant disulphide bonds involves thenormally unpaired cysteine residues cysteine 6 and cysteine111 in the spinal cord of ALS transgenic mice models [96]Studies show that mutant TDP-43 aggregation is causeddue to increased disulphide bonds [97] Similarly oxidativestress causes aberrant disulphide cross-linking and subcel-lular localisation of TDP-43 [97] as well as accumulation ofFUS into the cytoplasm [98] Mutant SOD1 readily formsmonomers oligomers or inclusions which are insoluble [55]It is unclear how conformational changes cause misfoldingbut one possible explanation could be the modification andalteration of protein structure by ROS through oxidisation ofthe thiol group forming aberrant disulphide bonds
33 Glutamate Excitotoxicity The levels of glutamate presentinmammalian CNS aremuch higher than those of other neu-rotransmitters (5ndash10mmolkg) indicating the importance ofglutamate in neuronal function [99] However excitotoxicityoccurs when the levels of glutamate are increased in neuronsresulting in increased calcium intake and neuronal injury[100 101] Motor neurons are particularly susceptible to highlevels of glutamate [102] Glutamate uptake from the synapseis controlled by glutamate transporters astroglial GLASTGLT1 and neuronal EAAC1 which possess a redox regulatedcysteine residue [103] N-methyl-D aspartic acid (NMDA)
glutamate receptors are also redox regulated suggesting thatredox dysfunction may further affect glutamate regulationIncreased levels of intracellular glutamate and decreaseduptake of glutamate from the synapse have been observedin ALS patients [104 105] Indeed Rothstein and coworkersshowed an absence of GLT1 transporter in ALS patients[106] ROS can reduce the uptake of glutamate in mammals[107] however increased calcium levels in the mitochondriadue to dysfunctional glutamate regulation can result inoverproduction of ROS and cause oxidative stress [108] Thequestion remains whether oxidative stress causes glutamatedysregulation or vice versa
34 Lipid Peroxidation and Cholesterol Esterification TheER is also the main site of lipid and sterol synthesis [109]Lipids are major targets of oxidative stress resulting in lipidperoxidation via a chain-reaction process [11] Sphingolipidsare localised in the plasma membrane and ER membranesand with cholesterol are processed into domains knownas lipid rafts [68] Lipid rafts can form macroplatformsfor redox signalling providing critical mediation for cel-lular functioning [110] Lipid peroxidation and cholesterolesterification have been implicated in the pathogenesis ofALS [68 69 111] Excitotoxicity and oxidative stress altersphingolipid metabolism resulting in the accumulation oflong-chain ceramides sphingomyelin and cholesterol estersin the spinal cords of ALS patients and CuZn SOD1 miceThis occurs at the early presymptomatic stage of disease in theSOD1mice [68] thus implicating aberrant lipidmetabolism inthe pathophysiology of ALS Further evidence of lipid dysreg-ulation in ALS comes from studies which reported that ALSpatients demonstrated a tendency towards hyperlipidemiaAdditionally correlational studies have shown that ALSpatients with the highest low density lipoprotein (LDL) highdensity lipoprotein (HDL) ratio have a significant increasein survival time and respiratory function [112 113] Fur-thermore recently an interaction between SOD1 aggregateswith lipid was found to alter lipid membrane permeability[114]
Lipid peroxidation products such as 4-hydroxynonenalhave been detected at higher levels in ALS patients spinalcord than controls and this has been linked to modificationof astrocytic glutamate transporter EAAT2 and excitotoxicity[111] Excitotoxicity was also linked to upregulation of sterolregulatory binding element 1 (SREBP1) in the spinal cordsof FALS and SALS patients and SOD1G93A transgenic micesuggesting cholesterol depletion [115] Furthermore the linkbetween ALS and statins a class of drug which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reduc-tase may suggest that suppressing cholesterol synthesisincreases the incidence [116 117] progression and severityof ALS [118] although this has been questioned [119] Lipidraft alteration has also been linked to the pathogenesis ofALS Endogenous wild-type and mutant SOD1G93A proteinswere recruited into lipid rafts isolated from spinal cords oftransgenic SOD1mice [120] Hence together the data suggestthat oxidative stress may alter sphingolipid and cholesterolmetabolism and deregulate lipid raft redox signalling leading
4 Oxidative Medicine and Cellular Longevity
to the accumulation of toxic ceramides and cholesterol esterswhich may ultimately result in motor neuron death [68]
35 Mitochondrial Dysfunction Mitochondria are impor-tant players in redox regulation and oxidative stress hasthe potential to cause mitochondrial dysfunction [70 121]Indeed damaged mitochondria are observed in the spinalcord cells of SALS patients [122ndash124] The mitochondrialgenome is particularly susceptible to oxidative damage [125]hence any increase in cellular ROS would potentially per-turb mitochondrial functions Mitochondria participate inneuronal apoptotic signalling pathways through the releaseof mitochondrial proteins including cytochrome c into thecytoplasm [126] There is substantial evidence that molecularcomponents of mitochondrial apoptosis play a role in neu-rodegeneration in both SOD1 rodents and in mutant SOD1overexpressed in cell culture [127] The enzymatic activityof cytochrome c oxidase (COX) in mitochondria is alsoreduced in the spinal cord cells of SALS patients [122ndash124128 129] Mitochondria have been well studied in relation toALS pathogenesis Degenerating or abnormal mitochondriahave been described in mouse models [62 130] culturedneuronal cellular models [131 132] and ALS patients [133134] although how nonfunctioning mitochondria relate toALS is unclear Possible explanations include inhibition ofaxonal transport dysregulation of calcium buffering [135] oractivation of mitochondrial-dependent apoptosis [128 136]Recent studies have shown that overexpression of TDP-43causes mitochondrial dysfunction and induces mitophagy incell culture [137]The presence of ROS and impairment of themitochondrial respiratory chain have also been observed inTDP-43 models [138 139]
Mutant SOD1 has also been implicated in mitochondrialrespiratory complex impairment [140] and a shift in the redoxstate of mitochondria towards oxidation [141] How SOD1functions in the mitochondria is still not clear althoughsome data suggests that SOD1 is crucial for maintenanceof the mitochondrial redox state [142 143] and that ALSmutations affect the localisation or function of SOD1 inmitochondria [135] However mutant misfolded SOD1 hasbeen found localised with various compartments of themitochondria [144] Significantly any pathological changesin regulation of the electron transport chain would result inmore oxidative stress [145] triggering further cellular redoxdysregulation leading to a potential vicious cycle of damageand degeneration
36 Impaired Axonal Transport Axonal transport is a keymechanism required for cellular viability in neuronal cellsMost proteins required in the axon and in synaptic terminalsmust be transported along the axon after synthesis in the cellbody Similarly RNA and organelles also need to be trans-ported over long distances and these transport processesrequire molecular motors such as kinesins dyneins andmyosins that operate along the cellular cytoskeleton Dys-function of axonal transport has now been well documentedin ALS [61] Whilst many of these studies implicate dyneinin this process [146] several also highlight the importance
of kinesin in ALS particularly kinesin heavy chains KIF5Aand KIF1B120573 which transport mitochondria synaptic vesi-cles and macromolecular complexes Interestingly a recentstudy demonstrated that oxidised wild-type SOD1 immuno-purified from SALS patient tissues inhibited kinesin-basedaxonal transport in amanner similar tomutant SOD1 in FALSproviding evidence for common pathogenic mechanisms inboth SALS and FALS [94]
Neurofilaments (NF) accumulation in motor neuronsis another histopathological hallmark of ALS [147 148]Also transgenic mice that overexpress NF subunits in motorneurons develop a motor neuron disease with impairedaxonal flow as axonal defects cause delay in transportationof components required for the maintenance of axon [149]However ONOOminus formed during oxidative stress fromnitrooxide and superoxide can affect NF assembly and causeNF accumulation in motor neurons [8] Chou and coworkersshowed NF aggregations are associated with SOD1 and nitricoxide synthase activities leading to nitrotyrosine formationon NF [150] Nitrotyrosine can inhibit phosphorylation ofheavy or light NF subunits and may alter axonal transportand trigger motor neuron death [150] Taken together thesefindings suggest a relation between redox regulation andaxonal transport dysfunctions in ALS
37 Autophagy Autophagy is a normal homeostatic mecha-nism to dispose large protein aggregates damaged organellesand long-lived proteins Autophagic stress results when thenumber of autophagosomes increases relative to the pro-portion of degradable proteins The presence of high levelsof superoxide and hydrogen peroxide species can induceautophagy in vitro [151] but consequently autophagy canfurther induce oxidative or nitrative stress thus creating avicious cycle [152] Dysregulated redox activity also influ-ences autophagy Cathepsin a class of proteases which havehighly regulated thiol groups [152] and other key regulatoryautophagic complexes such as Beclin 1 and Rubicon alsohave the presence of cysteine residues [152] The presence ofcysteine residues suggests that they are redox regulated andlikely to be affected by ROS ATG 4 another protease is atarget of oxidation by hydrogen peroxide However directassociation of these with ALS has not yet been identifiedAltered autophagic levels have been observed in SOD1G93Amice and sporadic and familial patients but whether theincreased levels are protective or not is still questionable [153ndash156]
38 ER Stress and Protein Disulphide Isomerase (PDI) in ALSThe ER is redox regulated and another important locationfor the production of ROS It plays key roles in protein andlipid synthesis and protein folding Proteinmisfolding withinthe ER triggers ER stress which induces the unfolded proteinresponse (UPR) a distinct signalling pathway which aims torelieve stress [157] While initially protective prolonged UPRcauses apoptosis [158 159] Recent studies suggest that ERstress is an early and important pathogenic mechanism inALS [66 158 160] ER stress is induced in animal modelsof SOD1 in cells expressing mutant FUS and in patients
Oxidative Medicine and Cellular Longevity 5
CGHC CGHC KDEL
119886 119887 119888119909119887998400
119886998400
Figure 1 Schematic diagram showing domain structure of PDIThioredoxin-like 119886 domain (orange) and 1198861015840 domain (purple) pos-sessing the catalyticmotif catalytically inactive 119887 domain (blue) and1198871015840 domain (red) Green represents the linker region 119909 which allowsflexibility between domainsTheC terminal domain is shown in greyfollowed by the ER retrieval signal KDEL
[20 161] Oxidative stress driven by changes in fatty acidcomposition mitochondrial function andor proteosomeactivity leads to oxidative stress and contributes to ER stressin SALS patients [162 163] PDI is an ER chaperone whichis induced during UPR and has been implicated in severalneurodegenerative disorders including ALS [164ndash166]
PDI is a member of an extended family of foldasesand chaperones which are responsible for the formationand isomerisation of protein disulphide bonds [167] ThePDI family comprises 21 members which have structuralsimilarities but different functions [168] and all have asimilar active site to thioredoxin [169] Thioredoxin is anintracellular protein which regulates redox conditions andwhich is effective against oxidative stress [170] PDI is mostabundant in the ER but it is also found in other subcellularlocations such as the nucleus and extracellular matrix [171]and it constitutes 08 of the total cellular protein [172]The yeast PDI crystal structure was recently solved [173]which suggests that 119886 and 1198861015840 domains are responsible forthe formation of disulphide bonds (Figure 1) These domainscontain a redox active CGHCmotif which isomerases proteindisulphide bonds and is involved in redox regulation [173]PDI also contains 119887 and 1198871015840 domains which are responsiblefor substrate binding [174 175] Misfolded proteins attach tothe hydrophobic region of an inverted U shape structure [173176] The C-terminal region also aids in polypeptide bindingand contributes chaperone activity [177] Compared to otherfamilymembers PDI has broad substrate specificities and caninteract with glycosylated as well as nonglycosylated proteins[178]
4 PDI and Redox Regulation
PDI forms protein disulphide bonds by the oxidation ofthiols within the PDI active site cysteine residues [179 180]When PDI is in an oxidised state it transfers a disulphide tothe substrates thereby oxidising the substrate and becomingreduced itself Conversely substrates which need disulphidebond rearrangement are reduced by PDI in the reduced statethus oxidising PDI in the process [168 181] This continualcycling regulates redox conditions within the ER A thiolcontaining tripeptide protein and glutathione also maintainsER redox homeostasis by similar shuffling between oxidizedand reduced cysteine residues Glutathione is also requiredfor the isomerisation and rearrangement of disulphide bonds[182] The redox potential of PDI (minus110mV) is lower than
other family members [183] due to intervening residuespresent between the reactive cysteines thus facilitating disul-phide bonds [183] ERO1 oxidises PDI also aiding disulphidebond formations [184] but PDI is also oxidised throughperoxiredoxin 4 vitamin K glutathione peroxidase andquiescin sulfhydryl oxidase [181] During ER stress highlevels of ERO1 have been observed which accelerates proteinoxidation suggesting interplay between oxidative stress andER stress The transfer of electrons from the thiol groupof PDI to ERO1 results in the production of excess ROSdecreasing the levels of glutathione available for reductionand increasing ERO1 thus altering the redox conditions [185186] Hence imbalance in the redox state of the ERmay resultin dysregulation of thiol containing proteins and triggers
41 The Role of PDI in ALS Due to its function in preventingprotein misfolding PDI is important in protein quality con-trol [166] also deletion of PDI is embryonically lethal [187]Hence regulated expression of PDI is critical for normalcellular functionThere is now growing evidence for a role ofPDI in ALS PDI levels are upregulated in transgenic modelsof ALS and spinal cord tissues of ALS patients [66 158]Overexpression of PDI is also protective againstmutant SOD1mediated aggregation and reduces cell death in vitro [20] PDIcoimmunoprecipitates with both SOD1 and FUS [158 161] italso colocalises with SOD1 TDP-43 and FUS in ALS patientssuggesting a physical interaction exists between PDI andother key misfolded proteins in ALS [66 161 188] SimilarlyPDI also colocalises with TDP-43 in ALS tissues and withVAPB inclusions in a Drosophila melanogaster model ofALS [188 189] A small mimic of the active site of PDIdithiol (plusmn)-trans-12-bis (mercaptoacetamido) cyclohexane(BMC) is also protective in cell culture and it reduces mutantSOD1 aggregation in a dose dependent manner [20] Furtherevidences for a role for disulphide interchange activity in ALScomes from studies showing that another PDI familymemberERp57 is also upregulated in transgenic SOD1 mice and ALSpatients [66] Furthermore thioredoxin is also upregulated inthe erythrocytes of FALS patients [19]
The upregulation of these thiol containing proteins inALS suggests a cellular defensive mechanism is triggeredin disease as a defence against oxidative stress Howeverthere is evidence that normal protective function of PDI isinhibited in disease [20] Modifications of active site thiolgroups through direct oxidation S-glutathiolation and S-nitrosylation can lead to inactivation of the normal enzy-matic activity of PDI [13 190 191] PDI was recently shownto be S-nitrosylated in ALS [20 192] as in other neurodegen-erative disorders such as Parkinsonrsquos and Alzheimerrsquos disease[191] S-nitrosylation occurs when there is an increased pro-duction of RNS during oxidative stress resulting in additionof a nitrogen monoxide group to the thiol side of PDI[20 164] Experiments performed by Chen and coworkerssuggested that in the presence of S-nitrosylated PDI theformation of mutant SOD1 aggregates increases in vitro [192]It is also likely that inactivation of PDI could lead to activationof the UPR as observed in other neurodegenerative disorders[191] The loss of PDI functional activity can directly lead to
6 Oxidative Medicine and Cellular Longevity
Impaired axonaltransport
AutophagyMitochondrialdysfunction
ER stress Proteinmisfolding
Redox dysregulation
PDI dysfunction Oxidative stress
Figure 2 Redox dysfunction and its relationship to other patholo-gies in ALS Alteration in the enzymatic activity of PDI due toredox dysregulation and oxidative stress can further increase theload of misfolded proteins ER stress oxidative stress autophagymitochondrial dysfunction and axonal impairment leading toneuronal cell death
apoptosis or indirectly to a range of cellular abnormalitiessuch as oxidative stress and protein misfolding which againlead to cell death [164 166] Hence the redox regulationof PDI is a crucial component in the maintenance of abalanced redox environment and inhibition of its enzymaticactivity will lead to important consequences for the cell(Figure 2)
Neurons are highly susceptible to redox dysregulationdue to their high metabolic requirements large size andlower ability to maintain the balance between antioxidantsand ROS [15] In disease states such as ALS oxidativestress and altered enzymatic activity of PDI which normallyreduces ROS and the burden of misfolded protein can causeserious damage to the neuron Since multiple mechanismsare involved in neurodegeneration any imbalance in redoxregulation can lead to an imbalance in the production offree radical species which consequently cause mitochondrialdamage and excitotoxicity thus elevating the levels of freeradicals [193] Furthermore an excess of free radicals canalso lead to DNA damage and may also result in aggregationof NF [194] and structural destabilization of other proteinsthus inducing ER stress and apoptosis Since ALS is a slowprogressive disorder it could be hypothesised that these cyclicevents due to loss of functional activity of PDImay graduallylead to neuronal degradation In such a scenario the redoxregulatory function of PDI may therefore have an importantprotective effect
5 Conclusion
Redox regulation is an important mechanism of homeostasisin eukaryotic cells especially neuronal cells where oxygen
levels are high [15] Many cellular processes rely on it includ-ing proper functioning of the mitochondria and ER calciumregulation axonal transport regulated autophagy and pro-tein folding Links between redox dysregulation and ALSare becoming well documented in the literature althoughthe directionality of these links and their underlying causeare still quite unknown One possible key player in redox reg-ulation in ALS is PDI whose role in ALS pathogenesis is thetopic of much new research As the critical protein involvedin thiol reduction any dysregulation of PDI activity can leadto oxidative stress and redox dysregulation Due to its activityPDI itself also contains an active site thiol group suggestingthat it can also be affected by oxidative stress leading to anescalating cycle that perpetuates redox dysregulation HowPDI becomes nonfunctional in the first place is still unclearalthough somepapers point to S-nitrosylation as having a role[20] Regardless of its exact role any mechanism to improvethe catalytic activity of PDI should have a reductive effect onoxidative stress levels in neurons It is therefore tempting tospeculate about PDI as a possible therapeutic target in thetreatment of ALS
Acknowledgments
This work was supported by the National Health and Med-ical Research Council of Australia (project Grants 4547491006141 and 1030513) Amyotrophic Lateral Sclerosis Asso-ciation (USA) MND Research Institute of Australia Beth-lehem Griffiths Research Council Henry H Roth CharitableFoundation Grant for MND Research Australian RotaryHealth and the Brain Foundation S Parakh holds a La TrobeUniversity Post Graduate Research Scholarship
References
[1] H Kamata and H Hirata ldquoRedox regulation of cellular sig-nallingrdquo Cellular Signalling vol 11 no 1 pp 1ndash14 1999
[2] A R Cross and O T G Jones ldquoEnzymic mechanisms ofsuperoxide productionrdquoBiochimica et BiophysicaActa vol 1057no 3 pp 281ndash298 1991
[3] VAdler Z YinKD Tew andZRonai ldquoRole of redox potentialand reactive oxygen species in stress signalingrdquo Oncogene vol18 no 45 pp 6104ndash6111 1999
[4] J Nordberg and E S J Arner ldquoReactive oxygen speciesantioxidants and the mammalian thioredoxin systemrdquo FreeRadical Biology andMedicine vol 31 no 11 pp 1287ndash1312 2001
[5] M G Espey K M Miranda D D Thomas et al ldquoA chemicalperspective on the interplay between NO reactive oxygenspecies and Reactive Nitrogen Oxide Speciesrdquo Annals of theNew York Academy of Sciences vol 962 pp 195ndash206 2002
[6] W A Pryor and G L Squadrito ldquoThe chemistry of per-oxynitrite a product from the reaction of nitric oxide withsuperoxiderdquo American Journal of Physiology-Lung Cellular andMolecular Physiology vol 268 no 5 pp L699ndashL722 1995
[7] K Abe L H Pan M Watanabe H Konno T Kato andY Itoyama ldquoUpregulation of protein-tyrosine nitration in theanterior horn cells of amyotrophic lateral sclerosisrdquo Neurologi-cal Research vol 19 no 2 pp 124ndash128 1997
Oxidative Medicine and Cellular Longevity 7
[8] J S Beckman M Carson C D Smith and W H KoppenolldquoALS SOD and peroxynitriterdquoNature vol 364 no 6438 p 5841993
[9] S C Barber and P J Shaw ldquoOxidative stress in ALS key rolein motor neuron injury and therapeutic targetrdquo Free RadicalBiology and Medicine vol 48 no 5 pp 629ndash641 2010
[10] M C Martınez and R Andriantsitohaina ldquoReactive nitrogenspecies molecular mechanisms and potential significance inhealth and diseaserdquo Antioxidants and Redox Signaling vol 11no 3 pp 669ndash702 2009
[11] D Trachootham W Lu M A Ogasawara N R D Valle andP Huang ldquoRedox regulation of cell survivalrdquo Antioxidants andRedox Signaling vol 10 no 8 pp 1343ndash1374 2008
[12] C E Cooper R P Patel P S Brookes and VM Darley-UsmarldquoNanotransducers in cellular redox signaling modification ofthiols by reactive oxygen and nitrogen speciesrdquo Trends inBiochemical Sciences vol 27 no 10 pp 489ndash492 2002
[13] H Nakamura K Nakamura and J Yodoi ldquoRedox regulation ofcellular activationrdquo Annual Review of Immunology vol 15 pp351ndash369 1997
[14] S A Lipton Y B Choi Z H Pan et al ldquoA redox-based mech-anism for the neuroprotective and neurodestructive effects ofnitric oxide and related nitroso-compoundsrdquo Nature vol 364no 6438 pp 626ndash632 1993
[15] B Halliwell ldquoOxidative stress and neurodegeneration whereare we nowrdquo Journal of Neurochemistry vol 97 no 6 pp 1634ndash1658 2006
[16] R P Guttmann and T J Powell ldquoRedox regulation of cysteine-dependent enzymes in neurodegenerationrdquo International Jour-nal of Cell Biology vol 2012 Article ID 703164 8 pages 2012
[17] H Tohgi T Abe K Yamazaki T Murata E Ishizaki and CIsobe ldquoIncrease in oxidized NO products and reduction inoxidized glutathione in cerebrospinal fluid from patients withsporadic form of amyotrophic lateral sclerosisrdquo NeuroscienceLetters vol 260 no 3 pp 204ndash206 1999
[18] D R Rosen T Siddique D Patterson et al ldquoMutations inCuZn superoxide dismutase gene are associated with familialamyotrophic lateral sclerosisrdquoNature vol 362 no 6415 pp 59ndash62 1993
[19] Y Ogawa H Kosaka T Nakanishi et al ldquoStability of mutantsuperoxide dismutase-1 associated with familial amyotrophiclateral sclerosis determines the manner of copper release andinduction of thioredoxin in erythrocytesrdquo Biochemical andBiophysical Research Communications vol 241 no 2 pp 251ndash257 1997
[20] A KWalker M A Farg C R Bye C AMcLeanM K Horneand J D Atkin ldquoProtein disulphide isomerase protects againstprotein aggregation and is S-nitrosylated in amyotrophic lateralsclerosisrdquo Brain vol 133 no 1 pp 105ndash116 2010
[21] M W Akhtar C R Sunico T Nakamura and S A Lip-ton ldquoRedox regulation of protein function via cysteine S-nitrosylation and its relevance to neurodegenerative diseasesrdquoInternational Journal of Cell Biology vol 2012 Article ID463756 9 pages 2012
[22] J D Rothstein ldquoCurrent hypotheses for the underlying biologyof amyotrophic lateral sclerosisrdquo Annals of Neurology vol 65no 1 pp S3ndashS9 2009
[23] J Mitchell and G Borasio ldquoAmyotrophic lateral sclerosisrdquoLancet vol 369 no 9578 pp 2031ndash2041 2007
[24] L CWijesekera and PN Leigh ldquoAmyotrophic lateral sclerosisrdquoOrphanet Journal of Rare Diseases vol 4 no 1 p 3 2009
[25] G Bensimon L Lacomblez and V Meininger ldquoA controlledtrial of riluzole in amyotrophic lateral sclerosisrdquo New EnglandJournal of Medicine vol 330 no 9 pp 585ndash591 1994
[26] R G Miller J D Mitchell M Lyon and D HMoore ldquoRiluzolefor amyotrophic lateral sclerosis (ALS)motor neuron disease(MND)rdquoCochraneDatabase of Systematic Reviews no 1 ArticleID CD001447 2007
[27] A Alonso G Logroscino S S Jick and M A HernanldquoAssociation of smoking with amyotrophic lateral sclerosis riskand survival in men and women a prospective studyrdquo BMCNeurology vol 10 no 1 p 6 2010
[28] A Verma and J R Berger ldquoALS syndrome in patients withHIV-1 infectionrdquo Journal of the Neurological Sciences vol 240 no 1-2pp 59ndash64 2006
[29] A Chio B J Traynor F Lombardo et al ldquoPrevalence of SOD1mutations in the Italian ALS populationrdquoNeurology vol 70 no7 pp 533ndash537 2008
[30] L Corrado R Del Bo B Castellotti et al ldquoMutations ofFUS gene in sporadic amyotrophic lateral sclerosisrdquo Journal ofMedical Genetics vol 47 no 3 pp 190ndash194 2010
[31] J Sreedharan I P Blair V B Tripathi et al ldquoTDP-43mutationsin familial and sporadic amyotrophic lateral sclerosisrdquo Sciencevol 319 no 5870 pp 1668ndash1672 2008
[32] E Pupillo P Messina G Logroscino et al ldquoTrauma andamyotrophic lateral sclerosis a case-control study from apopulation-based registryrdquo European Journal of Neurology vol19 no 12 pp 1509ndash1517 2012
[33] S Beretta M T Carrı E Beghi A Chio and C Ferrarese ldquoThesinister side of Italian soccerrdquo Lancet Neurology vol 2 no 11pp 656ndash657 2003
[34] M R Turner C Wotton K Talbot and M J GoldacreldquoCardiovascular fitness as a risk factor for amyotrophic lateralsclerosis indirect evidence from record linkage studyrdquo Journalof Neurology Neurosurgery amp Psychiatry vol 83 pp 395ndash3982012
[35] P A Dion H Daoud and G A Rouleau ldquoGenetics of motorneuron disorders new insights into pathogenic mechanismsrdquoNature Reviews Genetics vol 10 no 11 pp 769ndash782 2009
[36] T Arai M Hasegawa H Akiyama et al ldquoTDP-43 is a compo-nent of ubiquitin-positive tau-negative inclusions in frontotem-poral lobar degeneration and amyotrophic lateral sclerosisrdquoBiochemical and Biophysical Research Communications vol 351no 3 pp 602ndash611 2006
[37] M Neumann D M Sampathu L K Kwong et al ldquoUbiq-uitinated TDP-43 in frontotemporal lobar degeneration andamyotrophic lateral sclerosisrdquo Science vol 314 no 5796 pp130ndash133 2006
[38] C Vance B Rogelj T Hortobagyi et al ldquoMutations in FUSan RNA processing protein cause familial amyotrophic lateralsclerosis type 6rdquo Science vol 323 no 5918 pp 1208ndash1211 2009
[39] Y Yang A Hentati H X Deng et al ldquoThe gene encodingalsin a protein with three guanine-nucleotide exchange factordomains is mutated in a form of recessive amyotrophic lateralsclerosisrdquo Nature Genetics vol 29 pp 160ndash165 2001
[40] A L Nishimura M Mitne-Neto H C A Silva et al ldquoAmutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclero-sisrdquoAmerican Journal of HumanGenetics vol 75 no 5 pp 822ndash831 2004
8 Oxidative Medicine and Cellular Longevity
[41] T J Kwiatkowski Jr D A Bosco A L LeClerc et al ldquoMutationsin the FUSTLS gene on chromosome 16 cause familial amy-otrophic lateral sclerosisrdquo Science vol 323 no 5918 pp 1205ndash1208 2009
[42] HMaruyamaHMorinoH Ito et al ldquoMutations of optineurinin amyotrophic lateral sclerosisrdquo Nature vol 465 no 7295 pp223ndash226 2010
[43] H X Deng W Chen S T Hong et al ldquoMutations in UBQLN2cause dominant X-linked juvenile and adult-onset ALS andALSdementiardquo Nature vol 477 pp 211ndash215 2011
[44] M DeJesus-Hernandez I R Mackenzie B F Boeve et alldquoExpanded GGGGCC hexanucleotide repeat in noncodingregion of C9ORF72 causes chromosome 9p-linked FTD andALSrdquo Neuron vol 72 no 2 pp 245ndash256 2011
[45] L I Bruijn T M Miller and D W Cleveland ldquoUnraveling themechanisms involved in motor neuron degeneration in ALSrdquoAnnual Review of Neuroscience vol 27 pp 723ndash749 2004
[46] H D Durham J Roy L Dong and D A Figlewicz ldquoAggrega-tion of mutant CuZn superoxide dismutase proteins in a cul-turemodel ofALSrdquo Journal ofNeuropathology andExperimentalNeurology vol 56 no 5 pp 523ndash530 1997
[47] M Watanabe M Dykes-Hoberg V Cizewski Culotta D LPrice P C Wong and J D Rothstein ldquoHistological evidenceof protein aggregation in mutant SOD1 transgenic mice andin amyotrophic lateral sclerosis neural tissuesrdquo Neurobiology ofDisease vol 8 no 6 pp 933ndash941 2001
[48] C Soto ldquoUnfolding the role of protein misfolding in neurode-generative diseasesrdquo Nature Reviews Neuroscience vol 4 no 1pp 49ndash60 2003
[49] J Wang G Xu and D R Borchelt ldquoMapping superoxidedismutase 1 domains of non-native interaction roles of intra-and intermolecular disulfide bonding in aggregationrdquo Journalof Neurochemistry vol 96 no 5 pp 1277ndash1288 2006
[50] B S Johnson D Snead J J Lee J M McCaffery J Shorterand A D Gitler ldquoTDP-43 is intrinsically aggregation-proneand amyotrophic lateral sclerosis-linked mutations accelerateaggregation and increase toxicityrdquo Journal of Biological Chem-istry vol 284 pp 20329ndash20339 2009
[51] C Vance B Rogelj T Hortobagyi et al ldquoMutations in FUSan RNA processing protein cause familial amyotrophic lateralsclerosis type 6rdquo Science vol 323 no 5918 pp 1208ndash1211 2009
[52] T Arai M Hasegawa H Akiyama et al ldquoTDP-43 is a compo-nent of ubiquitin-positive tau-negative inclusions in frontotem-poral lobar degeneration and amyotrophic lateral sclerosisrdquoBiochemical and Biophysical Research Communications vol 351no 3 pp 602ndash611 2006
[53] N Shibata A Hirano M Kobayashi et al ldquoIntense super-oxide dismutase-1 immunoreactivity in intracytoplasmic hya-line inclusions of familial amyotrophic lateral sclerosis withposterior column involvementrdquo Journal of Neuropathology andExperimental Neurology vol 55 no 4 pp 481ndash490 1996
[54] J S Valentine P A Doucette and S Z Potter ldquoCopper-zinc superoxide dismutase and amyotrophic lateral sclerosisrdquoAnnual Review of Biochemistry vol 74 pp 563ndash593 2005
[55] F Arnesano L Banci I BertiniMMartinelli Y Furukawa andT V OrsquoHalloran ldquoThe unusually stable quaternary structureof human CuZn-superoxide dismutase 1 is controlled by bothmetal occupancy and disulfide statusrdquo Journal of BiologicalChemistry vol 279 no 46 pp 47998ndash48003 2004
[56] C Kayatekin J A Zitzewitz and C R Matthews ldquoDisulfide-Reduced ALS Variants of Cu Zn Superoxide Dismutase Exhibit
Increased Populations of Unfolded Speciesrdquo Journal of Molecu-lar Biology vol 398 no 2 pp 320ndash331 2010
[57] A E Svensson O Bilsel C Kayatekin J A Adefusika J AZitzewitz and C Robert Matthews ldquoMetal-free ALS variantsof dimeric human CuZn-superoxide dismutase have enhancedpopulations of monomeric speciesrdquo PLoS ONE vol 5 no 4Article ID e10064 2010
[58] M Cozzolino M G Pesaresi V Gerbino J Grosskreutzand M T Carr ldquoAmyotrophic lateral sclerosis new insightsinto underlying molecular mechanisms and opportunities fortherapeutic interventionrdquo Antioxidants amp Redox Signaling vol17 no 9 pp 1277ndash1330 2012
[59] O Spreux-Varoquaux G Bensimon L Lacomblez et al ldquoGlu-tamate levels in cerebrospinal fluid in amyotrophic lateralsclerosis a reappraisal using a new HPLC method with coulo-metric detection in a large cohort of patientsrdquo Journal of theNeurological Sciences vol 193 no 2 pp 73ndash78 2002
[60] I Puls C Jonnakuty B H LaMonte et al ldquoMutant dynactin inmotor neuron diseaserdquo Nature Genetics vol 33 no 4 pp 455ndash456 2003
[61] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[62] J Kong and Z Xu ldquoMassive mitochondrial degeneration inmotor neurons triggers the onset of amyotrophic lateral sclero-sis in mice expressing a mutant SOD1rdquo Journal of Neurosciencevol 18 no 9 pp 3241ndash3250 1998
[63] F R Wiedemann K Winkler A V Kuznetsov et al ldquoImpair-ment of mitochondrial function in skeletal muscle of patientswith amyotrophic lateral sclerosisrdquo Journal of the NeurologicalSciences vol 156 no 1 pp 65ndash72 1998
[64] AHiranoHDonnenfeld S Sasaki and I Nakano ldquoFine struc-tural observations of neurofilamentous changes in amyotrophiclateral sclerosisrdquo Journal of Neuropathology and ExperimentalNeurology vol 43 no 5 pp 461ndash470 1984
[65] J D Wood T P Beaujeux and P J Shaw ldquoProtein aggregationin motor neurone disordersrdquo Neuropathology and AppliedNeurobiology vol 29 no 6 pp 529ndash545 2003
[66] J D Atkin M A Farg A KWalker C McLean D Tomas andM K Horne ldquoEndoplasmic reticulum stress and induction ofthe unfolded protein response in human sporadic amyotrophiclateral sclerosisrdquoNeurobiology of Disease vol 30 no 3 pp 400ndash407 2008
[67] S Chen X Zhang L Song and W Le ldquoAutophagy dysregula-tion in amyotrophic lateral sclerosisrdquo Brain Pathology vol 22no 1 pp 110ndash116 2012
[68] R G Cutler W A Pedersen S Camandola J D Rothsteinand M P Mattson ldquoEvidence that accumulation of ceramidesand cholesterol esters mediates oxidative stress-induced deathof motor neurons in amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 52 no 4 pp 448ndash457 2002
[69] R J Ferrante S E Browne L A Shinobu et al ldquoEvidenceof increased oxidative damage in both sporadic and familialamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol69 no 5 pp 2064ndash2074 1997
[70] M Bogdanov R H Brown W Matson et al ldquoIncreasedoxidative damage to DNA in ALS patientsrdquo Free Radical Biologyand Medicine vol 29 no 7 pp 652ndash658 2000
[71] A W Girotti ldquoLipid hydroperoxide generation turnover andeffector action in biological systemsrdquo Journal of Lipid Researchvol 39 no 8 pp 1529ndash1542 1998
Oxidative Medicine and Cellular Longevity 9
[72] P J Shaw P G Ince G Falkous and D Mantle ldquoOxidativedamage to protein in sporadic motor neuron disease spinalcordrdquo Annals of Neurology vol 38 no 4 pp 691ndash695 1995
[73] D Liu J Wen J Liu and L Li ldquoThe roles of free radicalsin amyotrophic lateral sclerosis reactive oxygen species andelevated oxidation of protein DNA and membrane phospho-lipidsrdquo FASEB Journal vol 13 no 15 pp 2318ndash2328 1999
[74] B J Carter P Anklesaria S Choi and J F Engelhardt ldquoRedoxmodifier genes and pathways in amyotrophic lateral sclerosisrdquoAntioxidants and Redox Signaling vol 11 no 7 pp 1569ndash15862009
[75] H F Poon K Hensley V Thongboonkerd et al ldquoRedoxproteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice-a model of familial amyotrophic lateralsclerosisrdquo Free Radical Biology and Medicine vol 39 no 4 pp453ndash462 2005
[76] J J Haddad ldquoAntioxidant and prooxidant mechanisms in theregulation of redox(y)-sensitive transcription factorsrdquo CellularSignalling vol 14 no 11 pp 879ndash897 2002
[77] K T Turpaev ldquoReactive oxygen species and regulation of geneexpressionrdquo Biochemistry vol 67 no 3 pp 281ndash292 2002
[78] C Iaccarino M E Mura S Esposito et al ldquoBcl2-A1 interactswith pro-caspase-3 implications for amyotrophic lateral scle-rosisrdquo Neurobiology of Disease vol 43 no 3 pp 642ndash650 2011
[79] C Moreau P Gosset J Kluza et al ldquoDeregulation of thehypoxia inducible factor-1120572 pathway in monocytes from spo-radic amyotrophic lateral sclerosis patientsrdquo Neuroscience vol172 pp 110ndash117 2011
[80] C M Karch M Prudencio D D Winkler P J Hart andD R Borchelt ldquoRole of mutant SOD1 disulfide oxidation andaggregation in the pathogenesis of familial ALSrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 106 no 19 pp 7774ndash7779 2009
[81] J B ProescherM Son J L Elliott andV C Culotta ldquoBiologicaleffects of CCS in the absence of SOD1 enzyme activationimplications for disease in a mouse model for ALSrdquo HumanMolecular Genetics vol 17 no 12 pp 1728ndash1737 2008
[82] J M McCord and I Fridovich ldquoSuperoxide dismutase Anenzymic function for erythrocuprein (hemocuprein)rdquo Journalof Biological Chemistry vol 244 no 22 pp 6049ndash6055 1969
[83] D Sau S De Biasi L Vitellaro-Zuccarello et al ldquoMutation ofSOD1 in ALS a gain of a loss of functionrdquo Human MolecularGenetics vol 16 no 13 pp 1604ndash1618 2007
[84] J S Beckman M Carson C D Smith and W H KoppenolldquoALS SOD and peroxynitriterdquoNature vol 364 no 6438 p 5841993
[85] N V Blough and O C Zafiriou ldquoReaction of superoxide withnitric oxide to form peroxonitrite in alkaline aqueous solutionrdquoInorganic Chemistry vol 24 no 22 pp 3502ndash3504 1985
[86] M F Beal R J Ferrante S E Browne Jr R T Matthews NW Kowall and R H Brown ldquoIncreased 3-nitrotyrosine in bothsporadic and familial amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 42 no 4 pp 644ndash654 1997
[87] H Tohgi T Abe K Yamazaki T Murata E Ishizaki andC Isobe ldquoRemarkable increase in cerebrospinal fluid 3-nitrotyrosine in patients with sporadic amyotrophic lateralsclerosisrdquo Annals of Neurology vol 46 pp 129ndash131 1999
[88] F Casoni M Basso T Massignan et al ldquoProtein nitration in amouse model of familial amyotrophic lateral sclerosis possiblemultifunctional role in the pathogenesisrdquo Journal of BiologicalChemistry vol 280 no 16 pp 16295ndash16304 2005
[89] S Guareschi E Cova C Cereda et al ldquoAn over-oxidizedform of superoxide dismutase found in sporadic amyotrophiclateral sclerosiswith bulbar onset shares a toxicmechanismwithmutant SOD1rdquo Proceedings of the National Academy of Sciencesvol 109 no 13 pp 5074ndash5079 2012
[90] RW Orrell R J M Lane andM Ross ldquoA systematic review ofantioxidant treatment for amyotrophic lateral sclerosismotorneuron diseaserdquo Amyotrophic Lateral Sclerosis vol 9 no 4 pp195ndash211 2008
[91] S A Ezzi M Urushitani and J P Julien ldquoWild-type superoxidedismutase acquires binding and toxic properties of ALS-linkedmutant forms through oxidationrdquo Journal of Neurochemistryvol 102 no 1 pp 170ndash178 2007
[92] R L Redler K C Wilcox E A Proctor L Fee M Caplowand N V Dokholyan ldquoGlutathionylation at Cys-111 inducesdissociation of wild type and FALS mutant SOD1 dimersrdquoBiochemistry vol 50 no 32 pp 7057ndash7066 2011
[93] K Forsberg P A Jonsson P M Andersen et al ldquoNovelantibodies reveal inclusions containing non-native SOD1 insporadic ALS patientsrdquo PloS One vol 5 no 7 Article ID e115522010
[94] D A Bosco G Morfini N M Karabacak et al ldquoWild-type andmutant SOD1 share an aberrant conformation and a commonpathogenic pathway in ALSrdquo Nature Neuroscience vol 13 no11 pp 1396ndash1403 2010
[95] A C Estevez J P Crow J B Sampson et al ldquoInduction of nitricoxide-dependent apoptosis in motor neurons by zinc- deficientsuperoxide dismutaserdquo Science vol 286 no 5449 pp 2498ndash2500 1999
[96] Y Furukawa R Fu H X Deng T Siddique and T VOrsquoHalloran ldquoDisulfide cross-linked protein represents a signif-icant fraction of ALS-associated Cu Zn-superoxide dismutaseaggregates in spinal cords of model micerdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 18 pp 7148ndash7153 2006
[97] T J Cohen AWHwang T Unger J Q Trojanowski and VMY Lee ldquoRedox signalling directly regulates TDP-43 via cysteineoxidation and disulphide cross-linkingrdquo The EMBO Journalvol 31 no 5 pp 1241ndash1252 2011
[98] DDormann R Rodde D Edbauer et al ldquoALS-associated fusedin sarcoma (FUS) mutations disrupt transportin-mediatednuclear importrdquo EMBO Journal vol 29 no 16 pp 2841ndash28572010
[99] S P Butcher andAHamberger ldquoIn vivo studies on the extracel-lular and veratrine-releasable pools of endogenous amino acidsin the rat striatum effects of corticostriatal deafferentiation andkainic acid lesionrdquo Journal of Neurochemistry vol 48 no 3 pp713ndash721 1987
[100] I Sen A Nalini N B Joshi and P G Joshi ldquoCerebrospinalfluid from amyotrophic lateral sclerosis patients preferentiallyelevates intracellular calcium and toxicity in motor neurons viaAMPAkainate receptorrdquo Journal of the Neurological Sciencesvol 235 no 1-2 pp 45ndash54 2005
[101] A Plaitakis and J T Caroscio ldquoAbnormal glutamatemetabolism in amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 22 no 5 pp 575ndash579 1987
[102] L Van Den Bosch and W Robberecht ldquoDifferent receptorsmediate motor neuron death induced by short and long expo-sures to excitotoxicityrdquo Brain Research Bulletin vol 53 no 4 pp383ndash388 2000
10 Oxidative Medicine and Cellular Longevity
[103] D Trotti ldquoNeuronal and glial glutamate transporters possessan SH-based redox regulatory mechanismrdquo European Journalof Neuroscience vol 9 no 6 pp 1236ndash1243 1997
[104] A Plaitakis and E Constantakakis ldquoAlteredmetabolism of exci-tatory amino acids N-acetyl-aspartate and N- acetyl-aspartyl-glutamate in amyotrophic lateral sclerosisrdquo Brain ResearchBulletin vol 30 no 3-4 pp 381ndash386 1993
[105] J D Rothstein L J Martin and R W Kuncl ldquoDecreasedglutamate transport by the brain and spinal cord in amyotrophiclateral sclerosisrdquo New England Journal of Medicine vol 326 no22 pp 1464ndash1468 1992
[106] J D Rothstein M Van Kammen A I Levey L J Martin andRW Kuncl ldquoSelective loss of glial glutamate transporter GLT-1amyotrophic lateral sclerosisrdquo Annals of Neurology vol 38 no1 pp 73ndash84 1995
[107] A Volterra D Trotti C Tromba S Floridi and G RacagnildquoGlutamate uptake inhibition by oxygen free radicals in ratcortical astrocytesrdquo Journal of Neuroscience vol 14 no 5 pp2924ndash2932 1994
[108] P J Shaw ldquoGlutamate excitotoxicity and amyotrophic lateralsclerosisrdquo Journal of Neurology vol 244 no 2 pp S3ndashS14 1997
[109] W L Miller ldquoMinireview regulation of steroidogenesis byelectron transferrdquo Endocrinology vol 146 no 6 pp 2544ndash25502005
[110] S Jin F Zhou F Katirai and P L Li ldquoLipid raft redox signalingmolecular mechanisms in health and diseaserdquoAntioxidants andRedox Signaling vol 15 no 4 pp 1043ndash1083 2011
[111] W A Pedersen W Fu J N Keller et al ldquoProtein modificationby the lipid peroxidation product 4-hydroxynonenal in thespinal cords of amyotrophic lateral sclerosis patientsrdquo Annals ofNeurology vol 44 no 5 pp 819ndash824 1998
[112] L Dupuis P Corcia A Fergani et al ldquoDyslipidemia is aprotective factor in amyotrophic lateral sclerosisrdquo Neurologyvol 70 no 13 pp 1004ndash1009 2008
[113] L Dupuis and J P Loeffler ldquoNeuromuscular junction destruc-tion during amyotrophic lateral sclerosis insights from trans-genic modelsrdquo Current Opinion in Pharmacology vol 9 no 3pp 341ndash346 2009
[114] I Choi H D Song S Lee et al ldquoDirect observation ofdefects and increased ion permeability of a membrane inducedby structurally disordered CuZn-superoxide dismutase aggre-gatesrdquo PloS One vol 6 no 12 pp e28982ndashe28982 2011
[115] C Taghibiglou J Lu I R Mackenzie Y T Wang and NR Cashman ldquoSterol regulatory element binding protein-1(SREBP1) activation in motor neurons in excitotoxicity andamyotrophic lateral sclerosis (ALS) indip a potential therapeu-tic peptiderdquo Biochemical and Biophysical Research Communica-tions vol 413 no 2 pp 159ndash163 2011
[116] E Colman A Szarfman J Wyeth et al ldquoAn evaluation of adata mining signal for amyotrophic lateral sclerosis and statinsdetected in FDArsquos spontaneous adverse event reporting systemrdquoPharmacoepidemiology and Drug Safety vol 17 no 11 pp 1068ndash1076 2008
[117] I R Edwards K Star and A Kiuru ldquoStatins neuromusculardegenerative disease and an amyotrophic lateral sclerosis-likesyndrome an analysis of individual case safety reports fromvigibaserdquo Drug Safety vol 30 no 6 pp 515ndash525 2007
[118] L Zinman R Sadeghi M Gawel D Patton and A Kiss ldquoArestatin medications safe in patients with ALSrdquo AmyotrophicLateral Sclerosis vol 9 no 4 pp 223ndash228 2008
[119] HToftSoslashrensen andT L Lash ldquoStatins and amyotrophic lateralsclerosis-the level of evidence for an associationrdquo Journal ofInternal Medicine vol 266 no 6 pp 520ndash526 2009
[120] J Zhai A L Strom R Kilty et al ldquoProteomic characterizationof lipid raft proteins in amyotrophic lateral sclerosis mousespinal cordrdquo FEBS Journal vol 276 no 12 pp 3308ndash3323 2009
[121] M F Beal ldquoAging energy and oxidative stress in neurodegen-erative diseasesrdquoAnnals of Neurology vol 38 no 3 pp 357ndash3661995
[122] F RWiedemann GManfredi CMawrinM Flint Beal and EA Schon ldquoMitochondrial DNA and respiratory chain functionin spinal cords of ALS patientsrdquo Journal of Neurochemistry vol80 no 4 pp 616ndash625 2002
[123] G M Borthwick M A Johnson P G Ince P J Shaw and DM Turnbull ldquoMitochondrial enzyme activity in amyotrophiclateral sclerosis implications for the role of mitochondria inneuronal cell deathrdquoAnnals of Neurology vol 46 no 5 pp 787ndash790 2001
[124] P M Keeney and J P Bennett ldquoALS spinal neurons show variedand reducedmtDNAgene copy numbers and increasedmtDNAgene deletionsrdquoMolecular Neurodegeneration vol 5 no 1 p 212010
[125] M B Graeber E Grasbon-Frodl U V Eitzen and S K KoselldquoNeurodegeneration and aging role of the second genomerdquoJournal of Neuroscience Research vol 52 no 1 pp 1ndash6 1998
[126] K C Zimmermann C Bonzon andD R Green ldquoThemachin-ery of programmed cell deathrdquo Pharmacology andTherapeuticsvol 92 no 1 pp 57ndash70 2001
[127] P Nagley G C Higgins J D Atkin and P M Beart ldquoMul-tifaceted deaths orchestrated by mitochondria in neuronesrdquoBiochimica et Biophysica Acta vol 1802 no 1 pp 167ndash185 2010
[128] C GueganM Vila G Rosoklija A P Hays and S PrzedborskildquoRecruitment of the mitochondria-dependent apoptotic path-way in amyotrophic lateral sclerosisrdquo Journal of Neurosciencevol 21 no 17 pp 6569ndash6576 2001
[129] L J Martin Z Liu K Chen et al ldquoMotor neuron degenerationin amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice mechanisms of mitochondriopathy and celldeathrdquo Journal of Comparative Neurology vol 500 no 1 pp 20ndash46 2007
[130] P C Wong C A Pardo D R Borchelt et al ldquoAn adverseproperty of a familial ALS-linked SOD1 mutation causes motorneuron disease characterized by vacuolar degeneration ofmito-chondriardquo Neuron vol 14 no 6 pp 1105ndash1116 1995
[131] F M Menzies M R Cookson R W Taylor et al ldquoMitochon-drial dysfunction in a cell culturemodel of familial amyotrophiclateral sclerosisrdquo Brain vol 125 no 7 pp 1522ndash1533 2002
[132] M T Carrı A Ferri A Battistoni et al ldquoExpression of aCuZn superoxide dismutase typical of familial amyotrophiclateral sclerosis induces mitochondrial alteration and increaseof cytosolic Ca2+ concentration in transfected neuroblastomaSH-SY5Y cellsrdquo FEBS Letters vol 414 no 2 pp 365ndash368 1997
[133] S Sasaki and M Iwata ldquoUltrastructural study of synapses inthe anterior horn neurons of patients with amyotrophic lateralsclerosisrdquoNeuroscience Letters vol 204 no 1-2 pp 53ndash56 1996
[134] L Siklos J Engelhardt Y Harati R G Smith F Joo andS H Appel ldquoUltrastructural evidence for altered calcium inmotor nerve terminals in amyotrophic lateral sclerosisrdquo Annalsof Neurology vol 39 no 2 pp 203ndash216 1996
[135] M Cozzolino and M T Carrı ldquoMitochondrial dysfunction inALSrdquo Progress in Neurobiology vol 97 no 2 pp 54ndash66 2012
Oxidative Medicine and Cellular Longevity 11
[136] K Y Soo J D Atkin M Farg A K Walker M K Horne andP Nagley ldquoBim links ER stress and apoptosis in cells expressingmutant SOD1 associated with amyotrophic lateral sclerosisrdquoPloS One vol 7 no 4 Article ID e35413 2012
[137] K Hong Y Li W Duan et al ldquoFull-length TDP-43 and itsC-terminal fragments activate mitophagy in NSC34 cell linerdquoNeuroscience Letters vol 530 no 2 pp 144ndash149 2012
[138] R J Braun and B Westermann ldquoMitochondrial dynamics inyeast cell death and agingrdquo Biochemical Society Transactionsvol 39 pp 1520ndash1526 2011
[139] W Duan X Li J Shi Y Guo Z Li and C Li ldquoMutant TARDNA-binding protein-43 induces oxidative injury in motorneuron-like cellrdquo Neuroscience vol 169 no 4 pp 1621ndash16292010
[140] C Jung C M J Higgins and Z Xu ldquoMitochondrial electrontransport chain complex dysfunction in a transgenic mousemodel for amyotrophic lateral sclerosisrdquo Journal of Neurochem-istry vol 83 no 3 pp 535ndash545 2002
[141] A Ferri M Cozzolino C Crosio et al ldquoFamilial ALS-superoxide dismutases associate with mitochondria and shifttheir redox potentialsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 37 pp13860ndash13865 2006
[142] K Aquilano P Vigilanza G Rotilio and M R CiriololdquoMitochondrial damage due to SOD1 deficiency in SH-SY5Yneuroblastoma cells a rationale for the redundancy of SOD1rdquoThe FASEB Journal vol 20 no 10 pp 1683ndash1685 2006
[143] E M OrsquoBrien R Dirmeier M Engle and R O PoytonldquoMitochondrial protein oxidation in yeast mutants lackingmanganese- (MnSOD) or copper- and zinc-containing super-oxide dismutase (CuZnSOD) evidence that mnsod and cuzn-sod have both unique and overlapping functions in protectingmitochondrial proteins from oxidative damagerdquo Journal ofBiological Chemistry vol 279 no 50 pp 51817ndash51827 2004
[144] S Pickles and C V Velde ldquoMisfolded SOD1 and ALS zeroingin on mitochondriardquo Amyotrophic Lateral Sclerosis vol 13 pp333ndash340 2012
[145] B Bandy and A J Davison ldquoMitochondrial mutations mayincrease oxidative stress implications for carcinogenesis andagingrdquo Free Radical Biology andMedicine vol 8 no 6 pp 523ndash539 1990
[146] F Zhang A L Strom K Fukada S Lee L J Hayward andH Zhu ldquoInteraction between familial Amyotrophic LateralSclerosis (ALS)-linked SOD1mutants and the dynein complexrdquoJournal of Biological Chemistry vol 282 no 22 pp 16691ndash166992007
[147] S Sasaki and S Maruyama ldquoUltrastructutal study of skein-like inclusions in anterior horn neurons of patients with motorneuron diseaserdquoNeuroscience Letters vol 147 no 2 pp 121ndash1241992
[148] D A Figlewicz A Krizus M G Martinoli et al ldquoVariantsof the heavy neurofilament subunit are associated with thedevelopment of amyotrophic lateral sclerosisrdquo Human Molec-ular Genetics vol 3 no 10 pp 1757ndash1761 1994
[149] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[150] S M Chou H S Wang and K Komai ldquoColocalization of NOSand SOD1 in neurofilament accumulation within motor neu-rons of amyotrophic lateral sclerosis an immunohistochemicalstudyrdquo Journal of Chemical Neuroanatomy vol 10 no 3-4 pp249ndash258 1996
[151] H Zhang X Kong J Kang et al ldquoOxidative stress inducesparallel autophagy and mitochondria dysfunction in humangliomaU251 cellsrdquoToxicological Sciences vol 110 no 2 pp 376ndash388 2009
[152] J Lee S Giordano and J Zhang ldquoAutophagymitochondria andoxidative stress cross-talk and redox signallingrdquo BiochemicalJournal vol 441 pp 523ndash540 2012
[153] A Li X Zhang and W Le ldquoAltered macroautophagy in thespinal cord of SOD1 mutant micerdquo Autophagy vol 4 no 3 pp290ndash293 2008
[154] Y Zhong Q J Wang X Li et al ldquoDistinct regulation ofautophagic activity by Atg14L and Rubicon associated withBeclin 1-phosphatidylinositol-3-kinase complexrdquo Nature CellBiology vol 11 no 4 pp 468ndash476 2009
[155] S Sasaki ldquoAutophagy in spinal cord motor neurons in sporadicamyotrophic lateral sclerosisrdquo Journal of Neuropathology andExperimental Neurology vol 70 no 5 pp 349ndash359 2011
[156] N Morimoto M Nagai Y Ohta et al ldquoIncreased autophagyin transgenic mice with a G93A mutant SOD1 generdquo BrainResearch vol 1167 no 1 pp 112ndash117 2007
[157] M Schroder ldquoEndoplasmic reticulum stress responsesrdquo Cellu-lar andMolecular Life Sciences vol 65 no 6 pp 862ndash894 2008
[158] J D Atkin M A Farg B J Turner et al ldquoInduction ofthe unfolded protein response in familial amyotrophic lateralsclerosis and association of protein-disulfide isomerase withsuperoxide dismutase 1rdquo Journal of Biological Chemistry vol281 no 40 pp 30152ndash30165 2006
[159] C M Haynes E A Titus and A A Cooper ldquoDegradation ofmisfolded proteins prevents ER-derived oxidative stress and celldeathrdquoMolecular Cell vol 15 no 5 pp 767ndash776 2004
[160] K Kanekura H Suzuki S Aiso and M Matsuoka ldquoER stressand unfolded protein response in amyotrophic lateral sclerosisrdquoMolecular Neurobiology vol 39 no 2 pp 81ndash89 2009
[161] M A Farg K Y Soo A K Walker et al ldquoMutant FUS inducesendoplasmic reticulum stress in amyotrophic lateral sclerosisand interacts with protein disulfide-isomeraserdquoNeurobiology ofAging vol 33 no 12 pp 2855ndash2868 2012
[162] E V Ilieva V Ayala M Jove et al ldquoOxidative and endoplas-mic reticulum stress interplay in sporadic amyotrophic lateralsclerosisrdquo Brain vol 130 no 12 pp 3111ndash3123 2007
[163] J D Malhotra and R J Kaufman ldquoEndoplasmic reticulumstress and oxidative stress a vicious cycle or a double-edgedswordrdquo Antioxidants and Redox Signaling vol 9 no 12 pp2277ndash2293 2007
[164] A K Walker and J D Atkin ldquoMechanisms of neuroprotectionby protein disulphide isomerase in amyotrophic lateral scle-rosisrdquo Neurology Research International vol 2011 Article ID317340 7 pages 2011
[165] R B Freedman T R Hirst andM F Tuite ldquoProtein disulphideisomerase building bridges in protein foldingrdquo Trends inBiochemical Sciences vol 19 no 8 pp 331ndash336 1994
[166] C I Andreu U Woehlbier M Torres and C Hetz ldquoProteindisulfide isomerases in neurodegeneration from disease mech-anisms to biomedical applicationsrdquo FEBS Letters vol 586 no18 pp 2826ndash2834 2012
[167] J J Galligan and D R Petersen ldquoThe human protein disulfideisomerase gene familyrdquoHuman Genomics vol 6 no 1 pp 1ndash152012
[168] L Ellgaard and L W Ruddock ldquoThe human protein disulphideisomerase family substrate interactions and functional proper-tiesrdquo EMBO Reports vol 6 no 1 pp 28ndash32 2005
12 Oxidative Medicine and Cellular Longevity
[169] B Wilkinson and H F Gilbert ldquoProtein disulfide isomeraserdquoBiochimica et Biophysica Acta vol 1699 no 1-2 pp 35ndash44 2004
[170] T Tanaka H Nakamura A Nishiyama et al ldquoRedox regulationby thioredoxin superfamily protection against oxidative stressand agingrdquo Free Radical Research vol 33 no 6 pp 851ndash8552000
[171] C Turano S Coppari F Altieri and A Ferraro ldquoProteins ofthe PDI family unpredicted non-ER locations and functionsrdquoJournal of Cellular Physiology vol 193 no 2 pp 154ndash163 2002
[172] D M Ferrari and H D Soling ldquoThe protein disulphide-isomerase family unravelling a string of foldsrdquo BiochemicalJournal vol 339 no 1 pp 1ndash10 1999
[173] G Tian S Xiang R Noiva W J Lennarz and H SchindelinldquoThe crystal structure of yeast protein disulfide isomerasesuggests cooperativity between its active sitesrdquo Cell vol 124 no1 pp 61ndash73 2006
[174] P Klappa LW Ruddock N J Darby and R B Freedman ldquoThebrsquo domain provides the principal peptide-binding site of proteindisulfide isomerase but all domains contribute to binding ofmisfolded proteinsrdquo EMBO Journal vol 17 no 4 pp 927ndash9351998
[175] A Pirneskoski P Klappa M Lobell et al ldquoMolecular char-acterization of the principal substrate binding site of theubiquitous folding catalyst protein disulfide isomeraserdquo Journalof Biological Chemistry vol 279 no 11 pp 10374ndash10381 2004
[176] G Kozlov P Maattanen D Y Thomas and K Gehring ldquoAstructural overview of the PDI family of proteinsrdquo FEBS Journalvol 277 no 19 pp 3924ndash3936 2010
[177] Y Dai and C C Wang ldquoA mutant truncated protein disulfideisomerase with no chaperone activityrdquo Journal of BiologicalChemistry vol 272 no 44 pp 27572ndash27576 1997
[178] C E Jessop R H Watkins J J Simmons M Tasab andN J Bulleid ldquoProtein disulphide isomerase family membersshow distinct substrate specificity P5 is targeted to BiP clientproteinsrdquo Journal of Cell Science vol 122 no 23 pp 4287ndash42952009
[179] C Appenzeller-Herzog J Riemer E Zito et al ldquoDisulphideproduction by Ero1120572-PDI relay is rapid and effectively regu-latedrdquo EMBO Journal vol 29 no 19 pp 3318ndash3329 2010
[180] F Hatahet and L W Ruddock ldquoProtein disulfide isomerase acritical evaluation of its function in disulfide bond formationrdquoAntioxidants and Redox Signaling vol 11 no 11 pp 2807ndash28502009
[181] N J Bulleid and L Ellgaard ldquoMultiple ways to make disulfidesrdquoTrends in Biochemical Sciences 2011
[182] S Chakravarthi C E Jessop and N J Bulleid ldquoThe role ofglutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stressrdquo EMBOReports vol 7 no3 pp 271ndash275 2006
[183] J Lundstrom and A Holmgren ldquoDetermination of thereduction-oxidation potential of the thioredoxin-like domainsof protein disulfide-isomerase from the equilibrium with glu-tathione and thioredoxinrdquo Biochemistry vol 32 no 26 pp6649ndash6655 1993
[184] E Gross C S Sevier N Heldman et al ldquoGenerating disulfidesenzymatically reaction products and electron acceptors of theendoplasmic reticulum thiol oxidase Ero1prdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 2 pp 299ndash304 2006
[185] P I Merksamer A Trusina and F R Papa ldquoReal-time redoxmeasurements during endoplasmic reticulum stress reveal
interlinked protein folding functionsrdquo Cell vol 135 no 5 pp933ndash947 2008
[186] J W Cuozzo and C A Kaiser ldquoCompetition between glu-tathione and protein thiols for disulphide-bond formationrdquoNature Cell Biology vol 1 no 3 pp 130ndash135 1999
[187] L A Rutkevich M F Cohen-Doyle U Brockmeier and DB Williams ldquoFunctional relationship between protein disulfideisomerase family members during the oxidative folding ofhuman secretory proteinsrdquoMolecular Biology of the Cell vol 21no 18 pp 3093ndash3105 2010
[188] Y Honjo S Kaneko H Ito et al ldquoProtein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateralsclerosisrdquo Amyotrophic Lateral Sclerosis vol 12 no 6 pp 444ndash450 2011
[189] H Tsuda S M Han Y Yang et al ldquoThe amyotrophic lateralsclerosis 8 proteinVAPB is cleaved secreted and acts as a ligandfor Eph receptorsrdquo Cell vol 133 no 6 pp 963ndash977 2008
[190] D M Townsend Y Manevich H Lin et al ldquoNitrosative stress-induced S-glutathionylation of protein disulfide isomerase leadsto activation of the unfolded protein responserdquoCancer Researchvol 69 no 19 pp 7626ndash7634 2009
[191] T Uehara T Nakamura D Yao et al ldquoS-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegen-erationrdquo Nature vol 441 no 7092 pp 513ndash517 2006
[192] X Chen C Li T Guan et al ldquoS-nitrosylated protein disul-phide isomerase contributes to mutant SOD1 aggregates inamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol124 no 1 pp 45ndash58 2012
[193] J D Rothstein ldquoTherapeutic horizons for amyotrophic lateralsclerosisrdquo Current Opinion in Neurobiology vol 6 no 5 pp679ndash687 1996
[194] D W Cleveland ldquoNeuronal growth and death order anddisorder in the axoplasmrdquoCell vol 84 no 5 pp 663ndash666 1996
was proposed that ALSmutations in SOD1 result in the loss ofits ability to act as an antioxidant but further research showedthat disease is not associated with its enzymatic activity[83] However mutations in SOD1 could produce ONOOminusor OHminus and lower its ability to catalyse superoxide [84] byreacting with nitric oxide [85] These intermediate productsare highly unstable and have been detected with other aminoacids such as tyrosine Nitrated proteins and high levelsof nitrotyrosine have been detected in the CSF of bothSALS and FALS patients suggesting that posttranslationalmodification via free radical production is present in ALS[17 86ndash88] Oxidised wild-type SOD1 in the lymphoblastsof SALS patients associates with mitochondrial Bcl-2 whichcauses mitochondrial damage [89] Oxidative damage is animportant phenomenon however treatment with antioxi-dants has not been very successful [90]
32 Protein Aggregation andMisfolding Redox dysregulationmay not only increase the production of ROSRNS but alsoaffect protein conformation and structure Posttranslationalmodification of SOD1 such as oxidation has an adverseeffect on the conformational arrangement of SOD1 [91]Glutathionylation a posttranslational modification of the 111cysteine residue causes destabilisation of SOD1 structure[92] Wild-type SOD1 has been shown in inclusions of SALSpatients suggesting its involvement in causing neurotoxicity[93] Evidence suggests that oxidised wild-type SOD1 hasthe ability to misfold and form aggregates and gain similarconformation as the mutant and has toxic functions in vitro[89 94] SOD1 depleted zinc and copper have altered redoxactivity and are more prone to oxidation [95]
An oxidising environment also causes abnormal disul-phide linkages and protein aggregation in ALS [80 96]SOD1 containing aberrant disulphide bonds involves thenormally unpaired cysteine residues cysteine 6 and cysteine111 in the spinal cord of ALS transgenic mice models [96]Studies show that mutant TDP-43 aggregation is causeddue to increased disulphide bonds [97] Similarly oxidativestress causes aberrant disulphide cross-linking and subcel-lular localisation of TDP-43 [97] as well as accumulation ofFUS into the cytoplasm [98] Mutant SOD1 readily formsmonomers oligomers or inclusions which are insoluble [55]It is unclear how conformational changes cause misfoldingbut one possible explanation could be the modification andalteration of protein structure by ROS through oxidisation ofthe thiol group forming aberrant disulphide bonds
33 Glutamate Excitotoxicity The levels of glutamate presentinmammalian CNS aremuch higher than those of other neu-rotransmitters (5ndash10mmolkg) indicating the importance ofglutamate in neuronal function [99] However excitotoxicityoccurs when the levels of glutamate are increased in neuronsresulting in increased calcium intake and neuronal injury[100 101] Motor neurons are particularly susceptible to highlevels of glutamate [102] Glutamate uptake from the synapseis controlled by glutamate transporters astroglial GLASTGLT1 and neuronal EAAC1 which possess a redox regulatedcysteine residue [103] N-methyl-D aspartic acid (NMDA)
glutamate receptors are also redox regulated suggesting thatredox dysfunction may further affect glutamate regulationIncreased levels of intracellular glutamate and decreaseduptake of glutamate from the synapse have been observedin ALS patients [104 105] Indeed Rothstein and coworkersshowed an absence of GLT1 transporter in ALS patients[106] ROS can reduce the uptake of glutamate in mammals[107] however increased calcium levels in the mitochondriadue to dysfunctional glutamate regulation can result inoverproduction of ROS and cause oxidative stress [108] Thequestion remains whether oxidative stress causes glutamatedysregulation or vice versa
34 Lipid Peroxidation and Cholesterol Esterification TheER is also the main site of lipid and sterol synthesis [109]Lipids are major targets of oxidative stress resulting in lipidperoxidation via a chain-reaction process [11] Sphingolipidsare localised in the plasma membrane and ER membranesand with cholesterol are processed into domains knownas lipid rafts [68] Lipid rafts can form macroplatformsfor redox signalling providing critical mediation for cel-lular functioning [110] Lipid peroxidation and cholesterolesterification have been implicated in the pathogenesis ofALS [68 69 111] Excitotoxicity and oxidative stress altersphingolipid metabolism resulting in the accumulation oflong-chain ceramides sphingomyelin and cholesterol estersin the spinal cords of ALS patients and CuZn SOD1 miceThis occurs at the early presymptomatic stage of disease in theSOD1mice [68] thus implicating aberrant lipidmetabolism inthe pathophysiology of ALS Further evidence of lipid dysreg-ulation in ALS comes from studies which reported that ALSpatients demonstrated a tendency towards hyperlipidemiaAdditionally correlational studies have shown that ALSpatients with the highest low density lipoprotein (LDL) highdensity lipoprotein (HDL) ratio have a significant increasein survival time and respiratory function [112 113] Fur-thermore recently an interaction between SOD1 aggregateswith lipid was found to alter lipid membrane permeability[114]
Lipid peroxidation products such as 4-hydroxynonenalhave been detected at higher levels in ALS patients spinalcord than controls and this has been linked to modificationof astrocytic glutamate transporter EAAT2 and excitotoxicity[111] Excitotoxicity was also linked to upregulation of sterolregulatory binding element 1 (SREBP1) in the spinal cordsof FALS and SALS patients and SOD1G93A transgenic micesuggesting cholesterol depletion [115] Furthermore the linkbetween ALS and statins a class of drug which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reduc-tase may suggest that suppressing cholesterol synthesisincreases the incidence [116 117] progression and severityof ALS [118] although this has been questioned [119] Lipidraft alteration has also been linked to the pathogenesis ofALS Endogenous wild-type and mutant SOD1G93A proteinswere recruited into lipid rafts isolated from spinal cords oftransgenic SOD1mice [120] Hence together the data suggestthat oxidative stress may alter sphingolipid and cholesterolmetabolism and deregulate lipid raft redox signalling leading
4 Oxidative Medicine and Cellular Longevity
to the accumulation of toxic ceramides and cholesterol esterswhich may ultimately result in motor neuron death [68]
35 Mitochondrial Dysfunction Mitochondria are impor-tant players in redox regulation and oxidative stress hasthe potential to cause mitochondrial dysfunction [70 121]Indeed damaged mitochondria are observed in the spinalcord cells of SALS patients [122ndash124] The mitochondrialgenome is particularly susceptible to oxidative damage [125]hence any increase in cellular ROS would potentially per-turb mitochondrial functions Mitochondria participate inneuronal apoptotic signalling pathways through the releaseof mitochondrial proteins including cytochrome c into thecytoplasm [126] There is substantial evidence that molecularcomponents of mitochondrial apoptosis play a role in neu-rodegeneration in both SOD1 rodents and in mutant SOD1overexpressed in cell culture [127] The enzymatic activityof cytochrome c oxidase (COX) in mitochondria is alsoreduced in the spinal cord cells of SALS patients [122ndash124128 129] Mitochondria have been well studied in relation toALS pathogenesis Degenerating or abnormal mitochondriahave been described in mouse models [62 130] culturedneuronal cellular models [131 132] and ALS patients [133134] although how nonfunctioning mitochondria relate toALS is unclear Possible explanations include inhibition ofaxonal transport dysregulation of calcium buffering [135] oractivation of mitochondrial-dependent apoptosis [128 136]Recent studies have shown that overexpression of TDP-43causes mitochondrial dysfunction and induces mitophagy incell culture [137]The presence of ROS and impairment of themitochondrial respiratory chain have also been observed inTDP-43 models [138 139]
Mutant SOD1 has also been implicated in mitochondrialrespiratory complex impairment [140] and a shift in the redoxstate of mitochondria towards oxidation [141] How SOD1functions in the mitochondria is still not clear althoughsome data suggests that SOD1 is crucial for maintenanceof the mitochondrial redox state [142 143] and that ALSmutations affect the localisation or function of SOD1 inmitochondria [135] However mutant misfolded SOD1 hasbeen found localised with various compartments of themitochondria [144] Significantly any pathological changesin regulation of the electron transport chain would result inmore oxidative stress [145] triggering further cellular redoxdysregulation leading to a potential vicious cycle of damageand degeneration
36 Impaired Axonal Transport Axonal transport is a keymechanism required for cellular viability in neuronal cellsMost proteins required in the axon and in synaptic terminalsmust be transported along the axon after synthesis in the cellbody Similarly RNA and organelles also need to be trans-ported over long distances and these transport processesrequire molecular motors such as kinesins dyneins andmyosins that operate along the cellular cytoskeleton Dys-function of axonal transport has now been well documentedin ALS [61] Whilst many of these studies implicate dyneinin this process [146] several also highlight the importance
of kinesin in ALS particularly kinesin heavy chains KIF5Aand KIF1B120573 which transport mitochondria synaptic vesi-cles and macromolecular complexes Interestingly a recentstudy demonstrated that oxidised wild-type SOD1 immuno-purified from SALS patient tissues inhibited kinesin-basedaxonal transport in amanner similar tomutant SOD1 in FALSproviding evidence for common pathogenic mechanisms inboth SALS and FALS [94]
Neurofilaments (NF) accumulation in motor neuronsis another histopathological hallmark of ALS [147 148]Also transgenic mice that overexpress NF subunits in motorneurons develop a motor neuron disease with impairedaxonal flow as axonal defects cause delay in transportationof components required for the maintenance of axon [149]However ONOOminus formed during oxidative stress fromnitrooxide and superoxide can affect NF assembly and causeNF accumulation in motor neurons [8] Chou and coworkersshowed NF aggregations are associated with SOD1 and nitricoxide synthase activities leading to nitrotyrosine formationon NF [150] Nitrotyrosine can inhibit phosphorylation ofheavy or light NF subunits and may alter axonal transportand trigger motor neuron death [150] Taken together thesefindings suggest a relation between redox regulation andaxonal transport dysfunctions in ALS
37 Autophagy Autophagy is a normal homeostatic mecha-nism to dispose large protein aggregates damaged organellesand long-lived proteins Autophagic stress results when thenumber of autophagosomes increases relative to the pro-portion of degradable proteins The presence of high levelsof superoxide and hydrogen peroxide species can induceautophagy in vitro [151] but consequently autophagy canfurther induce oxidative or nitrative stress thus creating avicious cycle [152] Dysregulated redox activity also influ-ences autophagy Cathepsin a class of proteases which havehighly regulated thiol groups [152] and other key regulatoryautophagic complexes such as Beclin 1 and Rubicon alsohave the presence of cysteine residues [152] The presence ofcysteine residues suggests that they are redox regulated andlikely to be affected by ROS ATG 4 another protease is atarget of oxidation by hydrogen peroxide However directassociation of these with ALS has not yet been identifiedAltered autophagic levels have been observed in SOD1G93Amice and sporadic and familial patients but whether theincreased levels are protective or not is still questionable [153ndash156]
38 ER Stress and Protein Disulphide Isomerase (PDI) in ALSThe ER is redox regulated and another important locationfor the production of ROS It plays key roles in protein andlipid synthesis and protein folding Proteinmisfolding withinthe ER triggers ER stress which induces the unfolded proteinresponse (UPR) a distinct signalling pathway which aims torelieve stress [157] While initially protective prolonged UPRcauses apoptosis [158 159] Recent studies suggest that ERstress is an early and important pathogenic mechanism inALS [66 158 160] ER stress is induced in animal modelsof SOD1 in cells expressing mutant FUS and in patients
Oxidative Medicine and Cellular Longevity 5
CGHC CGHC KDEL
119886 119887 119888119909119887998400
119886998400
Figure 1 Schematic diagram showing domain structure of PDIThioredoxin-like 119886 domain (orange) and 1198861015840 domain (purple) pos-sessing the catalyticmotif catalytically inactive 119887 domain (blue) and1198871015840 domain (red) Green represents the linker region 119909 which allowsflexibility between domainsTheC terminal domain is shown in greyfollowed by the ER retrieval signal KDEL
[20 161] Oxidative stress driven by changes in fatty acidcomposition mitochondrial function andor proteosomeactivity leads to oxidative stress and contributes to ER stressin SALS patients [162 163] PDI is an ER chaperone whichis induced during UPR and has been implicated in severalneurodegenerative disorders including ALS [164ndash166]
PDI is a member of an extended family of foldasesand chaperones which are responsible for the formationand isomerisation of protein disulphide bonds [167] ThePDI family comprises 21 members which have structuralsimilarities but different functions [168] and all have asimilar active site to thioredoxin [169] Thioredoxin is anintracellular protein which regulates redox conditions andwhich is effective against oxidative stress [170] PDI is mostabundant in the ER but it is also found in other subcellularlocations such as the nucleus and extracellular matrix [171]and it constitutes 08 of the total cellular protein [172]The yeast PDI crystal structure was recently solved [173]which suggests that 119886 and 1198861015840 domains are responsible forthe formation of disulphide bonds (Figure 1) These domainscontain a redox active CGHCmotif which isomerases proteindisulphide bonds and is involved in redox regulation [173]PDI also contains 119887 and 1198871015840 domains which are responsiblefor substrate binding [174 175] Misfolded proteins attach tothe hydrophobic region of an inverted U shape structure [173176] The C-terminal region also aids in polypeptide bindingand contributes chaperone activity [177] Compared to otherfamilymembers PDI has broad substrate specificities and caninteract with glycosylated as well as nonglycosylated proteins[178]
4 PDI and Redox Regulation
PDI forms protein disulphide bonds by the oxidation ofthiols within the PDI active site cysteine residues [179 180]When PDI is in an oxidised state it transfers a disulphide tothe substrates thereby oxidising the substrate and becomingreduced itself Conversely substrates which need disulphidebond rearrangement are reduced by PDI in the reduced statethus oxidising PDI in the process [168 181] This continualcycling regulates redox conditions within the ER A thiolcontaining tripeptide protein and glutathione also maintainsER redox homeostasis by similar shuffling between oxidizedand reduced cysteine residues Glutathione is also requiredfor the isomerisation and rearrangement of disulphide bonds[182] The redox potential of PDI (minus110mV) is lower than
other family members [183] due to intervening residuespresent between the reactive cysteines thus facilitating disul-phide bonds [183] ERO1 oxidises PDI also aiding disulphidebond formations [184] but PDI is also oxidised throughperoxiredoxin 4 vitamin K glutathione peroxidase andquiescin sulfhydryl oxidase [181] During ER stress highlevels of ERO1 have been observed which accelerates proteinoxidation suggesting interplay between oxidative stress andER stress The transfer of electrons from the thiol groupof PDI to ERO1 results in the production of excess ROSdecreasing the levels of glutathione available for reductionand increasing ERO1 thus altering the redox conditions [185186] Hence imbalance in the redox state of the ERmay resultin dysregulation of thiol containing proteins and triggers
41 The Role of PDI in ALS Due to its function in preventingprotein misfolding PDI is important in protein quality con-trol [166] also deletion of PDI is embryonically lethal [187]Hence regulated expression of PDI is critical for normalcellular functionThere is now growing evidence for a role ofPDI in ALS PDI levels are upregulated in transgenic modelsof ALS and spinal cord tissues of ALS patients [66 158]Overexpression of PDI is also protective againstmutant SOD1mediated aggregation and reduces cell death in vitro [20] PDIcoimmunoprecipitates with both SOD1 and FUS [158 161] italso colocalises with SOD1 TDP-43 and FUS in ALS patientssuggesting a physical interaction exists between PDI andother key misfolded proteins in ALS [66 161 188] SimilarlyPDI also colocalises with TDP-43 in ALS tissues and withVAPB inclusions in a Drosophila melanogaster model ofALS [188 189] A small mimic of the active site of PDIdithiol (plusmn)-trans-12-bis (mercaptoacetamido) cyclohexane(BMC) is also protective in cell culture and it reduces mutantSOD1 aggregation in a dose dependent manner [20] Furtherevidences for a role for disulphide interchange activity in ALScomes from studies showing that another PDI familymemberERp57 is also upregulated in transgenic SOD1 mice and ALSpatients [66] Furthermore thioredoxin is also upregulated inthe erythrocytes of FALS patients [19]
The upregulation of these thiol containing proteins inALS suggests a cellular defensive mechanism is triggeredin disease as a defence against oxidative stress Howeverthere is evidence that normal protective function of PDI isinhibited in disease [20] Modifications of active site thiolgroups through direct oxidation S-glutathiolation and S-nitrosylation can lead to inactivation of the normal enzy-matic activity of PDI [13 190 191] PDI was recently shownto be S-nitrosylated in ALS [20 192] as in other neurodegen-erative disorders such as Parkinsonrsquos and Alzheimerrsquos disease[191] S-nitrosylation occurs when there is an increased pro-duction of RNS during oxidative stress resulting in additionof a nitrogen monoxide group to the thiol side of PDI[20 164] Experiments performed by Chen and coworkerssuggested that in the presence of S-nitrosylated PDI theformation of mutant SOD1 aggregates increases in vitro [192]It is also likely that inactivation of PDI could lead to activationof the UPR as observed in other neurodegenerative disorders[191] The loss of PDI functional activity can directly lead to
6 Oxidative Medicine and Cellular Longevity
Impaired axonaltransport
AutophagyMitochondrialdysfunction
ER stress Proteinmisfolding
Redox dysregulation
PDI dysfunction Oxidative stress
Figure 2 Redox dysfunction and its relationship to other patholo-gies in ALS Alteration in the enzymatic activity of PDI due toredox dysregulation and oxidative stress can further increase theload of misfolded proteins ER stress oxidative stress autophagymitochondrial dysfunction and axonal impairment leading toneuronal cell death
apoptosis or indirectly to a range of cellular abnormalitiessuch as oxidative stress and protein misfolding which againlead to cell death [164 166] Hence the redox regulationof PDI is a crucial component in the maintenance of abalanced redox environment and inhibition of its enzymaticactivity will lead to important consequences for the cell(Figure 2)
Neurons are highly susceptible to redox dysregulationdue to their high metabolic requirements large size andlower ability to maintain the balance between antioxidantsand ROS [15] In disease states such as ALS oxidativestress and altered enzymatic activity of PDI which normallyreduces ROS and the burden of misfolded protein can causeserious damage to the neuron Since multiple mechanismsare involved in neurodegeneration any imbalance in redoxregulation can lead to an imbalance in the production offree radical species which consequently cause mitochondrialdamage and excitotoxicity thus elevating the levels of freeradicals [193] Furthermore an excess of free radicals canalso lead to DNA damage and may also result in aggregationof NF [194] and structural destabilization of other proteinsthus inducing ER stress and apoptosis Since ALS is a slowprogressive disorder it could be hypothesised that these cyclicevents due to loss of functional activity of PDImay graduallylead to neuronal degradation In such a scenario the redoxregulatory function of PDI may therefore have an importantprotective effect
5 Conclusion
Redox regulation is an important mechanism of homeostasisin eukaryotic cells especially neuronal cells where oxygen
levels are high [15] Many cellular processes rely on it includ-ing proper functioning of the mitochondria and ER calciumregulation axonal transport regulated autophagy and pro-tein folding Links between redox dysregulation and ALSare becoming well documented in the literature althoughthe directionality of these links and their underlying causeare still quite unknown One possible key player in redox reg-ulation in ALS is PDI whose role in ALS pathogenesis is thetopic of much new research As the critical protein involvedin thiol reduction any dysregulation of PDI activity can leadto oxidative stress and redox dysregulation Due to its activityPDI itself also contains an active site thiol group suggestingthat it can also be affected by oxidative stress leading to anescalating cycle that perpetuates redox dysregulation HowPDI becomes nonfunctional in the first place is still unclearalthough somepapers point to S-nitrosylation as having a role[20] Regardless of its exact role any mechanism to improvethe catalytic activity of PDI should have a reductive effect onoxidative stress levels in neurons It is therefore tempting tospeculate about PDI as a possible therapeutic target in thetreatment of ALS
Acknowledgments
This work was supported by the National Health and Med-ical Research Council of Australia (project Grants 4547491006141 and 1030513) Amyotrophic Lateral Sclerosis Asso-ciation (USA) MND Research Institute of Australia Beth-lehem Griffiths Research Council Henry H Roth CharitableFoundation Grant for MND Research Australian RotaryHealth and the Brain Foundation S Parakh holds a La TrobeUniversity Post Graduate Research Scholarship
References
[1] H Kamata and H Hirata ldquoRedox regulation of cellular sig-nallingrdquo Cellular Signalling vol 11 no 1 pp 1ndash14 1999
[2] A R Cross and O T G Jones ldquoEnzymic mechanisms ofsuperoxide productionrdquoBiochimica et BiophysicaActa vol 1057no 3 pp 281ndash298 1991
[3] VAdler Z YinKD Tew andZRonai ldquoRole of redox potentialand reactive oxygen species in stress signalingrdquo Oncogene vol18 no 45 pp 6104ndash6111 1999
[4] J Nordberg and E S J Arner ldquoReactive oxygen speciesantioxidants and the mammalian thioredoxin systemrdquo FreeRadical Biology andMedicine vol 31 no 11 pp 1287ndash1312 2001
[5] M G Espey K M Miranda D D Thomas et al ldquoA chemicalperspective on the interplay between NO reactive oxygenspecies and Reactive Nitrogen Oxide Speciesrdquo Annals of theNew York Academy of Sciences vol 962 pp 195ndash206 2002
[6] W A Pryor and G L Squadrito ldquoThe chemistry of per-oxynitrite a product from the reaction of nitric oxide withsuperoxiderdquo American Journal of Physiology-Lung Cellular andMolecular Physiology vol 268 no 5 pp L699ndashL722 1995
[7] K Abe L H Pan M Watanabe H Konno T Kato andY Itoyama ldquoUpregulation of protein-tyrosine nitration in theanterior horn cells of amyotrophic lateral sclerosisrdquo Neurologi-cal Research vol 19 no 2 pp 124ndash128 1997
Oxidative Medicine and Cellular Longevity 7
[8] J S Beckman M Carson C D Smith and W H KoppenolldquoALS SOD and peroxynitriterdquoNature vol 364 no 6438 p 5841993
[9] S C Barber and P J Shaw ldquoOxidative stress in ALS key rolein motor neuron injury and therapeutic targetrdquo Free RadicalBiology and Medicine vol 48 no 5 pp 629ndash641 2010
[10] M C Martınez and R Andriantsitohaina ldquoReactive nitrogenspecies molecular mechanisms and potential significance inhealth and diseaserdquo Antioxidants and Redox Signaling vol 11no 3 pp 669ndash702 2009
[11] D Trachootham W Lu M A Ogasawara N R D Valle andP Huang ldquoRedox regulation of cell survivalrdquo Antioxidants andRedox Signaling vol 10 no 8 pp 1343ndash1374 2008
[12] C E Cooper R P Patel P S Brookes and VM Darley-UsmarldquoNanotransducers in cellular redox signaling modification ofthiols by reactive oxygen and nitrogen speciesrdquo Trends inBiochemical Sciences vol 27 no 10 pp 489ndash492 2002
[13] H Nakamura K Nakamura and J Yodoi ldquoRedox regulation ofcellular activationrdquo Annual Review of Immunology vol 15 pp351ndash369 1997
[14] S A Lipton Y B Choi Z H Pan et al ldquoA redox-based mech-anism for the neuroprotective and neurodestructive effects ofnitric oxide and related nitroso-compoundsrdquo Nature vol 364no 6438 pp 626ndash632 1993
[15] B Halliwell ldquoOxidative stress and neurodegeneration whereare we nowrdquo Journal of Neurochemistry vol 97 no 6 pp 1634ndash1658 2006
[16] R P Guttmann and T J Powell ldquoRedox regulation of cysteine-dependent enzymes in neurodegenerationrdquo International Jour-nal of Cell Biology vol 2012 Article ID 703164 8 pages 2012
[17] H Tohgi T Abe K Yamazaki T Murata E Ishizaki and CIsobe ldquoIncrease in oxidized NO products and reduction inoxidized glutathione in cerebrospinal fluid from patients withsporadic form of amyotrophic lateral sclerosisrdquo NeuroscienceLetters vol 260 no 3 pp 204ndash206 1999
[18] D R Rosen T Siddique D Patterson et al ldquoMutations inCuZn superoxide dismutase gene are associated with familialamyotrophic lateral sclerosisrdquoNature vol 362 no 6415 pp 59ndash62 1993
[19] Y Ogawa H Kosaka T Nakanishi et al ldquoStability of mutantsuperoxide dismutase-1 associated with familial amyotrophiclateral sclerosis determines the manner of copper release andinduction of thioredoxin in erythrocytesrdquo Biochemical andBiophysical Research Communications vol 241 no 2 pp 251ndash257 1997
[20] A KWalker M A Farg C R Bye C AMcLeanM K Horneand J D Atkin ldquoProtein disulphide isomerase protects againstprotein aggregation and is S-nitrosylated in amyotrophic lateralsclerosisrdquo Brain vol 133 no 1 pp 105ndash116 2010
[21] M W Akhtar C R Sunico T Nakamura and S A Lip-ton ldquoRedox regulation of protein function via cysteine S-nitrosylation and its relevance to neurodegenerative diseasesrdquoInternational Journal of Cell Biology vol 2012 Article ID463756 9 pages 2012
[22] J D Rothstein ldquoCurrent hypotheses for the underlying biologyof amyotrophic lateral sclerosisrdquo Annals of Neurology vol 65no 1 pp S3ndashS9 2009
[23] J Mitchell and G Borasio ldquoAmyotrophic lateral sclerosisrdquoLancet vol 369 no 9578 pp 2031ndash2041 2007
[24] L CWijesekera and PN Leigh ldquoAmyotrophic lateral sclerosisrdquoOrphanet Journal of Rare Diseases vol 4 no 1 p 3 2009
[25] G Bensimon L Lacomblez and V Meininger ldquoA controlledtrial of riluzole in amyotrophic lateral sclerosisrdquo New EnglandJournal of Medicine vol 330 no 9 pp 585ndash591 1994
[26] R G Miller J D Mitchell M Lyon and D HMoore ldquoRiluzolefor amyotrophic lateral sclerosis (ALS)motor neuron disease(MND)rdquoCochraneDatabase of Systematic Reviews no 1 ArticleID CD001447 2007
[27] A Alonso G Logroscino S S Jick and M A HernanldquoAssociation of smoking with amyotrophic lateral sclerosis riskand survival in men and women a prospective studyrdquo BMCNeurology vol 10 no 1 p 6 2010
[28] A Verma and J R Berger ldquoALS syndrome in patients withHIV-1 infectionrdquo Journal of the Neurological Sciences vol 240 no 1-2pp 59ndash64 2006
[29] A Chio B J Traynor F Lombardo et al ldquoPrevalence of SOD1mutations in the Italian ALS populationrdquoNeurology vol 70 no7 pp 533ndash537 2008
[30] L Corrado R Del Bo B Castellotti et al ldquoMutations ofFUS gene in sporadic amyotrophic lateral sclerosisrdquo Journal ofMedical Genetics vol 47 no 3 pp 190ndash194 2010
[31] J Sreedharan I P Blair V B Tripathi et al ldquoTDP-43mutationsin familial and sporadic amyotrophic lateral sclerosisrdquo Sciencevol 319 no 5870 pp 1668ndash1672 2008
[32] E Pupillo P Messina G Logroscino et al ldquoTrauma andamyotrophic lateral sclerosis a case-control study from apopulation-based registryrdquo European Journal of Neurology vol19 no 12 pp 1509ndash1517 2012
[33] S Beretta M T Carrı E Beghi A Chio and C Ferrarese ldquoThesinister side of Italian soccerrdquo Lancet Neurology vol 2 no 11pp 656ndash657 2003
[34] M R Turner C Wotton K Talbot and M J GoldacreldquoCardiovascular fitness as a risk factor for amyotrophic lateralsclerosis indirect evidence from record linkage studyrdquo Journalof Neurology Neurosurgery amp Psychiatry vol 83 pp 395ndash3982012
[35] P A Dion H Daoud and G A Rouleau ldquoGenetics of motorneuron disorders new insights into pathogenic mechanismsrdquoNature Reviews Genetics vol 10 no 11 pp 769ndash782 2009
[36] T Arai M Hasegawa H Akiyama et al ldquoTDP-43 is a compo-nent of ubiquitin-positive tau-negative inclusions in frontotem-poral lobar degeneration and amyotrophic lateral sclerosisrdquoBiochemical and Biophysical Research Communications vol 351no 3 pp 602ndash611 2006
[37] M Neumann D M Sampathu L K Kwong et al ldquoUbiq-uitinated TDP-43 in frontotemporal lobar degeneration andamyotrophic lateral sclerosisrdquo Science vol 314 no 5796 pp130ndash133 2006
[38] C Vance B Rogelj T Hortobagyi et al ldquoMutations in FUSan RNA processing protein cause familial amyotrophic lateralsclerosis type 6rdquo Science vol 323 no 5918 pp 1208ndash1211 2009
[39] Y Yang A Hentati H X Deng et al ldquoThe gene encodingalsin a protein with three guanine-nucleotide exchange factordomains is mutated in a form of recessive amyotrophic lateralsclerosisrdquo Nature Genetics vol 29 pp 160ndash165 2001
[40] A L Nishimura M Mitne-Neto H C A Silva et al ldquoAmutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclero-sisrdquoAmerican Journal of HumanGenetics vol 75 no 5 pp 822ndash831 2004
8 Oxidative Medicine and Cellular Longevity
[41] T J Kwiatkowski Jr D A Bosco A L LeClerc et al ldquoMutationsin the FUSTLS gene on chromosome 16 cause familial amy-otrophic lateral sclerosisrdquo Science vol 323 no 5918 pp 1205ndash1208 2009
[42] HMaruyamaHMorinoH Ito et al ldquoMutations of optineurinin amyotrophic lateral sclerosisrdquo Nature vol 465 no 7295 pp223ndash226 2010
[43] H X Deng W Chen S T Hong et al ldquoMutations in UBQLN2cause dominant X-linked juvenile and adult-onset ALS andALSdementiardquo Nature vol 477 pp 211ndash215 2011
[44] M DeJesus-Hernandez I R Mackenzie B F Boeve et alldquoExpanded GGGGCC hexanucleotide repeat in noncodingregion of C9ORF72 causes chromosome 9p-linked FTD andALSrdquo Neuron vol 72 no 2 pp 245ndash256 2011
[45] L I Bruijn T M Miller and D W Cleveland ldquoUnraveling themechanisms involved in motor neuron degeneration in ALSrdquoAnnual Review of Neuroscience vol 27 pp 723ndash749 2004
[46] H D Durham J Roy L Dong and D A Figlewicz ldquoAggrega-tion of mutant CuZn superoxide dismutase proteins in a cul-turemodel ofALSrdquo Journal ofNeuropathology andExperimentalNeurology vol 56 no 5 pp 523ndash530 1997
[47] M Watanabe M Dykes-Hoberg V Cizewski Culotta D LPrice P C Wong and J D Rothstein ldquoHistological evidenceof protein aggregation in mutant SOD1 transgenic mice andin amyotrophic lateral sclerosis neural tissuesrdquo Neurobiology ofDisease vol 8 no 6 pp 933ndash941 2001
[48] C Soto ldquoUnfolding the role of protein misfolding in neurode-generative diseasesrdquo Nature Reviews Neuroscience vol 4 no 1pp 49ndash60 2003
[49] J Wang G Xu and D R Borchelt ldquoMapping superoxidedismutase 1 domains of non-native interaction roles of intra-and intermolecular disulfide bonding in aggregationrdquo Journalof Neurochemistry vol 96 no 5 pp 1277ndash1288 2006
[50] B S Johnson D Snead J J Lee J M McCaffery J Shorterand A D Gitler ldquoTDP-43 is intrinsically aggregation-proneand amyotrophic lateral sclerosis-linked mutations accelerateaggregation and increase toxicityrdquo Journal of Biological Chem-istry vol 284 pp 20329ndash20339 2009
[51] C Vance B Rogelj T Hortobagyi et al ldquoMutations in FUSan RNA processing protein cause familial amyotrophic lateralsclerosis type 6rdquo Science vol 323 no 5918 pp 1208ndash1211 2009
[52] T Arai M Hasegawa H Akiyama et al ldquoTDP-43 is a compo-nent of ubiquitin-positive tau-negative inclusions in frontotem-poral lobar degeneration and amyotrophic lateral sclerosisrdquoBiochemical and Biophysical Research Communications vol 351no 3 pp 602ndash611 2006
[53] N Shibata A Hirano M Kobayashi et al ldquoIntense super-oxide dismutase-1 immunoreactivity in intracytoplasmic hya-line inclusions of familial amyotrophic lateral sclerosis withposterior column involvementrdquo Journal of Neuropathology andExperimental Neurology vol 55 no 4 pp 481ndash490 1996
[54] J S Valentine P A Doucette and S Z Potter ldquoCopper-zinc superoxide dismutase and amyotrophic lateral sclerosisrdquoAnnual Review of Biochemistry vol 74 pp 563ndash593 2005
[55] F Arnesano L Banci I BertiniMMartinelli Y Furukawa andT V OrsquoHalloran ldquoThe unusually stable quaternary structureof human CuZn-superoxide dismutase 1 is controlled by bothmetal occupancy and disulfide statusrdquo Journal of BiologicalChemistry vol 279 no 46 pp 47998ndash48003 2004
[56] C Kayatekin J A Zitzewitz and C R Matthews ldquoDisulfide-Reduced ALS Variants of Cu Zn Superoxide Dismutase Exhibit
Increased Populations of Unfolded Speciesrdquo Journal of Molecu-lar Biology vol 398 no 2 pp 320ndash331 2010
[57] A E Svensson O Bilsel C Kayatekin J A Adefusika J AZitzewitz and C Robert Matthews ldquoMetal-free ALS variantsof dimeric human CuZn-superoxide dismutase have enhancedpopulations of monomeric speciesrdquo PLoS ONE vol 5 no 4Article ID e10064 2010
[58] M Cozzolino M G Pesaresi V Gerbino J Grosskreutzand M T Carr ldquoAmyotrophic lateral sclerosis new insightsinto underlying molecular mechanisms and opportunities fortherapeutic interventionrdquo Antioxidants amp Redox Signaling vol17 no 9 pp 1277ndash1330 2012
[59] O Spreux-Varoquaux G Bensimon L Lacomblez et al ldquoGlu-tamate levels in cerebrospinal fluid in amyotrophic lateralsclerosis a reappraisal using a new HPLC method with coulo-metric detection in a large cohort of patientsrdquo Journal of theNeurological Sciences vol 193 no 2 pp 73ndash78 2002
[60] I Puls C Jonnakuty B H LaMonte et al ldquoMutant dynactin inmotor neuron diseaserdquo Nature Genetics vol 33 no 4 pp 455ndash456 2003
[61] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[62] J Kong and Z Xu ldquoMassive mitochondrial degeneration inmotor neurons triggers the onset of amyotrophic lateral sclero-sis in mice expressing a mutant SOD1rdquo Journal of Neurosciencevol 18 no 9 pp 3241ndash3250 1998
[63] F R Wiedemann K Winkler A V Kuznetsov et al ldquoImpair-ment of mitochondrial function in skeletal muscle of patientswith amyotrophic lateral sclerosisrdquo Journal of the NeurologicalSciences vol 156 no 1 pp 65ndash72 1998
[64] AHiranoHDonnenfeld S Sasaki and I Nakano ldquoFine struc-tural observations of neurofilamentous changes in amyotrophiclateral sclerosisrdquo Journal of Neuropathology and ExperimentalNeurology vol 43 no 5 pp 461ndash470 1984
[65] J D Wood T P Beaujeux and P J Shaw ldquoProtein aggregationin motor neurone disordersrdquo Neuropathology and AppliedNeurobiology vol 29 no 6 pp 529ndash545 2003
[66] J D Atkin M A Farg A KWalker C McLean D Tomas andM K Horne ldquoEndoplasmic reticulum stress and induction ofthe unfolded protein response in human sporadic amyotrophiclateral sclerosisrdquoNeurobiology of Disease vol 30 no 3 pp 400ndash407 2008
[67] S Chen X Zhang L Song and W Le ldquoAutophagy dysregula-tion in amyotrophic lateral sclerosisrdquo Brain Pathology vol 22no 1 pp 110ndash116 2012
[68] R G Cutler W A Pedersen S Camandola J D Rothsteinand M P Mattson ldquoEvidence that accumulation of ceramidesand cholesterol esters mediates oxidative stress-induced deathof motor neurons in amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 52 no 4 pp 448ndash457 2002
[69] R J Ferrante S E Browne L A Shinobu et al ldquoEvidenceof increased oxidative damage in both sporadic and familialamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol69 no 5 pp 2064ndash2074 1997
[70] M Bogdanov R H Brown W Matson et al ldquoIncreasedoxidative damage to DNA in ALS patientsrdquo Free Radical Biologyand Medicine vol 29 no 7 pp 652ndash658 2000
[71] A W Girotti ldquoLipid hydroperoxide generation turnover andeffector action in biological systemsrdquo Journal of Lipid Researchvol 39 no 8 pp 1529ndash1542 1998
Oxidative Medicine and Cellular Longevity 9
[72] P J Shaw P G Ince G Falkous and D Mantle ldquoOxidativedamage to protein in sporadic motor neuron disease spinalcordrdquo Annals of Neurology vol 38 no 4 pp 691ndash695 1995
[73] D Liu J Wen J Liu and L Li ldquoThe roles of free radicalsin amyotrophic lateral sclerosis reactive oxygen species andelevated oxidation of protein DNA and membrane phospho-lipidsrdquo FASEB Journal vol 13 no 15 pp 2318ndash2328 1999
[74] B J Carter P Anklesaria S Choi and J F Engelhardt ldquoRedoxmodifier genes and pathways in amyotrophic lateral sclerosisrdquoAntioxidants and Redox Signaling vol 11 no 7 pp 1569ndash15862009
[75] H F Poon K Hensley V Thongboonkerd et al ldquoRedoxproteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice-a model of familial amyotrophic lateralsclerosisrdquo Free Radical Biology and Medicine vol 39 no 4 pp453ndash462 2005
[76] J J Haddad ldquoAntioxidant and prooxidant mechanisms in theregulation of redox(y)-sensitive transcription factorsrdquo CellularSignalling vol 14 no 11 pp 879ndash897 2002
[77] K T Turpaev ldquoReactive oxygen species and regulation of geneexpressionrdquo Biochemistry vol 67 no 3 pp 281ndash292 2002
[78] C Iaccarino M E Mura S Esposito et al ldquoBcl2-A1 interactswith pro-caspase-3 implications for amyotrophic lateral scle-rosisrdquo Neurobiology of Disease vol 43 no 3 pp 642ndash650 2011
[79] C Moreau P Gosset J Kluza et al ldquoDeregulation of thehypoxia inducible factor-1120572 pathway in monocytes from spo-radic amyotrophic lateral sclerosis patientsrdquo Neuroscience vol172 pp 110ndash117 2011
[80] C M Karch M Prudencio D D Winkler P J Hart andD R Borchelt ldquoRole of mutant SOD1 disulfide oxidation andaggregation in the pathogenesis of familial ALSrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 106 no 19 pp 7774ndash7779 2009
[81] J B ProescherM Son J L Elliott andV C Culotta ldquoBiologicaleffects of CCS in the absence of SOD1 enzyme activationimplications for disease in a mouse model for ALSrdquo HumanMolecular Genetics vol 17 no 12 pp 1728ndash1737 2008
[82] J M McCord and I Fridovich ldquoSuperoxide dismutase Anenzymic function for erythrocuprein (hemocuprein)rdquo Journalof Biological Chemistry vol 244 no 22 pp 6049ndash6055 1969
[83] D Sau S De Biasi L Vitellaro-Zuccarello et al ldquoMutation ofSOD1 in ALS a gain of a loss of functionrdquo Human MolecularGenetics vol 16 no 13 pp 1604ndash1618 2007
[84] J S Beckman M Carson C D Smith and W H KoppenolldquoALS SOD and peroxynitriterdquoNature vol 364 no 6438 p 5841993
[85] N V Blough and O C Zafiriou ldquoReaction of superoxide withnitric oxide to form peroxonitrite in alkaline aqueous solutionrdquoInorganic Chemistry vol 24 no 22 pp 3502ndash3504 1985
[86] M F Beal R J Ferrante S E Browne Jr R T Matthews NW Kowall and R H Brown ldquoIncreased 3-nitrotyrosine in bothsporadic and familial amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 42 no 4 pp 644ndash654 1997
[87] H Tohgi T Abe K Yamazaki T Murata E Ishizaki andC Isobe ldquoRemarkable increase in cerebrospinal fluid 3-nitrotyrosine in patients with sporadic amyotrophic lateralsclerosisrdquo Annals of Neurology vol 46 pp 129ndash131 1999
[88] F Casoni M Basso T Massignan et al ldquoProtein nitration in amouse model of familial amyotrophic lateral sclerosis possiblemultifunctional role in the pathogenesisrdquo Journal of BiologicalChemistry vol 280 no 16 pp 16295ndash16304 2005
[89] S Guareschi E Cova C Cereda et al ldquoAn over-oxidizedform of superoxide dismutase found in sporadic amyotrophiclateral sclerosiswith bulbar onset shares a toxicmechanismwithmutant SOD1rdquo Proceedings of the National Academy of Sciencesvol 109 no 13 pp 5074ndash5079 2012
[90] RW Orrell R J M Lane andM Ross ldquoA systematic review ofantioxidant treatment for amyotrophic lateral sclerosismotorneuron diseaserdquo Amyotrophic Lateral Sclerosis vol 9 no 4 pp195ndash211 2008
[91] S A Ezzi M Urushitani and J P Julien ldquoWild-type superoxidedismutase acquires binding and toxic properties of ALS-linkedmutant forms through oxidationrdquo Journal of Neurochemistryvol 102 no 1 pp 170ndash178 2007
[92] R L Redler K C Wilcox E A Proctor L Fee M Caplowand N V Dokholyan ldquoGlutathionylation at Cys-111 inducesdissociation of wild type and FALS mutant SOD1 dimersrdquoBiochemistry vol 50 no 32 pp 7057ndash7066 2011
[93] K Forsberg P A Jonsson P M Andersen et al ldquoNovelantibodies reveal inclusions containing non-native SOD1 insporadic ALS patientsrdquo PloS One vol 5 no 7 Article ID e115522010
[94] D A Bosco G Morfini N M Karabacak et al ldquoWild-type andmutant SOD1 share an aberrant conformation and a commonpathogenic pathway in ALSrdquo Nature Neuroscience vol 13 no11 pp 1396ndash1403 2010
[95] A C Estevez J P Crow J B Sampson et al ldquoInduction of nitricoxide-dependent apoptosis in motor neurons by zinc- deficientsuperoxide dismutaserdquo Science vol 286 no 5449 pp 2498ndash2500 1999
[96] Y Furukawa R Fu H X Deng T Siddique and T VOrsquoHalloran ldquoDisulfide cross-linked protein represents a signif-icant fraction of ALS-associated Cu Zn-superoxide dismutaseaggregates in spinal cords of model micerdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 18 pp 7148ndash7153 2006
[97] T J Cohen AWHwang T Unger J Q Trojanowski and VMY Lee ldquoRedox signalling directly regulates TDP-43 via cysteineoxidation and disulphide cross-linkingrdquo The EMBO Journalvol 31 no 5 pp 1241ndash1252 2011
[98] DDormann R Rodde D Edbauer et al ldquoALS-associated fusedin sarcoma (FUS) mutations disrupt transportin-mediatednuclear importrdquo EMBO Journal vol 29 no 16 pp 2841ndash28572010
[99] S P Butcher andAHamberger ldquoIn vivo studies on the extracel-lular and veratrine-releasable pools of endogenous amino acidsin the rat striatum effects of corticostriatal deafferentiation andkainic acid lesionrdquo Journal of Neurochemistry vol 48 no 3 pp713ndash721 1987
[100] I Sen A Nalini N B Joshi and P G Joshi ldquoCerebrospinalfluid from amyotrophic lateral sclerosis patients preferentiallyelevates intracellular calcium and toxicity in motor neurons viaAMPAkainate receptorrdquo Journal of the Neurological Sciencesvol 235 no 1-2 pp 45ndash54 2005
[101] A Plaitakis and J T Caroscio ldquoAbnormal glutamatemetabolism in amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 22 no 5 pp 575ndash579 1987
[102] L Van Den Bosch and W Robberecht ldquoDifferent receptorsmediate motor neuron death induced by short and long expo-sures to excitotoxicityrdquo Brain Research Bulletin vol 53 no 4 pp383ndash388 2000
10 Oxidative Medicine and Cellular Longevity
[103] D Trotti ldquoNeuronal and glial glutamate transporters possessan SH-based redox regulatory mechanismrdquo European Journalof Neuroscience vol 9 no 6 pp 1236ndash1243 1997
[104] A Plaitakis and E Constantakakis ldquoAlteredmetabolism of exci-tatory amino acids N-acetyl-aspartate and N- acetyl-aspartyl-glutamate in amyotrophic lateral sclerosisrdquo Brain ResearchBulletin vol 30 no 3-4 pp 381ndash386 1993
[105] J D Rothstein L J Martin and R W Kuncl ldquoDecreasedglutamate transport by the brain and spinal cord in amyotrophiclateral sclerosisrdquo New England Journal of Medicine vol 326 no22 pp 1464ndash1468 1992
[106] J D Rothstein M Van Kammen A I Levey L J Martin andRW Kuncl ldquoSelective loss of glial glutamate transporter GLT-1amyotrophic lateral sclerosisrdquo Annals of Neurology vol 38 no1 pp 73ndash84 1995
[107] A Volterra D Trotti C Tromba S Floridi and G RacagnildquoGlutamate uptake inhibition by oxygen free radicals in ratcortical astrocytesrdquo Journal of Neuroscience vol 14 no 5 pp2924ndash2932 1994
[108] P J Shaw ldquoGlutamate excitotoxicity and amyotrophic lateralsclerosisrdquo Journal of Neurology vol 244 no 2 pp S3ndashS14 1997
[109] W L Miller ldquoMinireview regulation of steroidogenesis byelectron transferrdquo Endocrinology vol 146 no 6 pp 2544ndash25502005
[110] S Jin F Zhou F Katirai and P L Li ldquoLipid raft redox signalingmolecular mechanisms in health and diseaserdquoAntioxidants andRedox Signaling vol 15 no 4 pp 1043ndash1083 2011
[111] W A Pedersen W Fu J N Keller et al ldquoProtein modificationby the lipid peroxidation product 4-hydroxynonenal in thespinal cords of amyotrophic lateral sclerosis patientsrdquo Annals ofNeurology vol 44 no 5 pp 819ndash824 1998
[112] L Dupuis P Corcia A Fergani et al ldquoDyslipidemia is aprotective factor in amyotrophic lateral sclerosisrdquo Neurologyvol 70 no 13 pp 1004ndash1009 2008
[113] L Dupuis and J P Loeffler ldquoNeuromuscular junction destruc-tion during amyotrophic lateral sclerosis insights from trans-genic modelsrdquo Current Opinion in Pharmacology vol 9 no 3pp 341ndash346 2009
[114] I Choi H D Song S Lee et al ldquoDirect observation ofdefects and increased ion permeability of a membrane inducedby structurally disordered CuZn-superoxide dismutase aggre-gatesrdquo PloS One vol 6 no 12 pp e28982ndashe28982 2011
[115] C Taghibiglou J Lu I R Mackenzie Y T Wang and NR Cashman ldquoSterol regulatory element binding protein-1(SREBP1) activation in motor neurons in excitotoxicity andamyotrophic lateral sclerosis (ALS) indip a potential therapeu-tic peptiderdquo Biochemical and Biophysical Research Communica-tions vol 413 no 2 pp 159ndash163 2011
[116] E Colman A Szarfman J Wyeth et al ldquoAn evaluation of adata mining signal for amyotrophic lateral sclerosis and statinsdetected in FDArsquos spontaneous adverse event reporting systemrdquoPharmacoepidemiology and Drug Safety vol 17 no 11 pp 1068ndash1076 2008
[117] I R Edwards K Star and A Kiuru ldquoStatins neuromusculardegenerative disease and an amyotrophic lateral sclerosis-likesyndrome an analysis of individual case safety reports fromvigibaserdquo Drug Safety vol 30 no 6 pp 515ndash525 2007
[118] L Zinman R Sadeghi M Gawel D Patton and A Kiss ldquoArestatin medications safe in patients with ALSrdquo AmyotrophicLateral Sclerosis vol 9 no 4 pp 223ndash228 2008
[119] HToftSoslashrensen andT L Lash ldquoStatins and amyotrophic lateralsclerosis-the level of evidence for an associationrdquo Journal ofInternal Medicine vol 266 no 6 pp 520ndash526 2009
[120] J Zhai A L Strom R Kilty et al ldquoProteomic characterizationof lipid raft proteins in amyotrophic lateral sclerosis mousespinal cordrdquo FEBS Journal vol 276 no 12 pp 3308ndash3323 2009
[121] M F Beal ldquoAging energy and oxidative stress in neurodegen-erative diseasesrdquoAnnals of Neurology vol 38 no 3 pp 357ndash3661995
[122] F RWiedemann GManfredi CMawrinM Flint Beal and EA Schon ldquoMitochondrial DNA and respiratory chain functionin spinal cords of ALS patientsrdquo Journal of Neurochemistry vol80 no 4 pp 616ndash625 2002
[123] G M Borthwick M A Johnson P G Ince P J Shaw and DM Turnbull ldquoMitochondrial enzyme activity in amyotrophiclateral sclerosis implications for the role of mitochondria inneuronal cell deathrdquoAnnals of Neurology vol 46 no 5 pp 787ndash790 2001
[124] P M Keeney and J P Bennett ldquoALS spinal neurons show variedand reducedmtDNAgene copy numbers and increasedmtDNAgene deletionsrdquoMolecular Neurodegeneration vol 5 no 1 p 212010
[125] M B Graeber E Grasbon-Frodl U V Eitzen and S K KoselldquoNeurodegeneration and aging role of the second genomerdquoJournal of Neuroscience Research vol 52 no 1 pp 1ndash6 1998
[126] K C Zimmermann C Bonzon andD R Green ldquoThemachin-ery of programmed cell deathrdquo Pharmacology andTherapeuticsvol 92 no 1 pp 57ndash70 2001
[127] P Nagley G C Higgins J D Atkin and P M Beart ldquoMul-tifaceted deaths orchestrated by mitochondria in neuronesrdquoBiochimica et Biophysica Acta vol 1802 no 1 pp 167ndash185 2010
[128] C GueganM Vila G Rosoklija A P Hays and S PrzedborskildquoRecruitment of the mitochondria-dependent apoptotic path-way in amyotrophic lateral sclerosisrdquo Journal of Neurosciencevol 21 no 17 pp 6569ndash6576 2001
[129] L J Martin Z Liu K Chen et al ldquoMotor neuron degenerationin amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice mechanisms of mitochondriopathy and celldeathrdquo Journal of Comparative Neurology vol 500 no 1 pp 20ndash46 2007
[130] P C Wong C A Pardo D R Borchelt et al ldquoAn adverseproperty of a familial ALS-linked SOD1 mutation causes motorneuron disease characterized by vacuolar degeneration ofmito-chondriardquo Neuron vol 14 no 6 pp 1105ndash1116 1995
[131] F M Menzies M R Cookson R W Taylor et al ldquoMitochon-drial dysfunction in a cell culturemodel of familial amyotrophiclateral sclerosisrdquo Brain vol 125 no 7 pp 1522ndash1533 2002
[132] M T Carrı A Ferri A Battistoni et al ldquoExpression of aCuZn superoxide dismutase typical of familial amyotrophiclateral sclerosis induces mitochondrial alteration and increaseof cytosolic Ca2+ concentration in transfected neuroblastomaSH-SY5Y cellsrdquo FEBS Letters vol 414 no 2 pp 365ndash368 1997
[133] S Sasaki and M Iwata ldquoUltrastructural study of synapses inthe anterior horn neurons of patients with amyotrophic lateralsclerosisrdquoNeuroscience Letters vol 204 no 1-2 pp 53ndash56 1996
[134] L Siklos J Engelhardt Y Harati R G Smith F Joo andS H Appel ldquoUltrastructural evidence for altered calcium inmotor nerve terminals in amyotrophic lateral sclerosisrdquo Annalsof Neurology vol 39 no 2 pp 203ndash216 1996
[135] M Cozzolino and M T Carrı ldquoMitochondrial dysfunction inALSrdquo Progress in Neurobiology vol 97 no 2 pp 54ndash66 2012
Oxidative Medicine and Cellular Longevity 11
[136] K Y Soo J D Atkin M Farg A K Walker M K Horne andP Nagley ldquoBim links ER stress and apoptosis in cells expressingmutant SOD1 associated with amyotrophic lateral sclerosisrdquoPloS One vol 7 no 4 Article ID e35413 2012
[137] K Hong Y Li W Duan et al ldquoFull-length TDP-43 and itsC-terminal fragments activate mitophagy in NSC34 cell linerdquoNeuroscience Letters vol 530 no 2 pp 144ndash149 2012
[138] R J Braun and B Westermann ldquoMitochondrial dynamics inyeast cell death and agingrdquo Biochemical Society Transactionsvol 39 pp 1520ndash1526 2011
[139] W Duan X Li J Shi Y Guo Z Li and C Li ldquoMutant TARDNA-binding protein-43 induces oxidative injury in motorneuron-like cellrdquo Neuroscience vol 169 no 4 pp 1621ndash16292010
[140] C Jung C M J Higgins and Z Xu ldquoMitochondrial electrontransport chain complex dysfunction in a transgenic mousemodel for amyotrophic lateral sclerosisrdquo Journal of Neurochem-istry vol 83 no 3 pp 535ndash545 2002
[141] A Ferri M Cozzolino C Crosio et al ldquoFamilial ALS-superoxide dismutases associate with mitochondria and shifttheir redox potentialsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 37 pp13860ndash13865 2006
[142] K Aquilano P Vigilanza G Rotilio and M R CiriololdquoMitochondrial damage due to SOD1 deficiency in SH-SY5Yneuroblastoma cells a rationale for the redundancy of SOD1rdquoThe FASEB Journal vol 20 no 10 pp 1683ndash1685 2006
[143] E M OrsquoBrien R Dirmeier M Engle and R O PoytonldquoMitochondrial protein oxidation in yeast mutants lackingmanganese- (MnSOD) or copper- and zinc-containing super-oxide dismutase (CuZnSOD) evidence that mnsod and cuzn-sod have both unique and overlapping functions in protectingmitochondrial proteins from oxidative damagerdquo Journal ofBiological Chemistry vol 279 no 50 pp 51817ndash51827 2004
[144] S Pickles and C V Velde ldquoMisfolded SOD1 and ALS zeroingin on mitochondriardquo Amyotrophic Lateral Sclerosis vol 13 pp333ndash340 2012
[145] B Bandy and A J Davison ldquoMitochondrial mutations mayincrease oxidative stress implications for carcinogenesis andagingrdquo Free Radical Biology andMedicine vol 8 no 6 pp 523ndash539 1990
[146] F Zhang A L Strom K Fukada S Lee L J Hayward andH Zhu ldquoInteraction between familial Amyotrophic LateralSclerosis (ALS)-linked SOD1mutants and the dynein complexrdquoJournal of Biological Chemistry vol 282 no 22 pp 16691ndash166992007
[147] S Sasaki and S Maruyama ldquoUltrastructutal study of skein-like inclusions in anterior horn neurons of patients with motorneuron diseaserdquoNeuroscience Letters vol 147 no 2 pp 121ndash1241992
[148] D A Figlewicz A Krizus M G Martinoli et al ldquoVariantsof the heavy neurofilament subunit are associated with thedevelopment of amyotrophic lateral sclerosisrdquo Human Molec-ular Genetics vol 3 no 10 pp 1757ndash1761 1994
[149] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[150] S M Chou H S Wang and K Komai ldquoColocalization of NOSand SOD1 in neurofilament accumulation within motor neu-rons of amyotrophic lateral sclerosis an immunohistochemicalstudyrdquo Journal of Chemical Neuroanatomy vol 10 no 3-4 pp249ndash258 1996
[151] H Zhang X Kong J Kang et al ldquoOxidative stress inducesparallel autophagy and mitochondria dysfunction in humangliomaU251 cellsrdquoToxicological Sciences vol 110 no 2 pp 376ndash388 2009
[152] J Lee S Giordano and J Zhang ldquoAutophagymitochondria andoxidative stress cross-talk and redox signallingrdquo BiochemicalJournal vol 441 pp 523ndash540 2012
[153] A Li X Zhang and W Le ldquoAltered macroautophagy in thespinal cord of SOD1 mutant micerdquo Autophagy vol 4 no 3 pp290ndash293 2008
[154] Y Zhong Q J Wang X Li et al ldquoDistinct regulation ofautophagic activity by Atg14L and Rubicon associated withBeclin 1-phosphatidylinositol-3-kinase complexrdquo Nature CellBiology vol 11 no 4 pp 468ndash476 2009
[155] S Sasaki ldquoAutophagy in spinal cord motor neurons in sporadicamyotrophic lateral sclerosisrdquo Journal of Neuropathology andExperimental Neurology vol 70 no 5 pp 349ndash359 2011
[156] N Morimoto M Nagai Y Ohta et al ldquoIncreased autophagyin transgenic mice with a G93A mutant SOD1 generdquo BrainResearch vol 1167 no 1 pp 112ndash117 2007
[157] M Schroder ldquoEndoplasmic reticulum stress responsesrdquo Cellu-lar andMolecular Life Sciences vol 65 no 6 pp 862ndash894 2008
[158] J D Atkin M A Farg B J Turner et al ldquoInduction ofthe unfolded protein response in familial amyotrophic lateralsclerosis and association of protein-disulfide isomerase withsuperoxide dismutase 1rdquo Journal of Biological Chemistry vol281 no 40 pp 30152ndash30165 2006
[159] C M Haynes E A Titus and A A Cooper ldquoDegradation ofmisfolded proteins prevents ER-derived oxidative stress and celldeathrdquoMolecular Cell vol 15 no 5 pp 767ndash776 2004
[160] K Kanekura H Suzuki S Aiso and M Matsuoka ldquoER stressand unfolded protein response in amyotrophic lateral sclerosisrdquoMolecular Neurobiology vol 39 no 2 pp 81ndash89 2009
[161] M A Farg K Y Soo A K Walker et al ldquoMutant FUS inducesendoplasmic reticulum stress in amyotrophic lateral sclerosisand interacts with protein disulfide-isomeraserdquoNeurobiology ofAging vol 33 no 12 pp 2855ndash2868 2012
[162] E V Ilieva V Ayala M Jove et al ldquoOxidative and endoplas-mic reticulum stress interplay in sporadic amyotrophic lateralsclerosisrdquo Brain vol 130 no 12 pp 3111ndash3123 2007
[163] J D Malhotra and R J Kaufman ldquoEndoplasmic reticulumstress and oxidative stress a vicious cycle or a double-edgedswordrdquo Antioxidants and Redox Signaling vol 9 no 12 pp2277ndash2293 2007
[164] A K Walker and J D Atkin ldquoMechanisms of neuroprotectionby protein disulphide isomerase in amyotrophic lateral scle-rosisrdquo Neurology Research International vol 2011 Article ID317340 7 pages 2011
[165] R B Freedman T R Hirst andM F Tuite ldquoProtein disulphideisomerase building bridges in protein foldingrdquo Trends inBiochemical Sciences vol 19 no 8 pp 331ndash336 1994
[166] C I Andreu U Woehlbier M Torres and C Hetz ldquoProteindisulfide isomerases in neurodegeneration from disease mech-anisms to biomedical applicationsrdquo FEBS Letters vol 586 no18 pp 2826ndash2834 2012
[167] J J Galligan and D R Petersen ldquoThe human protein disulfideisomerase gene familyrdquoHuman Genomics vol 6 no 1 pp 1ndash152012
[168] L Ellgaard and L W Ruddock ldquoThe human protein disulphideisomerase family substrate interactions and functional proper-tiesrdquo EMBO Reports vol 6 no 1 pp 28ndash32 2005
12 Oxidative Medicine and Cellular Longevity
[169] B Wilkinson and H F Gilbert ldquoProtein disulfide isomeraserdquoBiochimica et Biophysica Acta vol 1699 no 1-2 pp 35ndash44 2004
[170] T Tanaka H Nakamura A Nishiyama et al ldquoRedox regulationby thioredoxin superfamily protection against oxidative stressand agingrdquo Free Radical Research vol 33 no 6 pp 851ndash8552000
[171] C Turano S Coppari F Altieri and A Ferraro ldquoProteins ofthe PDI family unpredicted non-ER locations and functionsrdquoJournal of Cellular Physiology vol 193 no 2 pp 154ndash163 2002
[172] D M Ferrari and H D Soling ldquoThe protein disulphide-isomerase family unravelling a string of foldsrdquo BiochemicalJournal vol 339 no 1 pp 1ndash10 1999
[173] G Tian S Xiang R Noiva W J Lennarz and H SchindelinldquoThe crystal structure of yeast protein disulfide isomerasesuggests cooperativity between its active sitesrdquo Cell vol 124 no1 pp 61ndash73 2006
[174] P Klappa LW Ruddock N J Darby and R B Freedman ldquoThebrsquo domain provides the principal peptide-binding site of proteindisulfide isomerase but all domains contribute to binding ofmisfolded proteinsrdquo EMBO Journal vol 17 no 4 pp 927ndash9351998
[175] A Pirneskoski P Klappa M Lobell et al ldquoMolecular char-acterization of the principal substrate binding site of theubiquitous folding catalyst protein disulfide isomeraserdquo Journalof Biological Chemistry vol 279 no 11 pp 10374ndash10381 2004
[176] G Kozlov P Maattanen D Y Thomas and K Gehring ldquoAstructural overview of the PDI family of proteinsrdquo FEBS Journalvol 277 no 19 pp 3924ndash3936 2010
[177] Y Dai and C C Wang ldquoA mutant truncated protein disulfideisomerase with no chaperone activityrdquo Journal of BiologicalChemistry vol 272 no 44 pp 27572ndash27576 1997
[178] C E Jessop R H Watkins J J Simmons M Tasab andN J Bulleid ldquoProtein disulphide isomerase family membersshow distinct substrate specificity P5 is targeted to BiP clientproteinsrdquo Journal of Cell Science vol 122 no 23 pp 4287ndash42952009
[179] C Appenzeller-Herzog J Riemer E Zito et al ldquoDisulphideproduction by Ero1120572-PDI relay is rapid and effectively regu-latedrdquo EMBO Journal vol 29 no 19 pp 3318ndash3329 2010
[180] F Hatahet and L W Ruddock ldquoProtein disulfide isomerase acritical evaluation of its function in disulfide bond formationrdquoAntioxidants and Redox Signaling vol 11 no 11 pp 2807ndash28502009
[181] N J Bulleid and L Ellgaard ldquoMultiple ways to make disulfidesrdquoTrends in Biochemical Sciences 2011
[182] S Chakravarthi C E Jessop and N J Bulleid ldquoThe role ofglutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stressrdquo EMBOReports vol 7 no3 pp 271ndash275 2006
[183] J Lundstrom and A Holmgren ldquoDetermination of thereduction-oxidation potential of the thioredoxin-like domainsof protein disulfide-isomerase from the equilibrium with glu-tathione and thioredoxinrdquo Biochemistry vol 32 no 26 pp6649ndash6655 1993
[184] E Gross C S Sevier N Heldman et al ldquoGenerating disulfidesenzymatically reaction products and electron acceptors of theendoplasmic reticulum thiol oxidase Ero1prdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 2 pp 299ndash304 2006
[185] P I Merksamer A Trusina and F R Papa ldquoReal-time redoxmeasurements during endoplasmic reticulum stress reveal
interlinked protein folding functionsrdquo Cell vol 135 no 5 pp933ndash947 2008
[186] J W Cuozzo and C A Kaiser ldquoCompetition between glu-tathione and protein thiols for disulphide-bond formationrdquoNature Cell Biology vol 1 no 3 pp 130ndash135 1999
[187] L A Rutkevich M F Cohen-Doyle U Brockmeier and DB Williams ldquoFunctional relationship between protein disulfideisomerase family members during the oxidative folding ofhuman secretory proteinsrdquoMolecular Biology of the Cell vol 21no 18 pp 3093ndash3105 2010
[188] Y Honjo S Kaneko H Ito et al ldquoProtein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateralsclerosisrdquo Amyotrophic Lateral Sclerosis vol 12 no 6 pp 444ndash450 2011
[189] H Tsuda S M Han Y Yang et al ldquoThe amyotrophic lateralsclerosis 8 proteinVAPB is cleaved secreted and acts as a ligandfor Eph receptorsrdquo Cell vol 133 no 6 pp 963ndash977 2008
[190] D M Townsend Y Manevich H Lin et al ldquoNitrosative stress-induced S-glutathionylation of protein disulfide isomerase leadsto activation of the unfolded protein responserdquoCancer Researchvol 69 no 19 pp 7626ndash7634 2009
[191] T Uehara T Nakamura D Yao et al ldquoS-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegen-erationrdquo Nature vol 441 no 7092 pp 513ndash517 2006
[192] X Chen C Li T Guan et al ldquoS-nitrosylated protein disul-phide isomerase contributes to mutant SOD1 aggregates inamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol124 no 1 pp 45ndash58 2012
[193] J D Rothstein ldquoTherapeutic horizons for amyotrophic lateralsclerosisrdquo Current Opinion in Neurobiology vol 6 no 5 pp679ndash687 1996
[194] D W Cleveland ldquoNeuronal growth and death order anddisorder in the axoplasmrdquoCell vol 84 no 5 pp 663ndash666 1996
to the accumulation of toxic ceramides and cholesterol esterswhich may ultimately result in motor neuron death [68]
35 Mitochondrial Dysfunction Mitochondria are impor-tant players in redox regulation and oxidative stress hasthe potential to cause mitochondrial dysfunction [70 121]Indeed damaged mitochondria are observed in the spinalcord cells of SALS patients [122ndash124] The mitochondrialgenome is particularly susceptible to oxidative damage [125]hence any increase in cellular ROS would potentially per-turb mitochondrial functions Mitochondria participate inneuronal apoptotic signalling pathways through the releaseof mitochondrial proteins including cytochrome c into thecytoplasm [126] There is substantial evidence that molecularcomponents of mitochondrial apoptosis play a role in neu-rodegeneration in both SOD1 rodents and in mutant SOD1overexpressed in cell culture [127] The enzymatic activityof cytochrome c oxidase (COX) in mitochondria is alsoreduced in the spinal cord cells of SALS patients [122ndash124128 129] Mitochondria have been well studied in relation toALS pathogenesis Degenerating or abnormal mitochondriahave been described in mouse models [62 130] culturedneuronal cellular models [131 132] and ALS patients [133134] although how nonfunctioning mitochondria relate toALS is unclear Possible explanations include inhibition ofaxonal transport dysregulation of calcium buffering [135] oractivation of mitochondrial-dependent apoptosis [128 136]Recent studies have shown that overexpression of TDP-43causes mitochondrial dysfunction and induces mitophagy incell culture [137]The presence of ROS and impairment of themitochondrial respiratory chain have also been observed inTDP-43 models [138 139]
Mutant SOD1 has also been implicated in mitochondrialrespiratory complex impairment [140] and a shift in the redoxstate of mitochondria towards oxidation [141] How SOD1functions in the mitochondria is still not clear althoughsome data suggests that SOD1 is crucial for maintenanceof the mitochondrial redox state [142 143] and that ALSmutations affect the localisation or function of SOD1 inmitochondria [135] However mutant misfolded SOD1 hasbeen found localised with various compartments of themitochondria [144] Significantly any pathological changesin regulation of the electron transport chain would result inmore oxidative stress [145] triggering further cellular redoxdysregulation leading to a potential vicious cycle of damageand degeneration
36 Impaired Axonal Transport Axonal transport is a keymechanism required for cellular viability in neuronal cellsMost proteins required in the axon and in synaptic terminalsmust be transported along the axon after synthesis in the cellbody Similarly RNA and organelles also need to be trans-ported over long distances and these transport processesrequire molecular motors such as kinesins dyneins andmyosins that operate along the cellular cytoskeleton Dys-function of axonal transport has now been well documentedin ALS [61] Whilst many of these studies implicate dyneinin this process [146] several also highlight the importance
of kinesin in ALS particularly kinesin heavy chains KIF5Aand KIF1B120573 which transport mitochondria synaptic vesi-cles and macromolecular complexes Interestingly a recentstudy demonstrated that oxidised wild-type SOD1 immuno-purified from SALS patient tissues inhibited kinesin-basedaxonal transport in amanner similar tomutant SOD1 in FALSproviding evidence for common pathogenic mechanisms inboth SALS and FALS [94]
Neurofilaments (NF) accumulation in motor neuronsis another histopathological hallmark of ALS [147 148]Also transgenic mice that overexpress NF subunits in motorneurons develop a motor neuron disease with impairedaxonal flow as axonal defects cause delay in transportationof components required for the maintenance of axon [149]However ONOOminus formed during oxidative stress fromnitrooxide and superoxide can affect NF assembly and causeNF accumulation in motor neurons [8] Chou and coworkersshowed NF aggregations are associated with SOD1 and nitricoxide synthase activities leading to nitrotyrosine formationon NF [150] Nitrotyrosine can inhibit phosphorylation ofheavy or light NF subunits and may alter axonal transportand trigger motor neuron death [150] Taken together thesefindings suggest a relation between redox regulation andaxonal transport dysfunctions in ALS
37 Autophagy Autophagy is a normal homeostatic mecha-nism to dispose large protein aggregates damaged organellesand long-lived proteins Autophagic stress results when thenumber of autophagosomes increases relative to the pro-portion of degradable proteins The presence of high levelsof superoxide and hydrogen peroxide species can induceautophagy in vitro [151] but consequently autophagy canfurther induce oxidative or nitrative stress thus creating avicious cycle [152] Dysregulated redox activity also influ-ences autophagy Cathepsin a class of proteases which havehighly regulated thiol groups [152] and other key regulatoryautophagic complexes such as Beclin 1 and Rubicon alsohave the presence of cysteine residues [152] The presence ofcysteine residues suggests that they are redox regulated andlikely to be affected by ROS ATG 4 another protease is atarget of oxidation by hydrogen peroxide However directassociation of these with ALS has not yet been identifiedAltered autophagic levels have been observed in SOD1G93Amice and sporadic and familial patients but whether theincreased levels are protective or not is still questionable [153ndash156]
38 ER Stress and Protein Disulphide Isomerase (PDI) in ALSThe ER is redox regulated and another important locationfor the production of ROS It plays key roles in protein andlipid synthesis and protein folding Proteinmisfolding withinthe ER triggers ER stress which induces the unfolded proteinresponse (UPR) a distinct signalling pathway which aims torelieve stress [157] While initially protective prolonged UPRcauses apoptosis [158 159] Recent studies suggest that ERstress is an early and important pathogenic mechanism inALS [66 158 160] ER stress is induced in animal modelsof SOD1 in cells expressing mutant FUS and in patients
Oxidative Medicine and Cellular Longevity 5
CGHC CGHC KDEL
119886 119887 119888119909119887998400
119886998400
Figure 1 Schematic diagram showing domain structure of PDIThioredoxin-like 119886 domain (orange) and 1198861015840 domain (purple) pos-sessing the catalyticmotif catalytically inactive 119887 domain (blue) and1198871015840 domain (red) Green represents the linker region 119909 which allowsflexibility between domainsTheC terminal domain is shown in greyfollowed by the ER retrieval signal KDEL
[20 161] Oxidative stress driven by changes in fatty acidcomposition mitochondrial function andor proteosomeactivity leads to oxidative stress and contributes to ER stressin SALS patients [162 163] PDI is an ER chaperone whichis induced during UPR and has been implicated in severalneurodegenerative disorders including ALS [164ndash166]
PDI is a member of an extended family of foldasesand chaperones which are responsible for the formationand isomerisation of protein disulphide bonds [167] ThePDI family comprises 21 members which have structuralsimilarities but different functions [168] and all have asimilar active site to thioredoxin [169] Thioredoxin is anintracellular protein which regulates redox conditions andwhich is effective against oxidative stress [170] PDI is mostabundant in the ER but it is also found in other subcellularlocations such as the nucleus and extracellular matrix [171]and it constitutes 08 of the total cellular protein [172]The yeast PDI crystal structure was recently solved [173]which suggests that 119886 and 1198861015840 domains are responsible forthe formation of disulphide bonds (Figure 1) These domainscontain a redox active CGHCmotif which isomerases proteindisulphide bonds and is involved in redox regulation [173]PDI also contains 119887 and 1198871015840 domains which are responsiblefor substrate binding [174 175] Misfolded proteins attach tothe hydrophobic region of an inverted U shape structure [173176] The C-terminal region also aids in polypeptide bindingand contributes chaperone activity [177] Compared to otherfamilymembers PDI has broad substrate specificities and caninteract with glycosylated as well as nonglycosylated proteins[178]
4 PDI and Redox Regulation
PDI forms protein disulphide bonds by the oxidation ofthiols within the PDI active site cysteine residues [179 180]When PDI is in an oxidised state it transfers a disulphide tothe substrates thereby oxidising the substrate and becomingreduced itself Conversely substrates which need disulphidebond rearrangement are reduced by PDI in the reduced statethus oxidising PDI in the process [168 181] This continualcycling regulates redox conditions within the ER A thiolcontaining tripeptide protein and glutathione also maintainsER redox homeostasis by similar shuffling between oxidizedand reduced cysteine residues Glutathione is also requiredfor the isomerisation and rearrangement of disulphide bonds[182] The redox potential of PDI (minus110mV) is lower than
other family members [183] due to intervening residuespresent between the reactive cysteines thus facilitating disul-phide bonds [183] ERO1 oxidises PDI also aiding disulphidebond formations [184] but PDI is also oxidised throughperoxiredoxin 4 vitamin K glutathione peroxidase andquiescin sulfhydryl oxidase [181] During ER stress highlevels of ERO1 have been observed which accelerates proteinoxidation suggesting interplay between oxidative stress andER stress The transfer of electrons from the thiol groupof PDI to ERO1 results in the production of excess ROSdecreasing the levels of glutathione available for reductionand increasing ERO1 thus altering the redox conditions [185186] Hence imbalance in the redox state of the ERmay resultin dysregulation of thiol containing proteins and triggers
41 The Role of PDI in ALS Due to its function in preventingprotein misfolding PDI is important in protein quality con-trol [166] also deletion of PDI is embryonically lethal [187]Hence regulated expression of PDI is critical for normalcellular functionThere is now growing evidence for a role ofPDI in ALS PDI levels are upregulated in transgenic modelsof ALS and spinal cord tissues of ALS patients [66 158]Overexpression of PDI is also protective againstmutant SOD1mediated aggregation and reduces cell death in vitro [20] PDIcoimmunoprecipitates with both SOD1 and FUS [158 161] italso colocalises with SOD1 TDP-43 and FUS in ALS patientssuggesting a physical interaction exists between PDI andother key misfolded proteins in ALS [66 161 188] SimilarlyPDI also colocalises with TDP-43 in ALS tissues and withVAPB inclusions in a Drosophila melanogaster model ofALS [188 189] A small mimic of the active site of PDIdithiol (plusmn)-trans-12-bis (mercaptoacetamido) cyclohexane(BMC) is also protective in cell culture and it reduces mutantSOD1 aggregation in a dose dependent manner [20] Furtherevidences for a role for disulphide interchange activity in ALScomes from studies showing that another PDI familymemberERp57 is also upregulated in transgenic SOD1 mice and ALSpatients [66] Furthermore thioredoxin is also upregulated inthe erythrocytes of FALS patients [19]
The upregulation of these thiol containing proteins inALS suggests a cellular defensive mechanism is triggeredin disease as a defence against oxidative stress Howeverthere is evidence that normal protective function of PDI isinhibited in disease [20] Modifications of active site thiolgroups through direct oxidation S-glutathiolation and S-nitrosylation can lead to inactivation of the normal enzy-matic activity of PDI [13 190 191] PDI was recently shownto be S-nitrosylated in ALS [20 192] as in other neurodegen-erative disorders such as Parkinsonrsquos and Alzheimerrsquos disease[191] S-nitrosylation occurs when there is an increased pro-duction of RNS during oxidative stress resulting in additionof a nitrogen monoxide group to the thiol side of PDI[20 164] Experiments performed by Chen and coworkerssuggested that in the presence of S-nitrosylated PDI theformation of mutant SOD1 aggregates increases in vitro [192]It is also likely that inactivation of PDI could lead to activationof the UPR as observed in other neurodegenerative disorders[191] The loss of PDI functional activity can directly lead to
6 Oxidative Medicine and Cellular Longevity
Impaired axonaltransport
AutophagyMitochondrialdysfunction
ER stress Proteinmisfolding
Redox dysregulation
PDI dysfunction Oxidative stress
Figure 2 Redox dysfunction and its relationship to other patholo-gies in ALS Alteration in the enzymatic activity of PDI due toredox dysregulation and oxidative stress can further increase theload of misfolded proteins ER stress oxidative stress autophagymitochondrial dysfunction and axonal impairment leading toneuronal cell death
apoptosis or indirectly to a range of cellular abnormalitiessuch as oxidative stress and protein misfolding which againlead to cell death [164 166] Hence the redox regulationof PDI is a crucial component in the maintenance of abalanced redox environment and inhibition of its enzymaticactivity will lead to important consequences for the cell(Figure 2)
Neurons are highly susceptible to redox dysregulationdue to their high metabolic requirements large size andlower ability to maintain the balance between antioxidantsand ROS [15] In disease states such as ALS oxidativestress and altered enzymatic activity of PDI which normallyreduces ROS and the burden of misfolded protein can causeserious damage to the neuron Since multiple mechanismsare involved in neurodegeneration any imbalance in redoxregulation can lead to an imbalance in the production offree radical species which consequently cause mitochondrialdamage and excitotoxicity thus elevating the levels of freeradicals [193] Furthermore an excess of free radicals canalso lead to DNA damage and may also result in aggregationof NF [194] and structural destabilization of other proteinsthus inducing ER stress and apoptosis Since ALS is a slowprogressive disorder it could be hypothesised that these cyclicevents due to loss of functional activity of PDImay graduallylead to neuronal degradation In such a scenario the redoxregulatory function of PDI may therefore have an importantprotective effect
5 Conclusion
Redox regulation is an important mechanism of homeostasisin eukaryotic cells especially neuronal cells where oxygen
levels are high [15] Many cellular processes rely on it includ-ing proper functioning of the mitochondria and ER calciumregulation axonal transport regulated autophagy and pro-tein folding Links between redox dysregulation and ALSare becoming well documented in the literature althoughthe directionality of these links and their underlying causeare still quite unknown One possible key player in redox reg-ulation in ALS is PDI whose role in ALS pathogenesis is thetopic of much new research As the critical protein involvedin thiol reduction any dysregulation of PDI activity can leadto oxidative stress and redox dysregulation Due to its activityPDI itself also contains an active site thiol group suggestingthat it can also be affected by oxidative stress leading to anescalating cycle that perpetuates redox dysregulation HowPDI becomes nonfunctional in the first place is still unclearalthough somepapers point to S-nitrosylation as having a role[20] Regardless of its exact role any mechanism to improvethe catalytic activity of PDI should have a reductive effect onoxidative stress levels in neurons It is therefore tempting tospeculate about PDI as a possible therapeutic target in thetreatment of ALS
Acknowledgments
This work was supported by the National Health and Med-ical Research Council of Australia (project Grants 4547491006141 and 1030513) Amyotrophic Lateral Sclerosis Asso-ciation (USA) MND Research Institute of Australia Beth-lehem Griffiths Research Council Henry H Roth CharitableFoundation Grant for MND Research Australian RotaryHealth and the Brain Foundation S Parakh holds a La TrobeUniversity Post Graduate Research Scholarship
References
[1] H Kamata and H Hirata ldquoRedox regulation of cellular sig-nallingrdquo Cellular Signalling vol 11 no 1 pp 1ndash14 1999
[2] A R Cross and O T G Jones ldquoEnzymic mechanisms ofsuperoxide productionrdquoBiochimica et BiophysicaActa vol 1057no 3 pp 281ndash298 1991
[3] VAdler Z YinKD Tew andZRonai ldquoRole of redox potentialand reactive oxygen species in stress signalingrdquo Oncogene vol18 no 45 pp 6104ndash6111 1999
[4] J Nordberg and E S J Arner ldquoReactive oxygen speciesantioxidants and the mammalian thioredoxin systemrdquo FreeRadical Biology andMedicine vol 31 no 11 pp 1287ndash1312 2001
[5] M G Espey K M Miranda D D Thomas et al ldquoA chemicalperspective on the interplay between NO reactive oxygenspecies and Reactive Nitrogen Oxide Speciesrdquo Annals of theNew York Academy of Sciences vol 962 pp 195ndash206 2002
[6] W A Pryor and G L Squadrito ldquoThe chemistry of per-oxynitrite a product from the reaction of nitric oxide withsuperoxiderdquo American Journal of Physiology-Lung Cellular andMolecular Physiology vol 268 no 5 pp L699ndashL722 1995
[7] K Abe L H Pan M Watanabe H Konno T Kato andY Itoyama ldquoUpregulation of protein-tyrosine nitration in theanterior horn cells of amyotrophic lateral sclerosisrdquo Neurologi-cal Research vol 19 no 2 pp 124ndash128 1997
Oxidative Medicine and Cellular Longevity 7
[8] J S Beckman M Carson C D Smith and W H KoppenolldquoALS SOD and peroxynitriterdquoNature vol 364 no 6438 p 5841993
[9] S C Barber and P J Shaw ldquoOxidative stress in ALS key rolein motor neuron injury and therapeutic targetrdquo Free RadicalBiology and Medicine vol 48 no 5 pp 629ndash641 2010
[10] M C Martınez and R Andriantsitohaina ldquoReactive nitrogenspecies molecular mechanisms and potential significance inhealth and diseaserdquo Antioxidants and Redox Signaling vol 11no 3 pp 669ndash702 2009
[11] D Trachootham W Lu M A Ogasawara N R D Valle andP Huang ldquoRedox regulation of cell survivalrdquo Antioxidants andRedox Signaling vol 10 no 8 pp 1343ndash1374 2008
[12] C E Cooper R P Patel P S Brookes and VM Darley-UsmarldquoNanotransducers in cellular redox signaling modification ofthiols by reactive oxygen and nitrogen speciesrdquo Trends inBiochemical Sciences vol 27 no 10 pp 489ndash492 2002
[13] H Nakamura K Nakamura and J Yodoi ldquoRedox regulation ofcellular activationrdquo Annual Review of Immunology vol 15 pp351ndash369 1997
[14] S A Lipton Y B Choi Z H Pan et al ldquoA redox-based mech-anism for the neuroprotective and neurodestructive effects ofnitric oxide and related nitroso-compoundsrdquo Nature vol 364no 6438 pp 626ndash632 1993
[15] B Halliwell ldquoOxidative stress and neurodegeneration whereare we nowrdquo Journal of Neurochemistry vol 97 no 6 pp 1634ndash1658 2006
[16] R P Guttmann and T J Powell ldquoRedox regulation of cysteine-dependent enzymes in neurodegenerationrdquo International Jour-nal of Cell Biology vol 2012 Article ID 703164 8 pages 2012
[17] H Tohgi T Abe K Yamazaki T Murata E Ishizaki and CIsobe ldquoIncrease in oxidized NO products and reduction inoxidized glutathione in cerebrospinal fluid from patients withsporadic form of amyotrophic lateral sclerosisrdquo NeuroscienceLetters vol 260 no 3 pp 204ndash206 1999
[18] D R Rosen T Siddique D Patterson et al ldquoMutations inCuZn superoxide dismutase gene are associated with familialamyotrophic lateral sclerosisrdquoNature vol 362 no 6415 pp 59ndash62 1993
[19] Y Ogawa H Kosaka T Nakanishi et al ldquoStability of mutantsuperoxide dismutase-1 associated with familial amyotrophiclateral sclerosis determines the manner of copper release andinduction of thioredoxin in erythrocytesrdquo Biochemical andBiophysical Research Communications vol 241 no 2 pp 251ndash257 1997
[20] A KWalker M A Farg C R Bye C AMcLeanM K Horneand J D Atkin ldquoProtein disulphide isomerase protects againstprotein aggregation and is S-nitrosylated in amyotrophic lateralsclerosisrdquo Brain vol 133 no 1 pp 105ndash116 2010
[21] M W Akhtar C R Sunico T Nakamura and S A Lip-ton ldquoRedox regulation of protein function via cysteine S-nitrosylation and its relevance to neurodegenerative diseasesrdquoInternational Journal of Cell Biology vol 2012 Article ID463756 9 pages 2012
[22] J D Rothstein ldquoCurrent hypotheses for the underlying biologyof amyotrophic lateral sclerosisrdquo Annals of Neurology vol 65no 1 pp S3ndashS9 2009
[23] J Mitchell and G Borasio ldquoAmyotrophic lateral sclerosisrdquoLancet vol 369 no 9578 pp 2031ndash2041 2007
[24] L CWijesekera and PN Leigh ldquoAmyotrophic lateral sclerosisrdquoOrphanet Journal of Rare Diseases vol 4 no 1 p 3 2009
[25] G Bensimon L Lacomblez and V Meininger ldquoA controlledtrial of riluzole in amyotrophic lateral sclerosisrdquo New EnglandJournal of Medicine vol 330 no 9 pp 585ndash591 1994
[26] R G Miller J D Mitchell M Lyon and D HMoore ldquoRiluzolefor amyotrophic lateral sclerosis (ALS)motor neuron disease(MND)rdquoCochraneDatabase of Systematic Reviews no 1 ArticleID CD001447 2007
[27] A Alonso G Logroscino S S Jick and M A HernanldquoAssociation of smoking with amyotrophic lateral sclerosis riskand survival in men and women a prospective studyrdquo BMCNeurology vol 10 no 1 p 6 2010
[28] A Verma and J R Berger ldquoALS syndrome in patients withHIV-1 infectionrdquo Journal of the Neurological Sciences vol 240 no 1-2pp 59ndash64 2006
[29] A Chio B J Traynor F Lombardo et al ldquoPrevalence of SOD1mutations in the Italian ALS populationrdquoNeurology vol 70 no7 pp 533ndash537 2008
[30] L Corrado R Del Bo B Castellotti et al ldquoMutations ofFUS gene in sporadic amyotrophic lateral sclerosisrdquo Journal ofMedical Genetics vol 47 no 3 pp 190ndash194 2010
[31] J Sreedharan I P Blair V B Tripathi et al ldquoTDP-43mutationsin familial and sporadic amyotrophic lateral sclerosisrdquo Sciencevol 319 no 5870 pp 1668ndash1672 2008
[32] E Pupillo P Messina G Logroscino et al ldquoTrauma andamyotrophic lateral sclerosis a case-control study from apopulation-based registryrdquo European Journal of Neurology vol19 no 12 pp 1509ndash1517 2012
[33] S Beretta M T Carrı E Beghi A Chio and C Ferrarese ldquoThesinister side of Italian soccerrdquo Lancet Neurology vol 2 no 11pp 656ndash657 2003
[34] M R Turner C Wotton K Talbot and M J GoldacreldquoCardiovascular fitness as a risk factor for amyotrophic lateralsclerosis indirect evidence from record linkage studyrdquo Journalof Neurology Neurosurgery amp Psychiatry vol 83 pp 395ndash3982012
[35] P A Dion H Daoud and G A Rouleau ldquoGenetics of motorneuron disorders new insights into pathogenic mechanismsrdquoNature Reviews Genetics vol 10 no 11 pp 769ndash782 2009
[36] T Arai M Hasegawa H Akiyama et al ldquoTDP-43 is a compo-nent of ubiquitin-positive tau-negative inclusions in frontotem-poral lobar degeneration and amyotrophic lateral sclerosisrdquoBiochemical and Biophysical Research Communications vol 351no 3 pp 602ndash611 2006
[37] M Neumann D M Sampathu L K Kwong et al ldquoUbiq-uitinated TDP-43 in frontotemporal lobar degeneration andamyotrophic lateral sclerosisrdquo Science vol 314 no 5796 pp130ndash133 2006
[38] C Vance B Rogelj T Hortobagyi et al ldquoMutations in FUSan RNA processing protein cause familial amyotrophic lateralsclerosis type 6rdquo Science vol 323 no 5918 pp 1208ndash1211 2009
[39] Y Yang A Hentati H X Deng et al ldquoThe gene encodingalsin a protein with three guanine-nucleotide exchange factordomains is mutated in a form of recessive amyotrophic lateralsclerosisrdquo Nature Genetics vol 29 pp 160ndash165 2001
[40] A L Nishimura M Mitne-Neto H C A Silva et al ldquoAmutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclero-sisrdquoAmerican Journal of HumanGenetics vol 75 no 5 pp 822ndash831 2004
8 Oxidative Medicine and Cellular Longevity
[41] T J Kwiatkowski Jr D A Bosco A L LeClerc et al ldquoMutationsin the FUSTLS gene on chromosome 16 cause familial amy-otrophic lateral sclerosisrdquo Science vol 323 no 5918 pp 1205ndash1208 2009
[42] HMaruyamaHMorinoH Ito et al ldquoMutations of optineurinin amyotrophic lateral sclerosisrdquo Nature vol 465 no 7295 pp223ndash226 2010
[43] H X Deng W Chen S T Hong et al ldquoMutations in UBQLN2cause dominant X-linked juvenile and adult-onset ALS andALSdementiardquo Nature vol 477 pp 211ndash215 2011
[44] M DeJesus-Hernandez I R Mackenzie B F Boeve et alldquoExpanded GGGGCC hexanucleotide repeat in noncodingregion of C9ORF72 causes chromosome 9p-linked FTD andALSrdquo Neuron vol 72 no 2 pp 245ndash256 2011
[45] L I Bruijn T M Miller and D W Cleveland ldquoUnraveling themechanisms involved in motor neuron degeneration in ALSrdquoAnnual Review of Neuroscience vol 27 pp 723ndash749 2004
[46] H D Durham J Roy L Dong and D A Figlewicz ldquoAggrega-tion of mutant CuZn superoxide dismutase proteins in a cul-turemodel ofALSrdquo Journal ofNeuropathology andExperimentalNeurology vol 56 no 5 pp 523ndash530 1997
[47] M Watanabe M Dykes-Hoberg V Cizewski Culotta D LPrice P C Wong and J D Rothstein ldquoHistological evidenceof protein aggregation in mutant SOD1 transgenic mice andin amyotrophic lateral sclerosis neural tissuesrdquo Neurobiology ofDisease vol 8 no 6 pp 933ndash941 2001
[48] C Soto ldquoUnfolding the role of protein misfolding in neurode-generative diseasesrdquo Nature Reviews Neuroscience vol 4 no 1pp 49ndash60 2003
[49] J Wang G Xu and D R Borchelt ldquoMapping superoxidedismutase 1 domains of non-native interaction roles of intra-and intermolecular disulfide bonding in aggregationrdquo Journalof Neurochemistry vol 96 no 5 pp 1277ndash1288 2006
[50] B S Johnson D Snead J J Lee J M McCaffery J Shorterand A D Gitler ldquoTDP-43 is intrinsically aggregation-proneand amyotrophic lateral sclerosis-linked mutations accelerateaggregation and increase toxicityrdquo Journal of Biological Chem-istry vol 284 pp 20329ndash20339 2009
[51] C Vance B Rogelj T Hortobagyi et al ldquoMutations in FUSan RNA processing protein cause familial amyotrophic lateralsclerosis type 6rdquo Science vol 323 no 5918 pp 1208ndash1211 2009
[52] T Arai M Hasegawa H Akiyama et al ldquoTDP-43 is a compo-nent of ubiquitin-positive tau-negative inclusions in frontotem-poral lobar degeneration and amyotrophic lateral sclerosisrdquoBiochemical and Biophysical Research Communications vol 351no 3 pp 602ndash611 2006
[53] N Shibata A Hirano M Kobayashi et al ldquoIntense super-oxide dismutase-1 immunoreactivity in intracytoplasmic hya-line inclusions of familial amyotrophic lateral sclerosis withposterior column involvementrdquo Journal of Neuropathology andExperimental Neurology vol 55 no 4 pp 481ndash490 1996
[54] J S Valentine P A Doucette and S Z Potter ldquoCopper-zinc superoxide dismutase and amyotrophic lateral sclerosisrdquoAnnual Review of Biochemistry vol 74 pp 563ndash593 2005
[55] F Arnesano L Banci I BertiniMMartinelli Y Furukawa andT V OrsquoHalloran ldquoThe unusually stable quaternary structureof human CuZn-superoxide dismutase 1 is controlled by bothmetal occupancy and disulfide statusrdquo Journal of BiologicalChemistry vol 279 no 46 pp 47998ndash48003 2004
[56] C Kayatekin J A Zitzewitz and C R Matthews ldquoDisulfide-Reduced ALS Variants of Cu Zn Superoxide Dismutase Exhibit
Increased Populations of Unfolded Speciesrdquo Journal of Molecu-lar Biology vol 398 no 2 pp 320ndash331 2010
[57] A E Svensson O Bilsel C Kayatekin J A Adefusika J AZitzewitz and C Robert Matthews ldquoMetal-free ALS variantsof dimeric human CuZn-superoxide dismutase have enhancedpopulations of monomeric speciesrdquo PLoS ONE vol 5 no 4Article ID e10064 2010
[58] M Cozzolino M G Pesaresi V Gerbino J Grosskreutzand M T Carr ldquoAmyotrophic lateral sclerosis new insightsinto underlying molecular mechanisms and opportunities fortherapeutic interventionrdquo Antioxidants amp Redox Signaling vol17 no 9 pp 1277ndash1330 2012
[59] O Spreux-Varoquaux G Bensimon L Lacomblez et al ldquoGlu-tamate levels in cerebrospinal fluid in amyotrophic lateralsclerosis a reappraisal using a new HPLC method with coulo-metric detection in a large cohort of patientsrdquo Journal of theNeurological Sciences vol 193 no 2 pp 73ndash78 2002
[60] I Puls C Jonnakuty B H LaMonte et al ldquoMutant dynactin inmotor neuron diseaserdquo Nature Genetics vol 33 no 4 pp 455ndash456 2003
[61] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[62] J Kong and Z Xu ldquoMassive mitochondrial degeneration inmotor neurons triggers the onset of amyotrophic lateral sclero-sis in mice expressing a mutant SOD1rdquo Journal of Neurosciencevol 18 no 9 pp 3241ndash3250 1998
[63] F R Wiedemann K Winkler A V Kuznetsov et al ldquoImpair-ment of mitochondrial function in skeletal muscle of patientswith amyotrophic lateral sclerosisrdquo Journal of the NeurologicalSciences vol 156 no 1 pp 65ndash72 1998
[64] AHiranoHDonnenfeld S Sasaki and I Nakano ldquoFine struc-tural observations of neurofilamentous changes in amyotrophiclateral sclerosisrdquo Journal of Neuropathology and ExperimentalNeurology vol 43 no 5 pp 461ndash470 1984
[65] J D Wood T P Beaujeux and P J Shaw ldquoProtein aggregationin motor neurone disordersrdquo Neuropathology and AppliedNeurobiology vol 29 no 6 pp 529ndash545 2003
[66] J D Atkin M A Farg A KWalker C McLean D Tomas andM K Horne ldquoEndoplasmic reticulum stress and induction ofthe unfolded protein response in human sporadic amyotrophiclateral sclerosisrdquoNeurobiology of Disease vol 30 no 3 pp 400ndash407 2008
[67] S Chen X Zhang L Song and W Le ldquoAutophagy dysregula-tion in amyotrophic lateral sclerosisrdquo Brain Pathology vol 22no 1 pp 110ndash116 2012
[68] R G Cutler W A Pedersen S Camandola J D Rothsteinand M P Mattson ldquoEvidence that accumulation of ceramidesand cholesterol esters mediates oxidative stress-induced deathof motor neurons in amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 52 no 4 pp 448ndash457 2002
[69] R J Ferrante S E Browne L A Shinobu et al ldquoEvidenceof increased oxidative damage in both sporadic and familialamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol69 no 5 pp 2064ndash2074 1997
[70] M Bogdanov R H Brown W Matson et al ldquoIncreasedoxidative damage to DNA in ALS patientsrdquo Free Radical Biologyand Medicine vol 29 no 7 pp 652ndash658 2000
[71] A W Girotti ldquoLipid hydroperoxide generation turnover andeffector action in biological systemsrdquo Journal of Lipid Researchvol 39 no 8 pp 1529ndash1542 1998
Oxidative Medicine and Cellular Longevity 9
[72] P J Shaw P G Ince G Falkous and D Mantle ldquoOxidativedamage to protein in sporadic motor neuron disease spinalcordrdquo Annals of Neurology vol 38 no 4 pp 691ndash695 1995
[73] D Liu J Wen J Liu and L Li ldquoThe roles of free radicalsin amyotrophic lateral sclerosis reactive oxygen species andelevated oxidation of protein DNA and membrane phospho-lipidsrdquo FASEB Journal vol 13 no 15 pp 2318ndash2328 1999
[74] B J Carter P Anklesaria S Choi and J F Engelhardt ldquoRedoxmodifier genes and pathways in amyotrophic lateral sclerosisrdquoAntioxidants and Redox Signaling vol 11 no 7 pp 1569ndash15862009
[75] H F Poon K Hensley V Thongboonkerd et al ldquoRedoxproteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice-a model of familial amyotrophic lateralsclerosisrdquo Free Radical Biology and Medicine vol 39 no 4 pp453ndash462 2005
[76] J J Haddad ldquoAntioxidant and prooxidant mechanisms in theregulation of redox(y)-sensitive transcription factorsrdquo CellularSignalling vol 14 no 11 pp 879ndash897 2002
[77] K T Turpaev ldquoReactive oxygen species and regulation of geneexpressionrdquo Biochemistry vol 67 no 3 pp 281ndash292 2002
[78] C Iaccarino M E Mura S Esposito et al ldquoBcl2-A1 interactswith pro-caspase-3 implications for amyotrophic lateral scle-rosisrdquo Neurobiology of Disease vol 43 no 3 pp 642ndash650 2011
[79] C Moreau P Gosset J Kluza et al ldquoDeregulation of thehypoxia inducible factor-1120572 pathway in monocytes from spo-radic amyotrophic lateral sclerosis patientsrdquo Neuroscience vol172 pp 110ndash117 2011
[80] C M Karch M Prudencio D D Winkler P J Hart andD R Borchelt ldquoRole of mutant SOD1 disulfide oxidation andaggregation in the pathogenesis of familial ALSrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 106 no 19 pp 7774ndash7779 2009
[81] J B ProescherM Son J L Elliott andV C Culotta ldquoBiologicaleffects of CCS in the absence of SOD1 enzyme activationimplications for disease in a mouse model for ALSrdquo HumanMolecular Genetics vol 17 no 12 pp 1728ndash1737 2008
[82] J M McCord and I Fridovich ldquoSuperoxide dismutase Anenzymic function for erythrocuprein (hemocuprein)rdquo Journalof Biological Chemistry vol 244 no 22 pp 6049ndash6055 1969
[83] D Sau S De Biasi L Vitellaro-Zuccarello et al ldquoMutation ofSOD1 in ALS a gain of a loss of functionrdquo Human MolecularGenetics vol 16 no 13 pp 1604ndash1618 2007
[84] J S Beckman M Carson C D Smith and W H KoppenolldquoALS SOD and peroxynitriterdquoNature vol 364 no 6438 p 5841993
[85] N V Blough and O C Zafiriou ldquoReaction of superoxide withnitric oxide to form peroxonitrite in alkaline aqueous solutionrdquoInorganic Chemistry vol 24 no 22 pp 3502ndash3504 1985
[86] M F Beal R J Ferrante S E Browne Jr R T Matthews NW Kowall and R H Brown ldquoIncreased 3-nitrotyrosine in bothsporadic and familial amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 42 no 4 pp 644ndash654 1997
[87] H Tohgi T Abe K Yamazaki T Murata E Ishizaki andC Isobe ldquoRemarkable increase in cerebrospinal fluid 3-nitrotyrosine in patients with sporadic amyotrophic lateralsclerosisrdquo Annals of Neurology vol 46 pp 129ndash131 1999
[88] F Casoni M Basso T Massignan et al ldquoProtein nitration in amouse model of familial amyotrophic lateral sclerosis possiblemultifunctional role in the pathogenesisrdquo Journal of BiologicalChemistry vol 280 no 16 pp 16295ndash16304 2005
[89] S Guareschi E Cova C Cereda et al ldquoAn over-oxidizedform of superoxide dismutase found in sporadic amyotrophiclateral sclerosiswith bulbar onset shares a toxicmechanismwithmutant SOD1rdquo Proceedings of the National Academy of Sciencesvol 109 no 13 pp 5074ndash5079 2012
[90] RW Orrell R J M Lane andM Ross ldquoA systematic review ofantioxidant treatment for amyotrophic lateral sclerosismotorneuron diseaserdquo Amyotrophic Lateral Sclerosis vol 9 no 4 pp195ndash211 2008
[91] S A Ezzi M Urushitani and J P Julien ldquoWild-type superoxidedismutase acquires binding and toxic properties of ALS-linkedmutant forms through oxidationrdquo Journal of Neurochemistryvol 102 no 1 pp 170ndash178 2007
[92] R L Redler K C Wilcox E A Proctor L Fee M Caplowand N V Dokholyan ldquoGlutathionylation at Cys-111 inducesdissociation of wild type and FALS mutant SOD1 dimersrdquoBiochemistry vol 50 no 32 pp 7057ndash7066 2011
[93] K Forsberg P A Jonsson P M Andersen et al ldquoNovelantibodies reveal inclusions containing non-native SOD1 insporadic ALS patientsrdquo PloS One vol 5 no 7 Article ID e115522010
[94] D A Bosco G Morfini N M Karabacak et al ldquoWild-type andmutant SOD1 share an aberrant conformation and a commonpathogenic pathway in ALSrdquo Nature Neuroscience vol 13 no11 pp 1396ndash1403 2010
[95] A C Estevez J P Crow J B Sampson et al ldquoInduction of nitricoxide-dependent apoptosis in motor neurons by zinc- deficientsuperoxide dismutaserdquo Science vol 286 no 5449 pp 2498ndash2500 1999
[96] Y Furukawa R Fu H X Deng T Siddique and T VOrsquoHalloran ldquoDisulfide cross-linked protein represents a signif-icant fraction of ALS-associated Cu Zn-superoxide dismutaseaggregates in spinal cords of model micerdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 18 pp 7148ndash7153 2006
[97] T J Cohen AWHwang T Unger J Q Trojanowski and VMY Lee ldquoRedox signalling directly regulates TDP-43 via cysteineoxidation and disulphide cross-linkingrdquo The EMBO Journalvol 31 no 5 pp 1241ndash1252 2011
[98] DDormann R Rodde D Edbauer et al ldquoALS-associated fusedin sarcoma (FUS) mutations disrupt transportin-mediatednuclear importrdquo EMBO Journal vol 29 no 16 pp 2841ndash28572010
[99] S P Butcher andAHamberger ldquoIn vivo studies on the extracel-lular and veratrine-releasable pools of endogenous amino acidsin the rat striatum effects of corticostriatal deafferentiation andkainic acid lesionrdquo Journal of Neurochemistry vol 48 no 3 pp713ndash721 1987
[100] I Sen A Nalini N B Joshi and P G Joshi ldquoCerebrospinalfluid from amyotrophic lateral sclerosis patients preferentiallyelevates intracellular calcium and toxicity in motor neurons viaAMPAkainate receptorrdquo Journal of the Neurological Sciencesvol 235 no 1-2 pp 45ndash54 2005
[101] A Plaitakis and J T Caroscio ldquoAbnormal glutamatemetabolism in amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 22 no 5 pp 575ndash579 1987
[102] L Van Den Bosch and W Robberecht ldquoDifferent receptorsmediate motor neuron death induced by short and long expo-sures to excitotoxicityrdquo Brain Research Bulletin vol 53 no 4 pp383ndash388 2000
10 Oxidative Medicine and Cellular Longevity
[103] D Trotti ldquoNeuronal and glial glutamate transporters possessan SH-based redox regulatory mechanismrdquo European Journalof Neuroscience vol 9 no 6 pp 1236ndash1243 1997
[104] A Plaitakis and E Constantakakis ldquoAlteredmetabolism of exci-tatory amino acids N-acetyl-aspartate and N- acetyl-aspartyl-glutamate in amyotrophic lateral sclerosisrdquo Brain ResearchBulletin vol 30 no 3-4 pp 381ndash386 1993
[105] J D Rothstein L J Martin and R W Kuncl ldquoDecreasedglutamate transport by the brain and spinal cord in amyotrophiclateral sclerosisrdquo New England Journal of Medicine vol 326 no22 pp 1464ndash1468 1992
[106] J D Rothstein M Van Kammen A I Levey L J Martin andRW Kuncl ldquoSelective loss of glial glutamate transporter GLT-1amyotrophic lateral sclerosisrdquo Annals of Neurology vol 38 no1 pp 73ndash84 1995
[107] A Volterra D Trotti C Tromba S Floridi and G RacagnildquoGlutamate uptake inhibition by oxygen free radicals in ratcortical astrocytesrdquo Journal of Neuroscience vol 14 no 5 pp2924ndash2932 1994
[108] P J Shaw ldquoGlutamate excitotoxicity and amyotrophic lateralsclerosisrdquo Journal of Neurology vol 244 no 2 pp S3ndashS14 1997
[109] W L Miller ldquoMinireview regulation of steroidogenesis byelectron transferrdquo Endocrinology vol 146 no 6 pp 2544ndash25502005
[110] S Jin F Zhou F Katirai and P L Li ldquoLipid raft redox signalingmolecular mechanisms in health and diseaserdquoAntioxidants andRedox Signaling vol 15 no 4 pp 1043ndash1083 2011
[111] W A Pedersen W Fu J N Keller et al ldquoProtein modificationby the lipid peroxidation product 4-hydroxynonenal in thespinal cords of amyotrophic lateral sclerosis patientsrdquo Annals ofNeurology vol 44 no 5 pp 819ndash824 1998
[112] L Dupuis P Corcia A Fergani et al ldquoDyslipidemia is aprotective factor in amyotrophic lateral sclerosisrdquo Neurologyvol 70 no 13 pp 1004ndash1009 2008
[113] L Dupuis and J P Loeffler ldquoNeuromuscular junction destruc-tion during amyotrophic lateral sclerosis insights from trans-genic modelsrdquo Current Opinion in Pharmacology vol 9 no 3pp 341ndash346 2009
[114] I Choi H D Song S Lee et al ldquoDirect observation ofdefects and increased ion permeability of a membrane inducedby structurally disordered CuZn-superoxide dismutase aggre-gatesrdquo PloS One vol 6 no 12 pp e28982ndashe28982 2011
[115] C Taghibiglou J Lu I R Mackenzie Y T Wang and NR Cashman ldquoSterol regulatory element binding protein-1(SREBP1) activation in motor neurons in excitotoxicity andamyotrophic lateral sclerosis (ALS) indip a potential therapeu-tic peptiderdquo Biochemical and Biophysical Research Communica-tions vol 413 no 2 pp 159ndash163 2011
[116] E Colman A Szarfman J Wyeth et al ldquoAn evaluation of adata mining signal for amyotrophic lateral sclerosis and statinsdetected in FDArsquos spontaneous adverse event reporting systemrdquoPharmacoepidemiology and Drug Safety vol 17 no 11 pp 1068ndash1076 2008
[117] I R Edwards K Star and A Kiuru ldquoStatins neuromusculardegenerative disease and an amyotrophic lateral sclerosis-likesyndrome an analysis of individual case safety reports fromvigibaserdquo Drug Safety vol 30 no 6 pp 515ndash525 2007
[118] L Zinman R Sadeghi M Gawel D Patton and A Kiss ldquoArestatin medications safe in patients with ALSrdquo AmyotrophicLateral Sclerosis vol 9 no 4 pp 223ndash228 2008
[119] HToftSoslashrensen andT L Lash ldquoStatins and amyotrophic lateralsclerosis-the level of evidence for an associationrdquo Journal ofInternal Medicine vol 266 no 6 pp 520ndash526 2009
[120] J Zhai A L Strom R Kilty et al ldquoProteomic characterizationof lipid raft proteins in amyotrophic lateral sclerosis mousespinal cordrdquo FEBS Journal vol 276 no 12 pp 3308ndash3323 2009
[121] M F Beal ldquoAging energy and oxidative stress in neurodegen-erative diseasesrdquoAnnals of Neurology vol 38 no 3 pp 357ndash3661995
[122] F RWiedemann GManfredi CMawrinM Flint Beal and EA Schon ldquoMitochondrial DNA and respiratory chain functionin spinal cords of ALS patientsrdquo Journal of Neurochemistry vol80 no 4 pp 616ndash625 2002
[123] G M Borthwick M A Johnson P G Ince P J Shaw and DM Turnbull ldquoMitochondrial enzyme activity in amyotrophiclateral sclerosis implications for the role of mitochondria inneuronal cell deathrdquoAnnals of Neurology vol 46 no 5 pp 787ndash790 2001
[124] P M Keeney and J P Bennett ldquoALS spinal neurons show variedand reducedmtDNAgene copy numbers and increasedmtDNAgene deletionsrdquoMolecular Neurodegeneration vol 5 no 1 p 212010
[125] M B Graeber E Grasbon-Frodl U V Eitzen and S K KoselldquoNeurodegeneration and aging role of the second genomerdquoJournal of Neuroscience Research vol 52 no 1 pp 1ndash6 1998
[126] K C Zimmermann C Bonzon andD R Green ldquoThemachin-ery of programmed cell deathrdquo Pharmacology andTherapeuticsvol 92 no 1 pp 57ndash70 2001
[127] P Nagley G C Higgins J D Atkin and P M Beart ldquoMul-tifaceted deaths orchestrated by mitochondria in neuronesrdquoBiochimica et Biophysica Acta vol 1802 no 1 pp 167ndash185 2010
[128] C GueganM Vila G Rosoklija A P Hays and S PrzedborskildquoRecruitment of the mitochondria-dependent apoptotic path-way in amyotrophic lateral sclerosisrdquo Journal of Neurosciencevol 21 no 17 pp 6569ndash6576 2001
[129] L J Martin Z Liu K Chen et al ldquoMotor neuron degenerationin amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice mechanisms of mitochondriopathy and celldeathrdquo Journal of Comparative Neurology vol 500 no 1 pp 20ndash46 2007
[130] P C Wong C A Pardo D R Borchelt et al ldquoAn adverseproperty of a familial ALS-linked SOD1 mutation causes motorneuron disease characterized by vacuolar degeneration ofmito-chondriardquo Neuron vol 14 no 6 pp 1105ndash1116 1995
[131] F M Menzies M R Cookson R W Taylor et al ldquoMitochon-drial dysfunction in a cell culturemodel of familial amyotrophiclateral sclerosisrdquo Brain vol 125 no 7 pp 1522ndash1533 2002
[132] M T Carrı A Ferri A Battistoni et al ldquoExpression of aCuZn superoxide dismutase typical of familial amyotrophiclateral sclerosis induces mitochondrial alteration and increaseof cytosolic Ca2+ concentration in transfected neuroblastomaSH-SY5Y cellsrdquo FEBS Letters vol 414 no 2 pp 365ndash368 1997
[133] S Sasaki and M Iwata ldquoUltrastructural study of synapses inthe anterior horn neurons of patients with amyotrophic lateralsclerosisrdquoNeuroscience Letters vol 204 no 1-2 pp 53ndash56 1996
[134] L Siklos J Engelhardt Y Harati R G Smith F Joo andS H Appel ldquoUltrastructural evidence for altered calcium inmotor nerve terminals in amyotrophic lateral sclerosisrdquo Annalsof Neurology vol 39 no 2 pp 203ndash216 1996
[135] M Cozzolino and M T Carrı ldquoMitochondrial dysfunction inALSrdquo Progress in Neurobiology vol 97 no 2 pp 54ndash66 2012
Oxidative Medicine and Cellular Longevity 11
[136] K Y Soo J D Atkin M Farg A K Walker M K Horne andP Nagley ldquoBim links ER stress and apoptosis in cells expressingmutant SOD1 associated with amyotrophic lateral sclerosisrdquoPloS One vol 7 no 4 Article ID e35413 2012
[137] K Hong Y Li W Duan et al ldquoFull-length TDP-43 and itsC-terminal fragments activate mitophagy in NSC34 cell linerdquoNeuroscience Letters vol 530 no 2 pp 144ndash149 2012
[138] R J Braun and B Westermann ldquoMitochondrial dynamics inyeast cell death and agingrdquo Biochemical Society Transactionsvol 39 pp 1520ndash1526 2011
[139] W Duan X Li J Shi Y Guo Z Li and C Li ldquoMutant TARDNA-binding protein-43 induces oxidative injury in motorneuron-like cellrdquo Neuroscience vol 169 no 4 pp 1621ndash16292010
[140] C Jung C M J Higgins and Z Xu ldquoMitochondrial electrontransport chain complex dysfunction in a transgenic mousemodel for amyotrophic lateral sclerosisrdquo Journal of Neurochem-istry vol 83 no 3 pp 535ndash545 2002
[141] A Ferri M Cozzolino C Crosio et al ldquoFamilial ALS-superoxide dismutases associate with mitochondria and shifttheir redox potentialsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 37 pp13860ndash13865 2006
[142] K Aquilano P Vigilanza G Rotilio and M R CiriololdquoMitochondrial damage due to SOD1 deficiency in SH-SY5Yneuroblastoma cells a rationale for the redundancy of SOD1rdquoThe FASEB Journal vol 20 no 10 pp 1683ndash1685 2006
[143] E M OrsquoBrien R Dirmeier M Engle and R O PoytonldquoMitochondrial protein oxidation in yeast mutants lackingmanganese- (MnSOD) or copper- and zinc-containing super-oxide dismutase (CuZnSOD) evidence that mnsod and cuzn-sod have both unique and overlapping functions in protectingmitochondrial proteins from oxidative damagerdquo Journal ofBiological Chemistry vol 279 no 50 pp 51817ndash51827 2004
[144] S Pickles and C V Velde ldquoMisfolded SOD1 and ALS zeroingin on mitochondriardquo Amyotrophic Lateral Sclerosis vol 13 pp333ndash340 2012
[145] B Bandy and A J Davison ldquoMitochondrial mutations mayincrease oxidative stress implications for carcinogenesis andagingrdquo Free Radical Biology andMedicine vol 8 no 6 pp 523ndash539 1990
[146] F Zhang A L Strom K Fukada S Lee L J Hayward andH Zhu ldquoInteraction between familial Amyotrophic LateralSclerosis (ALS)-linked SOD1mutants and the dynein complexrdquoJournal of Biological Chemistry vol 282 no 22 pp 16691ndash166992007
[147] S Sasaki and S Maruyama ldquoUltrastructutal study of skein-like inclusions in anterior horn neurons of patients with motorneuron diseaserdquoNeuroscience Letters vol 147 no 2 pp 121ndash1241992
[148] D A Figlewicz A Krizus M G Martinoli et al ldquoVariantsof the heavy neurofilament subunit are associated with thedevelopment of amyotrophic lateral sclerosisrdquo Human Molec-ular Genetics vol 3 no 10 pp 1757ndash1761 1994
[149] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[150] S M Chou H S Wang and K Komai ldquoColocalization of NOSand SOD1 in neurofilament accumulation within motor neu-rons of amyotrophic lateral sclerosis an immunohistochemicalstudyrdquo Journal of Chemical Neuroanatomy vol 10 no 3-4 pp249ndash258 1996
[151] H Zhang X Kong J Kang et al ldquoOxidative stress inducesparallel autophagy and mitochondria dysfunction in humangliomaU251 cellsrdquoToxicological Sciences vol 110 no 2 pp 376ndash388 2009
[152] J Lee S Giordano and J Zhang ldquoAutophagymitochondria andoxidative stress cross-talk and redox signallingrdquo BiochemicalJournal vol 441 pp 523ndash540 2012
[153] A Li X Zhang and W Le ldquoAltered macroautophagy in thespinal cord of SOD1 mutant micerdquo Autophagy vol 4 no 3 pp290ndash293 2008
[154] Y Zhong Q J Wang X Li et al ldquoDistinct regulation ofautophagic activity by Atg14L and Rubicon associated withBeclin 1-phosphatidylinositol-3-kinase complexrdquo Nature CellBiology vol 11 no 4 pp 468ndash476 2009
[155] S Sasaki ldquoAutophagy in spinal cord motor neurons in sporadicamyotrophic lateral sclerosisrdquo Journal of Neuropathology andExperimental Neurology vol 70 no 5 pp 349ndash359 2011
[156] N Morimoto M Nagai Y Ohta et al ldquoIncreased autophagyin transgenic mice with a G93A mutant SOD1 generdquo BrainResearch vol 1167 no 1 pp 112ndash117 2007
[157] M Schroder ldquoEndoplasmic reticulum stress responsesrdquo Cellu-lar andMolecular Life Sciences vol 65 no 6 pp 862ndash894 2008
[158] J D Atkin M A Farg B J Turner et al ldquoInduction ofthe unfolded protein response in familial amyotrophic lateralsclerosis and association of protein-disulfide isomerase withsuperoxide dismutase 1rdquo Journal of Biological Chemistry vol281 no 40 pp 30152ndash30165 2006
[159] C M Haynes E A Titus and A A Cooper ldquoDegradation ofmisfolded proteins prevents ER-derived oxidative stress and celldeathrdquoMolecular Cell vol 15 no 5 pp 767ndash776 2004
[160] K Kanekura H Suzuki S Aiso and M Matsuoka ldquoER stressand unfolded protein response in amyotrophic lateral sclerosisrdquoMolecular Neurobiology vol 39 no 2 pp 81ndash89 2009
[161] M A Farg K Y Soo A K Walker et al ldquoMutant FUS inducesendoplasmic reticulum stress in amyotrophic lateral sclerosisand interacts with protein disulfide-isomeraserdquoNeurobiology ofAging vol 33 no 12 pp 2855ndash2868 2012
[162] E V Ilieva V Ayala M Jove et al ldquoOxidative and endoplas-mic reticulum stress interplay in sporadic amyotrophic lateralsclerosisrdquo Brain vol 130 no 12 pp 3111ndash3123 2007
[163] J D Malhotra and R J Kaufman ldquoEndoplasmic reticulumstress and oxidative stress a vicious cycle or a double-edgedswordrdquo Antioxidants and Redox Signaling vol 9 no 12 pp2277ndash2293 2007
[164] A K Walker and J D Atkin ldquoMechanisms of neuroprotectionby protein disulphide isomerase in amyotrophic lateral scle-rosisrdquo Neurology Research International vol 2011 Article ID317340 7 pages 2011
[165] R B Freedman T R Hirst andM F Tuite ldquoProtein disulphideisomerase building bridges in protein foldingrdquo Trends inBiochemical Sciences vol 19 no 8 pp 331ndash336 1994
[166] C I Andreu U Woehlbier M Torres and C Hetz ldquoProteindisulfide isomerases in neurodegeneration from disease mech-anisms to biomedical applicationsrdquo FEBS Letters vol 586 no18 pp 2826ndash2834 2012
[167] J J Galligan and D R Petersen ldquoThe human protein disulfideisomerase gene familyrdquoHuman Genomics vol 6 no 1 pp 1ndash152012
[168] L Ellgaard and L W Ruddock ldquoThe human protein disulphideisomerase family substrate interactions and functional proper-tiesrdquo EMBO Reports vol 6 no 1 pp 28ndash32 2005
12 Oxidative Medicine and Cellular Longevity
[169] B Wilkinson and H F Gilbert ldquoProtein disulfide isomeraserdquoBiochimica et Biophysica Acta vol 1699 no 1-2 pp 35ndash44 2004
[170] T Tanaka H Nakamura A Nishiyama et al ldquoRedox regulationby thioredoxin superfamily protection against oxidative stressand agingrdquo Free Radical Research vol 33 no 6 pp 851ndash8552000
[171] C Turano S Coppari F Altieri and A Ferraro ldquoProteins ofthe PDI family unpredicted non-ER locations and functionsrdquoJournal of Cellular Physiology vol 193 no 2 pp 154ndash163 2002
[172] D M Ferrari and H D Soling ldquoThe protein disulphide-isomerase family unravelling a string of foldsrdquo BiochemicalJournal vol 339 no 1 pp 1ndash10 1999
[173] G Tian S Xiang R Noiva W J Lennarz and H SchindelinldquoThe crystal structure of yeast protein disulfide isomerasesuggests cooperativity between its active sitesrdquo Cell vol 124 no1 pp 61ndash73 2006
[174] P Klappa LW Ruddock N J Darby and R B Freedman ldquoThebrsquo domain provides the principal peptide-binding site of proteindisulfide isomerase but all domains contribute to binding ofmisfolded proteinsrdquo EMBO Journal vol 17 no 4 pp 927ndash9351998
[175] A Pirneskoski P Klappa M Lobell et al ldquoMolecular char-acterization of the principal substrate binding site of theubiquitous folding catalyst protein disulfide isomeraserdquo Journalof Biological Chemistry vol 279 no 11 pp 10374ndash10381 2004
[176] G Kozlov P Maattanen D Y Thomas and K Gehring ldquoAstructural overview of the PDI family of proteinsrdquo FEBS Journalvol 277 no 19 pp 3924ndash3936 2010
[177] Y Dai and C C Wang ldquoA mutant truncated protein disulfideisomerase with no chaperone activityrdquo Journal of BiologicalChemistry vol 272 no 44 pp 27572ndash27576 1997
[178] C E Jessop R H Watkins J J Simmons M Tasab andN J Bulleid ldquoProtein disulphide isomerase family membersshow distinct substrate specificity P5 is targeted to BiP clientproteinsrdquo Journal of Cell Science vol 122 no 23 pp 4287ndash42952009
[179] C Appenzeller-Herzog J Riemer E Zito et al ldquoDisulphideproduction by Ero1120572-PDI relay is rapid and effectively regu-latedrdquo EMBO Journal vol 29 no 19 pp 3318ndash3329 2010
[180] F Hatahet and L W Ruddock ldquoProtein disulfide isomerase acritical evaluation of its function in disulfide bond formationrdquoAntioxidants and Redox Signaling vol 11 no 11 pp 2807ndash28502009
[181] N J Bulleid and L Ellgaard ldquoMultiple ways to make disulfidesrdquoTrends in Biochemical Sciences 2011
[182] S Chakravarthi C E Jessop and N J Bulleid ldquoThe role ofglutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stressrdquo EMBOReports vol 7 no3 pp 271ndash275 2006
[183] J Lundstrom and A Holmgren ldquoDetermination of thereduction-oxidation potential of the thioredoxin-like domainsof protein disulfide-isomerase from the equilibrium with glu-tathione and thioredoxinrdquo Biochemistry vol 32 no 26 pp6649ndash6655 1993
[184] E Gross C S Sevier N Heldman et al ldquoGenerating disulfidesenzymatically reaction products and electron acceptors of theendoplasmic reticulum thiol oxidase Ero1prdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 2 pp 299ndash304 2006
[185] P I Merksamer A Trusina and F R Papa ldquoReal-time redoxmeasurements during endoplasmic reticulum stress reveal
interlinked protein folding functionsrdquo Cell vol 135 no 5 pp933ndash947 2008
[186] J W Cuozzo and C A Kaiser ldquoCompetition between glu-tathione and protein thiols for disulphide-bond formationrdquoNature Cell Biology vol 1 no 3 pp 130ndash135 1999
[187] L A Rutkevich M F Cohen-Doyle U Brockmeier and DB Williams ldquoFunctional relationship between protein disulfideisomerase family members during the oxidative folding ofhuman secretory proteinsrdquoMolecular Biology of the Cell vol 21no 18 pp 3093ndash3105 2010
[188] Y Honjo S Kaneko H Ito et al ldquoProtein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateralsclerosisrdquo Amyotrophic Lateral Sclerosis vol 12 no 6 pp 444ndash450 2011
[189] H Tsuda S M Han Y Yang et al ldquoThe amyotrophic lateralsclerosis 8 proteinVAPB is cleaved secreted and acts as a ligandfor Eph receptorsrdquo Cell vol 133 no 6 pp 963ndash977 2008
[190] D M Townsend Y Manevich H Lin et al ldquoNitrosative stress-induced S-glutathionylation of protein disulfide isomerase leadsto activation of the unfolded protein responserdquoCancer Researchvol 69 no 19 pp 7626ndash7634 2009
[191] T Uehara T Nakamura D Yao et al ldquoS-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegen-erationrdquo Nature vol 441 no 7092 pp 513ndash517 2006
[192] X Chen C Li T Guan et al ldquoS-nitrosylated protein disul-phide isomerase contributes to mutant SOD1 aggregates inamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol124 no 1 pp 45ndash58 2012
[193] J D Rothstein ldquoTherapeutic horizons for amyotrophic lateralsclerosisrdquo Current Opinion in Neurobiology vol 6 no 5 pp679ndash687 1996
[194] D W Cleveland ldquoNeuronal growth and death order anddisorder in the axoplasmrdquoCell vol 84 no 5 pp 663ndash666 1996
Figure 1 Schematic diagram showing domain structure of PDIThioredoxin-like 119886 domain (orange) and 1198861015840 domain (purple) pos-sessing the catalyticmotif catalytically inactive 119887 domain (blue) and1198871015840 domain (red) Green represents the linker region 119909 which allowsflexibility between domainsTheC terminal domain is shown in greyfollowed by the ER retrieval signal KDEL
[20 161] Oxidative stress driven by changes in fatty acidcomposition mitochondrial function andor proteosomeactivity leads to oxidative stress and contributes to ER stressin SALS patients [162 163] PDI is an ER chaperone whichis induced during UPR and has been implicated in severalneurodegenerative disorders including ALS [164ndash166]
PDI is a member of an extended family of foldasesand chaperones which are responsible for the formationand isomerisation of protein disulphide bonds [167] ThePDI family comprises 21 members which have structuralsimilarities but different functions [168] and all have asimilar active site to thioredoxin [169] Thioredoxin is anintracellular protein which regulates redox conditions andwhich is effective against oxidative stress [170] PDI is mostabundant in the ER but it is also found in other subcellularlocations such as the nucleus and extracellular matrix [171]and it constitutes 08 of the total cellular protein [172]The yeast PDI crystal structure was recently solved [173]which suggests that 119886 and 1198861015840 domains are responsible forthe formation of disulphide bonds (Figure 1) These domainscontain a redox active CGHCmotif which isomerases proteindisulphide bonds and is involved in redox regulation [173]PDI also contains 119887 and 1198871015840 domains which are responsiblefor substrate binding [174 175] Misfolded proteins attach tothe hydrophobic region of an inverted U shape structure [173176] The C-terminal region also aids in polypeptide bindingand contributes chaperone activity [177] Compared to otherfamilymembers PDI has broad substrate specificities and caninteract with glycosylated as well as nonglycosylated proteins[178]
4 PDI and Redox Regulation
PDI forms protein disulphide bonds by the oxidation ofthiols within the PDI active site cysteine residues [179 180]When PDI is in an oxidised state it transfers a disulphide tothe substrates thereby oxidising the substrate and becomingreduced itself Conversely substrates which need disulphidebond rearrangement are reduced by PDI in the reduced statethus oxidising PDI in the process [168 181] This continualcycling regulates redox conditions within the ER A thiolcontaining tripeptide protein and glutathione also maintainsER redox homeostasis by similar shuffling between oxidizedand reduced cysteine residues Glutathione is also requiredfor the isomerisation and rearrangement of disulphide bonds[182] The redox potential of PDI (minus110mV) is lower than
other family members [183] due to intervening residuespresent between the reactive cysteines thus facilitating disul-phide bonds [183] ERO1 oxidises PDI also aiding disulphidebond formations [184] but PDI is also oxidised throughperoxiredoxin 4 vitamin K glutathione peroxidase andquiescin sulfhydryl oxidase [181] During ER stress highlevels of ERO1 have been observed which accelerates proteinoxidation suggesting interplay between oxidative stress andER stress The transfer of electrons from the thiol groupof PDI to ERO1 results in the production of excess ROSdecreasing the levels of glutathione available for reductionand increasing ERO1 thus altering the redox conditions [185186] Hence imbalance in the redox state of the ERmay resultin dysregulation of thiol containing proteins and triggers
41 The Role of PDI in ALS Due to its function in preventingprotein misfolding PDI is important in protein quality con-trol [166] also deletion of PDI is embryonically lethal [187]Hence regulated expression of PDI is critical for normalcellular functionThere is now growing evidence for a role ofPDI in ALS PDI levels are upregulated in transgenic modelsof ALS and spinal cord tissues of ALS patients [66 158]Overexpression of PDI is also protective againstmutant SOD1mediated aggregation and reduces cell death in vitro [20] PDIcoimmunoprecipitates with both SOD1 and FUS [158 161] italso colocalises with SOD1 TDP-43 and FUS in ALS patientssuggesting a physical interaction exists between PDI andother key misfolded proteins in ALS [66 161 188] SimilarlyPDI also colocalises with TDP-43 in ALS tissues and withVAPB inclusions in a Drosophila melanogaster model ofALS [188 189] A small mimic of the active site of PDIdithiol (plusmn)-trans-12-bis (mercaptoacetamido) cyclohexane(BMC) is also protective in cell culture and it reduces mutantSOD1 aggregation in a dose dependent manner [20] Furtherevidences for a role for disulphide interchange activity in ALScomes from studies showing that another PDI familymemberERp57 is also upregulated in transgenic SOD1 mice and ALSpatients [66] Furthermore thioredoxin is also upregulated inthe erythrocytes of FALS patients [19]
The upregulation of these thiol containing proteins inALS suggests a cellular defensive mechanism is triggeredin disease as a defence against oxidative stress Howeverthere is evidence that normal protective function of PDI isinhibited in disease [20] Modifications of active site thiolgroups through direct oxidation S-glutathiolation and S-nitrosylation can lead to inactivation of the normal enzy-matic activity of PDI [13 190 191] PDI was recently shownto be S-nitrosylated in ALS [20 192] as in other neurodegen-erative disorders such as Parkinsonrsquos and Alzheimerrsquos disease[191] S-nitrosylation occurs when there is an increased pro-duction of RNS during oxidative stress resulting in additionof a nitrogen monoxide group to the thiol side of PDI[20 164] Experiments performed by Chen and coworkerssuggested that in the presence of S-nitrosylated PDI theformation of mutant SOD1 aggregates increases in vitro [192]It is also likely that inactivation of PDI could lead to activationof the UPR as observed in other neurodegenerative disorders[191] The loss of PDI functional activity can directly lead to
6 Oxidative Medicine and Cellular Longevity
Impaired axonaltransport
AutophagyMitochondrialdysfunction
ER stress Proteinmisfolding
Redox dysregulation
PDI dysfunction Oxidative stress
Figure 2 Redox dysfunction and its relationship to other patholo-gies in ALS Alteration in the enzymatic activity of PDI due toredox dysregulation and oxidative stress can further increase theload of misfolded proteins ER stress oxidative stress autophagymitochondrial dysfunction and axonal impairment leading toneuronal cell death
apoptosis or indirectly to a range of cellular abnormalitiessuch as oxidative stress and protein misfolding which againlead to cell death [164 166] Hence the redox regulationof PDI is a crucial component in the maintenance of abalanced redox environment and inhibition of its enzymaticactivity will lead to important consequences for the cell(Figure 2)
Neurons are highly susceptible to redox dysregulationdue to their high metabolic requirements large size andlower ability to maintain the balance between antioxidantsand ROS [15] In disease states such as ALS oxidativestress and altered enzymatic activity of PDI which normallyreduces ROS and the burden of misfolded protein can causeserious damage to the neuron Since multiple mechanismsare involved in neurodegeneration any imbalance in redoxregulation can lead to an imbalance in the production offree radical species which consequently cause mitochondrialdamage and excitotoxicity thus elevating the levels of freeradicals [193] Furthermore an excess of free radicals canalso lead to DNA damage and may also result in aggregationof NF [194] and structural destabilization of other proteinsthus inducing ER stress and apoptosis Since ALS is a slowprogressive disorder it could be hypothesised that these cyclicevents due to loss of functional activity of PDImay graduallylead to neuronal degradation In such a scenario the redoxregulatory function of PDI may therefore have an importantprotective effect
5 Conclusion
Redox regulation is an important mechanism of homeostasisin eukaryotic cells especially neuronal cells where oxygen
levels are high [15] Many cellular processes rely on it includ-ing proper functioning of the mitochondria and ER calciumregulation axonal transport regulated autophagy and pro-tein folding Links between redox dysregulation and ALSare becoming well documented in the literature althoughthe directionality of these links and their underlying causeare still quite unknown One possible key player in redox reg-ulation in ALS is PDI whose role in ALS pathogenesis is thetopic of much new research As the critical protein involvedin thiol reduction any dysregulation of PDI activity can leadto oxidative stress and redox dysregulation Due to its activityPDI itself also contains an active site thiol group suggestingthat it can also be affected by oxidative stress leading to anescalating cycle that perpetuates redox dysregulation HowPDI becomes nonfunctional in the first place is still unclearalthough somepapers point to S-nitrosylation as having a role[20] Regardless of its exact role any mechanism to improvethe catalytic activity of PDI should have a reductive effect onoxidative stress levels in neurons It is therefore tempting tospeculate about PDI as a possible therapeutic target in thetreatment of ALS
Acknowledgments
This work was supported by the National Health and Med-ical Research Council of Australia (project Grants 4547491006141 and 1030513) Amyotrophic Lateral Sclerosis Asso-ciation (USA) MND Research Institute of Australia Beth-lehem Griffiths Research Council Henry H Roth CharitableFoundation Grant for MND Research Australian RotaryHealth and the Brain Foundation S Parakh holds a La TrobeUniversity Post Graduate Research Scholarship
References
[1] H Kamata and H Hirata ldquoRedox regulation of cellular sig-nallingrdquo Cellular Signalling vol 11 no 1 pp 1ndash14 1999
[2] A R Cross and O T G Jones ldquoEnzymic mechanisms ofsuperoxide productionrdquoBiochimica et BiophysicaActa vol 1057no 3 pp 281ndash298 1991
[3] VAdler Z YinKD Tew andZRonai ldquoRole of redox potentialand reactive oxygen species in stress signalingrdquo Oncogene vol18 no 45 pp 6104ndash6111 1999
[4] J Nordberg and E S J Arner ldquoReactive oxygen speciesantioxidants and the mammalian thioredoxin systemrdquo FreeRadical Biology andMedicine vol 31 no 11 pp 1287ndash1312 2001
[5] M G Espey K M Miranda D D Thomas et al ldquoA chemicalperspective on the interplay between NO reactive oxygenspecies and Reactive Nitrogen Oxide Speciesrdquo Annals of theNew York Academy of Sciences vol 962 pp 195ndash206 2002
[6] W A Pryor and G L Squadrito ldquoThe chemistry of per-oxynitrite a product from the reaction of nitric oxide withsuperoxiderdquo American Journal of Physiology-Lung Cellular andMolecular Physiology vol 268 no 5 pp L699ndashL722 1995
[7] K Abe L H Pan M Watanabe H Konno T Kato andY Itoyama ldquoUpregulation of protein-tyrosine nitration in theanterior horn cells of amyotrophic lateral sclerosisrdquo Neurologi-cal Research vol 19 no 2 pp 124ndash128 1997
Oxidative Medicine and Cellular Longevity 7
[8] J S Beckman M Carson C D Smith and W H KoppenolldquoALS SOD and peroxynitriterdquoNature vol 364 no 6438 p 5841993
[9] S C Barber and P J Shaw ldquoOxidative stress in ALS key rolein motor neuron injury and therapeutic targetrdquo Free RadicalBiology and Medicine vol 48 no 5 pp 629ndash641 2010
[10] M C Martınez and R Andriantsitohaina ldquoReactive nitrogenspecies molecular mechanisms and potential significance inhealth and diseaserdquo Antioxidants and Redox Signaling vol 11no 3 pp 669ndash702 2009
[11] D Trachootham W Lu M A Ogasawara N R D Valle andP Huang ldquoRedox regulation of cell survivalrdquo Antioxidants andRedox Signaling vol 10 no 8 pp 1343ndash1374 2008
[12] C E Cooper R P Patel P S Brookes and VM Darley-UsmarldquoNanotransducers in cellular redox signaling modification ofthiols by reactive oxygen and nitrogen speciesrdquo Trends inBiochemical Sciences vol 27 no 10 pp 489ndash492 2002
[13] H Nakamura K Nakamura and J Yodoi ldquoRedox regulation ofcellular activationrdquo Annual Review of Immunology vol 15 pp351ndash369 1997
[14] S A Lipton Y B Choi Z H Pan et al ldquoA redox-based mech-anism for the neuroprotective and neurodestructive effects ofnitric oxide and related nitroso-compoundsrdquo Nature vol 364no 6438 pp 626ndash632 1993
[15] B Halliwell ldquoOxidative stress and neurodegeneration whereare we nowrdquo Journal of Neurochemistry vol 97 no 6 pp 1634ndash1658 2006
[16] R P Guttmann and T J Powell ldquoRedox regulation of cysteine-dependent enzymes in neurodegenerationrdquo International Jour-nal of Cell Biology vol 2012 Article ID 703164 8 pages 2012
[17] H Tohgi T Abe K Yamazaki T Murata E Ishizaki and CIsobe ldquoIncrease in oxidized NO products and reduction inoxidized glutathione in cerebrospinal fluid from patients withsporadic form of amyotrophic lateral sclerosisrdquo NeuroscienceLetters vol 260 no 3 pp 204ndash206 1999
[18] D R Rosen T Siddique D Patterson et al ldquoMutations inCuZn superoxide dismutase gene are associated with familialamyotrophic lateral sclerosisrdquoNature vol 362 no 6415 pp 59ndash62 1993
[19] Y Ogawa H Kosaka T Nakanishi et al ldquoStability of mutantsuperoxide dismutase-1 associated with familial amyotrophiclateral sclerosis determines the manner of copper release andinduction of thioredoxin in erythrocytesrdquo Biochemical andBiophysical Research Communications vol 241 no 2 pp 251ndash257 1997
[20] A KWalker M A Farg C R Bye C AMcLeanM K Horneand J D Atkin ldquoProtein disulphide isomerase protects againstprotein aggregation and is S-nitrosylated in amyotrophic lateralsclerosisrdquo Brain vol 133 no 1 pp 105ndash116 2010
[21] M W Akhtar C R Sunico T Nakamura and S A Lip-ton ldquoRedox regulation of protein function via cysteine S-nitrosylation and its relevance to neurodegenerative diseasesrdquoInternational Journal of Cell Biology vol 2012 Article ID463756 9 pages 2012
[22] J D Rothstein ldquoCurrent hypotheses for the underlying biologyof amyotrophic lateral sclerosisrdquo Annals of Neurology vol 65no 1 pp S3ndashS9 2009
[23] J Mitchell and G Borasio ldquoAmyotrophic lateral sclerosisrdquoLancet vol 369 no 9578 pp 2031ndash2041 2007
[24] L CWijesekera and PN Leigh ldquoAmyotrophic lateral sclerosisrdquoOrphanet Journal of Rare Diseases vol 4 no 1 p 3 2009
[25] G Bensimon L Lacomblez and V Meininger ldquoA controlledtrial of riluzole in amyotrophic lateral sclerosisrdquo New EnglandJournal of Medicine vol 330 no 9 pp 585ndash591 1994
[26] R G Miller J D Mitchell M Lyon and D HMoore ldquoRiluzolefor amyotrophic lateral sclerosis (ALS)motor neuron disease(MND)rdquoCochraneDatabase of Systematic Reviews no 1 ArticleID CD001447 2007
[27] A Alonso G Logroscino S S Jick and M A HernanldquoAssociation of smoking with amyotrophic lateral sclerosis riskand survival in men and women a prospective studyrdquo BMCNeurology vol 10 no 1 p 6 2010
[28] A Verma and J R Berger ldquoALS syndrome in patients withHIV-1 infectionrdquo Journal of the Neurological Sciences vol 240 no 1-2pp 59ndash64 2006
[29] A Chio B J Traynor F Lombardo et al ldquoPrevalence of SOD1mutations in the Italian ALS populationrdquoNeurology vol 70 no7 pp 533ndash537 2008
[30] L Corrado R Del Bo B Castellotti et al ldquoMutations ofFUS gene in sporadic amyotrophic lateral sclerosisrdquo Journal ofMedical Genetics vol 47 no 3 pp 190ndash194 2010
[31] J Sreedharan I P Blair V B Tripathi et al ldquoTDP-43mutationsin familial and sporadic amyotrophic lateral sclerosisrdquo Sciencevol 319 no 5870 pp 1668ndash1672 2008
[32] E Pupillo P Messina G Logroscino et al ldquoTrauma andamyotrophic lateral sclerosis a case-control study from apopulation-based registryrdquo European Journal of Neurology vol19 no 12 pp 1509ndash1517 2012
[33] S Beretta M T Carrı E Beghi A Chio and C Ferrarese ldquoThesinister side of Italian soccerrdquo Lancet Neurology vol 2 no 11pp 656ndash657 2003
[34] M R Turner C Wotton K Talbot and M J GoldacreldquoCardiovascular fitness as a risk factor for amyotrophic lateralsclerosis indirect evidence from record linkage studyrdquo Journalof Neurology Neurosurgery amp Psychiatry vol 83 pp 395ndash3982012
[35] P A Dion H Daoud and G A Rouleau ldquoGenetics of motorneuron disorders new insights into pathogenic mechanismsrdquoNature Reviews Genetics vol 10 no 11 pp 769ndash782 2009
[36] T Arai M Hasegawa H Akiyama et al ldquoTDP-43 is a compo-nent of ubiquitin-positive tau-negative inclusions in frontotem-poral lobar degeneration and amyotrophic lateral sclerosisrdquoBiochemical and Biophysical Research Communications vol 351no 3 pp 602ndash611 2006
[37] M Neumann D M Sampathu L K Kwong et al ldquoUbiq-uitinated TDP-43 in frontotemporal lobar degeneration andamyotrophic lateral sclerosisrdquo Science vol 314 no 5796 pp130ndash133 2006
[38] C Vance B Rogelj T Hortobagyi et al ldquoMutations in FUSan RNA processing protein cause familial amyotrophic lateralsclerosis type 6rdquo Science vol 323 no 5918 pp 1208ndash1211 2009
[39] Y Yang A Hentati H X Deng et al ldquoThe gene encodingalsin a protein with three guanine-nucleotide exchange factordomains is mutated in a form of recessive amyotrophic lateralsclerosisrdquo Nature Genetics vol 29 pp 160ndash165 2001
[40] A L Nishimura M Mitne-Neto H C A Silva et al ldquoAmutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclero-sisrdquoAmerican Journal of HumanGenetics vol 75 no 5 pp 822ndash831 2004
8 Oxidative Medicine and Cellular Longevity
[41] T J Kwiatkowski Jr D A Bosco A L LeClerc et al ldquoMutationsin the FUSTLS gene on chromosome 16 cause familial amy-otrophic lateral sclerosisrdquo Science vol 323 no 5918 pp 1205ndash1208 2009
[42] HMaruyamaHMorinoH Ito et al ldquoMutations of optineurinin amyotrophic lateral sclerosisrdquo Nature vol 465 no 7295 pp223ndash226 2010
[43] H X Deng W Chen S T Hong et al ldquoMutations in UBQLN2cause dominant X-linked juvenile and adult-onset ALS andALSdementiardquo Nature vol 477 pp 211ndash215 2011
[44] M DeJesus-Hernandez I R Mackenzie B F Boeve et alldquoExpanded GGGGCC hexanucleotide repeat in noncodingregion of C9ORF72 causes chromosome 9p-linked FTD andALSrdquo Neuron vol 72 no 2 pp 245ndash256 2011
[45] L I Bruijn T M Miller and D W Cleveland ldquoUnraveling themechanisms involved in motor neuron degeneration in ALSrdquoAnnual Review of Neuroscience vol 27 pp 723ndash749 2004
[46] H D Durham J Roy L Dong and D A Figlewicz ldquoAggrega-tion of mutant CuZn superoxide dismutase proteins in a cul-turemodel ofALSrdquo Journal ofNeuropathology andExperimentalNeurology vol 56 no 5 pp 523ndash530 1997
[47] M Watanabe M Dykes-Hoberg V Cizewski Culotta D LPrice P C Wong and J D Rothstein ldquoHistological evidenceof protein aggregation in mutant SOD1 transgenic mice andin amyotrophic lateral sclerosis neural tissuesrdquo Neurobiology ofDisease vol 8 no 6 pp 933ndash941 2001
[48] C Soto ldquoUnfolding the role of protein misfolding in neurode-generative diseasesrdquo Nature Reviews Neuroscience vol 4 no 1pp 49ndash60 2003
[49] J Wang G Xu and D R Borchelt ldquoMapping superoxidedismutase 1 domains of non-native interaction roles of intra-and intermolecular disulfide bonding in aggregationrdquo Journalof Neurochemistry vol 96 no 5 pp 1277ndash1288 2006
[50] B S Johnson D Snead J J Lee J M McCaffery J Shorterand A D Gitler ldquoTDP-43 is intrinsically aggregation-proneand amyotrophic lateral sclerosis-linked mutations accelerateaggregation and increase toxicityrdquo Journal of Biological Chem-istry vol 284 pp 20329ndash20339 2009
[51] C Vance B Rogelj T Hortobagyi et al ldquoMutations in FUSan RNA processing protein cause familial amyotrophic lateralsclerosis type 6rdquo Science vol 323 no 5918 pp 1208ndash1211 2009
[52] T Arai M Hasegawa H Akiyama et al ldquoTDP-43 is a compo-nent of ubiquitin-positive tau-negative inclusions in frontotem-poral lobar degeneration and amyotrophic lateral sclerosisrdquoBiochemical and Biophysical Research Communications vol 351no 3 pp 602ndash611 2006
[53] N Shibata A Hirano M Kobayashi et al ldquoIntense super-oxide dismutase-1 immunoreactivity in intracytoplasmic hya-line inclusions of familial amyotrophic lateral sclerosis withposterior column involvementrdquo Journal of Neuropathology andExperimental Neurology vol 55 no 4 pp 481ndash490 1996
[54] J S Valentine P A Doucette and S Z Potter ldquoCopper-zinc superoxide dismutase and amyotrophic lateral sclerosisrdquoAnnual Review of Biochemistry vol 74 pp 563ndash593 2005
[55] F Arnesano L Banci I BertiniMMartinelli Y Furukawa andT V OrsquoHalloran ldquoThe unusually stable quaternary structureof human CuZn-superoxide dismutase 1 is controlled by bothmetal occupancy and disulfide statusrdquo Journal of BiologicalChemistry vol 279 no 46 pp 47998ndash48003 2004
[56] C Kayatekin J A Zitzewitz and C R Matthews ldquoDisulfide-Reduced ALS Variants of Cu Zn Superoxide Dismutase Exhibit
Increased Populations of Unfolded Speciesrdquo Journal of Molecu-lar Biology vol 398 no 2 pp 320ndash331 2010
[57] A E Svensson O Bilsel C Kayatekin J A Adefusika J AZitzewitz and C Robert Matthews ldquoMetal-free ALS variantsof dimeric human CuZn-superoxide dismutase have enhancedpopulations of monomeric speciesrdquo PLoS ONE vol 5 no 4Article ID e10064 2010
[58] M Cozzolino M G Pesaresi V Gerbino J Grosskreutzand M T Carr ldquoAmyotrophic lateral sclerosis new insightsinto underlying molecular mechanisms and opportunities fortherapeutic interventionrdquo Antioxidants amp Redox Signaling vol17 no 9 pp 1277ndash1330 2012
[59] O Spreux-Varoquaux G Bensimon L Lacomblez et al ldquoGlu-tamate levels in cerebrospinal fluid in amyotrophic lateralsclerosis a reappraisal using a new HPLC method with coulo-metric detection in a large cohort of patientsrdquo Journal of theNeurological Sciences vol 193 no 2 pp 73ndash78 2002
[60] I Puls C Jonnakuty B H LaMonte et al ldquoMutant dynactin inmotor neuron diseaserdquo Nature Genetics vol 33 no 4 pp 455ndash456 2003
[61] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[62] J Kong and Z Xu ldquoMassive mitochondrial degeneration inmotor neurons triggers the onset of amyotrophic lateral sclero-sis in mice expressing a mutant SOD1rdquo Journal of Neurosciencevol 18 no 9 pp 3241ndash3250 1998
[63] F R Wiedemann K Winkler A V Kuznetsov et al ldquoImpair-ment of mitochondrial function in skeletal muscle of patientswith amyotrophic lateral sclerosisrdquo Journal of the NeurologicalSciences vol 156 no 1 pp 65ndash72 1998
[64] AHiranoHDonnenfeld S Sasaki and I Nakano ldquoFine struc-tural observations of neurofilamentous changes in amyotrophiclateral sclerosisrdquo Journal of Neuropathology and ExperimentalNeurology vol 43 no 5 pp 461ndash470 1984
[65] J D Wood T P Beaujeux and P J Shaw ldquoProtein aggregationin motor neurone disordersrdquo Neuropathology and AppliedNeurobiology vol 29 no 6 pp 529ndash545 2003
[66] J D Atkin M A Farg A KWalker C McLean D Tomas andM K Horne ldquoEndoplasmic reticulum stress and induction ofthe unfolded protein response in human sporadic amyotrophiclateral sclerosisrdquoNeurobiology of Disease vol 30 no 3 pp 400ndash407 2008
[67] S Chen X Zhang L Song and W Le ldquoAutophagy dysregula-tion in amyotrophic lateral sclerosisrdquo Brain Pathology vol 22no 1 pp 110ndash116 2012
[68] R G Cutler W A Pedersen S Camandola J D Rothsteinand M P Mattson ldquoEvidence that accumulation of ceramidesand cholesterol esters mediates oxidative stress-induced deathof motor neurons in amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 52 no 4 pp 448ndash457 2002
[69] R J Ferrante S E Browne L A Shinobu et al ldquoEvidenceof increased oxidative damage in both sporadic and familialamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol69 no 5 pp 2064ndash2074 1997
[70] M Bogdanov R H Brown W Matson et al ldquoIncreasedoxidative damage to DNA in ALS patientsrdquo Free Radical Biologyand Medicine vol 29 no 7 pp 652ndash658 2000
[71] A W Girotti ldquoLipid hydroperoxide generation turnover andeffector action in biological systemsrdquo Journal of Lipid Researchvol 39 no 8 pp 1529ndash1542 1998
Oxidative Medicine and Cellular Longevity 9
[72] P J Shaw P G Ince G Falkous and D Mantle ldquoOxidativedamage to protein in sporadic motor neuron disease spinalcordrdquo Annals of Neurology vol 38 no 4 pp 691ndash695 1995
[73] D Liu J Wen J Liu and L Li ldquoThe roles of free radicalsin amyotrophic lateral sclerosis reactive oxygen species andelevated oxidation of protein DNA and membrane phospho-lipidsrdquo FASEB Journal vol 13 no 15 pp 2318ndash2328 1999
[74] B J Carter P Anklesaria S Choi and J F Engelhardt ldquoRedoxmodifier genes and pathways in amyotrophic lateral sclerosisrdquoAntioxidants and Redox Signaling vol 11 no 7 pp 1569ndash15862009
[75] H F Poon K Hensley V Thongboonkerd et al ldquoRedoxproteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice-a model of familial amyotrophic lateralsclerosisrdquo Free Radical Biology and Medicine vol 39 no 4 pp453ndash462 2005
[76] J J Haddad ldquoAntioxidant and prooxidant mechanisms in theregulation of redox(y)-sensitive transcription factorsrdquo CellularSignalling vol 14 no 11 pp 879ndash897 2002
[77] K T Turpaev ldquoReactive oxygen species and regulation of geneexpressionrdquo Biochemistry vol 67 no 3 pp 281ndash292 2002
[78] C Iaccarino M E Mura S Esposito et al ldquoBcl2-A1 interactswith pro-caspase-3 implications for amyotrophic lateral scle-rosisrdquo Neurobiology of Disease vol 43 no 3 pp 642ndash650 2011
[79] C Moreau P Gosset J Kluza et al ldquoDeregulation of thehypoxia inducible factor-1120572 pathway in monocytes from spo-radic amyotrophic lateral sclerosis patientsrdquo Neuroscience vol172 pp 110ndash117 2011
[80] C M Karch M Prudencio D D Winkler P J Hart andD R Borchelt ldquoRole of mutant SOD1 disulfide oxidation andaggregation in the pathogenesis of familial ALSrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 106 no 19 pp 7774ndash7779 2009
[81] J B ProescherM Son J L Elliott andV C Culotta ldquoBiologicaleffects of CCS in the absence of SOD1 enzyme activationimplications for disease in a mouse model for ALSrdquo HumanMolecular Genetics vol 17 no 12 pp 1728ndash1737 2008
[82] J M McCord and I Fridovich ldquoSuperoxide dismutase Anenzymic function for erythrocuprein (hemocuprein)rdquo Journalof Biological Chemistry vol 244 no 22 pp 6049ndash6055 1969
[83] D Sau S De Biasi L Vitellaro-Zuccarello et al ldquoMutation ofSOD1 in ALS a gain of a loss of functionrdquo Human MolecularGenetics vol 16 no 13 pp 1604ndash1618 2007
[84] J S Beckman M Carson C D Smith and W H KoppenolldquoALS SOD and peroxynitriterdquoNature vol 364 no 6438 p 5841993
[85] N V Blough and O C Zafiriou ldquoReaction of superoxide withnitric oxide to form peroxonitrite in alkaline aqueous solutionrdquoInorganic Chemistry vol 24 no 22 pp 3502ndash3504 1985
[86] M F Beal R J Ferrante S E Browne Jr R T Matthews NW Kowall and R H Brown ldquoIncreased 3-nitrotyrosine in bothsporadic and familial amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 42 no 4 pp 644ndash654 1997
[87] H Tohgi T Abe K Yamazaki T Murata E Ishizaki andC Isobe ldquoRemarkable increase in cerebrospinal fluid 3-nitrotyrosine in patients with sporadic amyotrophic lateralsclerosisrdquo Annals of Neurology vol 46 pp 129ndash131 1999
[88] F Casoni M Basso T Massignan et al ldquoProtein nitration in amouse model of familial amyotrophic lateral sclerosis possiblemultifunctional role in the pathogenesisrdquo Journal of BiologicalChemistry vol 280 no 16 pp 16295ndash16304 2005
[89] S Guareschi E Cova C Cereda et al ldquoAn over-oxidizedform of superoxide dismutase found in sporadic amyotrophiclateral sclerosiswith bulbar onset shares a toxicmechanismwithmutant SOD1rdquo Proceedings of the National Academy of Sciencesvol 109 no 13 pp 5074ndash5079 2012
[90] RW Orrell R J M Lane andM Ross ldquoA systematic review ofantioxidant treatment for amyotrophic lateral sclerosismotorneuron diseaserdquo Amyotrophic Lateral Sclerosis vol 9 no 4 pp195ndash211 2008
[91] S A Ezzi M Urushitani and J P Julien ldquoWild-type superoxidedismutase acquires binding and toxic properties of ALS-linkedmutant forms through oxidationrdquo Journal of Neurochemistryvol 102 no 1 pp 170ndash178 2007
[92] R L Redler K C Wilcox E A Proctor L Fee M Caplowand N V Dokholyan ldquoGlutathionylation at Cys-111 inducesdissociation of wild type and FALS mutant SOD1 dimersrdquoBiochemistry vol 50 no 32 pp 7057ndash7066 2011
[93] K Forsberg P A Jonsson P M Andersen et al ldquoNovelantibodies reveal inclusions containing non-native SOD1 insporadic ALS patientsrdquo PloS One vol 5 no 7 Article ID e115522010
[94] D A Bosco G Morfini N M Karabacak et al ldquoWild-type andmutant SOD1 share an aberrant conformation and a commonpathogenic pathway in ALSrdquo Nature Neuroscience vol 13 no11 pp 1396ndash1403 2010
[95] A C Estevez J P Crow J B Sampson et al ldquoInduction of nitricoxide-dependent apoptosis in motor neurons by zinc- deficientsuperoxide dismutaserdquo Science vol 286 no 5449 pp 2498ndash2500 1999
[96] Y Furukawa R Fu H X Deng T Siddique and T VOrsquoHalloran ldquoDisulfide cross-linked protein represents a signif-icant fraction of ALS-associated Cu Zn-superoxide dismutaseaggregates in spinal cords of model micerdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 18 pp 7148ndash7153 2006
[97] T J Cohen AWHwang T Unger J Q Trojanowski and VMY Lee ldquoRedox signalling directly regulates TDP-43 via cysteineoxidation and disulphide cross-linkingrdquo The EMBO Journalvol 31 no 5 pp 1241ndash1252 2011
[98] DDormann R Rodde D Edbauer et al ldquoALS-associated fusedin sarcoma (FUS) mutations disrupt transportin-mediatednuclear importrdquo EMBO Journal vol 29 no 16 pp 2841ndash28572010
[99] S P Butcher andAHamberger ldquoIn vivo studies on the extracel-lular and veratrine-releasable pools of endogenous amino acidsin the rat striatum effects of corticostriatal deafferentiation andkainic acid lesionrdquo Journal of Neurochemistry vol 48 no 3 pp713ndash721 1987
[100] I Sen A Nalini N B Joshi and P G Joshi ldquoCerebrospinalfluid from amyotrophic lateral sclerosis patients preferentiallyelevates intracellular calcium and toxicity in motor neurons viaAMPAkainate receptorrdquo Journal of the Neurological Sciencesvol 235 no 1-2 pp 45ndash54 2005
[101] A Plaitakis and J T Caroscio ldquoAbnormal glutamatemetabolism in amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 22 no 5 pp 575ndash579 1987
[102] L Van Den Bosch and W Robberecht ldquoDifferent receptorsmediate motor neuron death induced by short and long expo-sures to excitotoxicityrdquo Brain Research Bulletin vol 53 no 4 pp383ndash388 2000
10 Oxidative Medicine and Cellular Longevity
[103] D Trotti ldquoNeuronal and glial glutamate transporters possessan SH-based redox regulatory mechanismrdquo European Journalof Neuroscience vol 9 no 6 pp 1236ndash1243 1997
[104] A Plaitakis and E Constantakakis ldquoAlteredmetabolism of exci-tatory amino acids N-acetyl-aspartate and N- acetyl-aspartyl-glutamate in amyotrophic lateral sclerosisrdquo Brain ResearchBulletin vol 30 no 3-4 pp 381ndash386 1993
[105] J D Rothstein L J Martin and R W Kuncl ldquoDecreasedglutamate transport by the brain and spinal cord in amyotrophiclateral sclerosisrdquo New England Journal of Medicine vol 326 no22 pp 1464ndash1468 1992
[106] J D Rothstein M Van Kammen A I Levey L J Martin andRW Kuncl ldquoSelective loss of glial glutamate transporter GLT-1amyotrophic lateral sclerosisrdquo Annals of Neurology vol 38 no1 pp 73ndash84 1995
[107] A Volterra D Trotti C Tromba S Floridi and G RacagnildquoGlutamate uptake inhibition by oxygen free radicals in ratcortical astrocytesrdquo Journal of Neuroscience vol 14 no 5 pp2924ndash2932 1994
[108] P J Shaw ldquoGlutamate excitotoxicity and amyotrophic lateralsclerosisrdquo Journal of Neurology vol 244 no 2 pp S3ndashS14 1997
[109] W L Miller ldquoMinireview regulation of steroidogenesis byelectron transferrdquo Endocrinology vol 146 no 6 pp 2544ndash25502005
[110] S Jin F Zhou F Katirai and P L Li ldquoLipid raft redox signalingmolecular mechanisms in health and diseaserdquoAntioxidants andRedox Signaling vol 15 no 4 pp 1043ndash1083 2011
[111] W A Pedersen W Fu J N Keller et al ldquoProtein modificationby the lipid peroxidation product 4-hydroxynonenal in thespinal cords of amyotrophic lateral sclerosis patientsrdquo Annals ofNeurology vol 44 no 5 pp 819ndash824 1998
[112] L Dupuis P Corcia A Fergani et al ldquoDyslipidemia is aprotective factor in amyotrophic lateral sclerosisrdquo Neurologyvol 70 no 13 pp 1004ndash1009 2008
[113] L Dupuis and J P Loeffler ldquoNeuromuscular junction destruc-tion during amyotrophic lateral sclerosis insights from trans-genic modelsrdquo Current Opinion in Pharmacology vol 9 no 3pp 341ndash346 2009
[114] I Choi H D Song S Lee et al ldquoDirect observation ofdefects and increased ion permeability of a membrane inducedby structurally disordered CuZn-superoxide dismutase aggre-gatesrdquo PloS One vol 6 no 12 pp e28982ndashe28982 2011
[115] C Taghibiglou J Lu I R Mackenzie Y T Wang and NR Cashman ldquoSterol regulatory element binding protein-1(SREBP1) activation in motor neurons in excitotoxicity andamyotrophic lateral sclerosis (ALS) indip a potential therapeu-tic peptiderdquo Biochemical and Biophysical Research Communica-tions vol 413 no 2 pp 159ndash163 2011
[116] E Colman A Szarfman J Wyeth et al ldquoAn evaluation of adata mining signal for amyotrophic lateral sclerosis and statinsdetected in FDArsquos spontaneous adverse event reporting systemrdquoPharmacoepidemiology and Drug Safety vol 17 no 11 pp 1068ndash1076 2008
[117] I R Edwards K Star and A Kiuru ldquoStatins neuromusculardegenerative disease and an amyotrophic lateral sclerosis-likesyndrome an analysis of individual case safety reports fromvigibaserdquo Drug Safety vol 30 no 6 pp 515ndash525 2007
[118] L Zinman R Sadeghi M Gawel D Patton and A Kiss ldquoArestatin medications safe in patients with ALSrdquo AmyotrophicLateral Sclerosis vol 9 no 4 pp 223ndash228 2008
[119] HToftSoslashrensen andT L Lash ldquoStatins and amyotrophic lateralsclerosis-the level of evidence for an associationrdquo Journal ofInternal Medicine vol 266 no 6 pp 520ndash526 2009
[120] J Zhai A L Strom R Kilty et al ldquoProteomic characterizationof lipid raft proteins in amyotrophic lateral sclerosis mousespinal cordrdquo FEBS Journal vol 276 no 12 pp 3308ndash3323 2009
[121] M F Beal ldquoAging energy and oxidative stress in neurodegen-erative diseasesrdquoAnnals of Neurology vol 38 no 3 pp 357ndash3661995
[122] F RWiedemann GManfredi CMawrinM Flint Beal and EA Schon ldquoMitochondrial DNA and respiratory chain functionin spinal cords of ALS patientsrdquo Journal of Neurochemistry vol80 no 4 pp 616ndash625 2002
[123] G M Borthwick M A Johnson P G Ince P J Shaw and DM Turnbull ldquoMitochondrial enzyme activity in amyotrophiclateral sclerosis implications for the role of mitochondria inneuronal cell deathrdquoAnnals of Neurology vol 46 no 5 pp 787ndash790 2001
[124] P M Keeney and J P Bennett ldquoALS spinal neurons show variedand reducedmtDNAgene copy numbers and increasedmtDNAgene deletionsrdquoMolecular Neurodegeneration vol 5 no 1 p 212010
[125] M B Graeber E Grasbon-Frodl U V Eitzen and S K KoselldquoNeurodegeneration and aging role of the second genomerdquoJournal of Neuroscience Research vol 52 no 1 pp 1ndash6 1998
[126] K C Zimmermann C Bonzon andD R Green ldquoThemachin-ery of programmed cell deathrdquo Pharmacology andTherapeuticsvol 92 no 1 pp 57ndash70 2001
[127] P Nagley G C Higgins J D Atkin and P M Beart ldquoMul-tifaceted deaths orchestrated by mitochondria in neuronesrdquoBiochimica et Biophysica Acta vol 1802 no 1 pp 167ndash185 2010
[128] C GueganM Vila G Rosoklija A P Hays and S PrzedborskildquoRecruitment of the mitochondria-dependent apoptotic path-way in amyotrophic lateral sclerosisrdquo Journal of Neurosciencevol 21 no 17 pp 6569ndash6576 2001
[129] L J Martin Z Liu K Chen et al ldquoMotor neuron degenerationin amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice mechanisms of mitochondriopathy and celldeathrdquo Journal of Comparative Neurology vol 500 no 1 pp 20ndash46 2007
[130] P C Wong C A Pardo D R Borchelt et al ldquoAn adverseproperty of a familial ALS-linked SOD1 mutation causes motorneuron disease characterized by vacuolar degeneration ofmito-chondriardquo Neuron vol 14 no 6 pp 1105ndash1116 1995
[131] F M Menzies M R Cookson R W Taylor et al ldquoMitochon-drial dysfunction in a cell culturemodel of familial amyotrophiclateral sclerosisrdquo Brain vol 125 no 7 pp 1522ndash1533 2002
[132] M T Carrı A Ferri A Battistoni et al ldquoExpression of aCuZn superoxide dismutase typical of familial amyotrophiclateral sclerosis induces mitochondrial alteration and increaseof cytosolic Ca2+ concentration in transfected neuroblastomaSH-SY5Y cellsrdquo FEBS Letters vol 414 no 2 pp 365ndash368 1997
[133] S Sasaki and M Iwata ldquoUltrastructural study of synapses inthe anterior horn neurons of patients with amyotrophic lateralsclerosisrdquoNeuroscience Letters vol 204 no 1-2 pp 53ndash56 1996
[134] L Siklos J Engelhardt Y Harati R G Smith F Joo andS H Appel ldquoUltrastructural evidence for altered calcium inmotor nerve terminals in amyotrophic lateral sclerosisrdquo Annalsof Neurology vol 39 no 2 pp 203ndash216 1996
[135] M Cozzolino and M T Carrı ldquoMitochondrial dysfunction inALSrdquo Progress in Neurobiology vol 97 no 2 pp 54ndash66 2012
Oxidative Medicine and Cellular Longevity 11
[136] K Y Soo J D Atkin M Farg A K Walker M K Horne andP Nagley ldquoBim links ER stress and apoptosis in cells expressingmutant SOD1 associated with amyotrophic lateral sclerosisrdquoPloS One vol 7 no 4 Article ID e35413 2012
[137] K Hong Y Li W Duan et al ldquoFull-length TDP-43 and itsC-terminal fragments activate mitophagy in NSC34 cell linerdquoNeuroscience Letters vol 530 no 2 pp 144ndash149 2012
[138] R J Braun and B Westermann ldquoMitochondrial dynamics inyeast cell death and agingrdquo Biochemical Society Transactionsvol 39 pp 1520ndash1526 2011
[139] W Duan X Li J Shi Y Guo Z Li and C Li ldquoMutant TARDNA-binding protein-43 induces oxidative injury in motorneuron-like cellrdquo Neuroscience vol 169 no 4 pp 1621ndash16292010
[140] C Jung C M J Higgins and Z Xu ldquoMitochondrial electrontransport chain complex dysfunction in a transgenic mousemodel for amyotrophic lateral sclerosisrdquo Journal of Neurochem-istry vol 83 no 3 pp 535ndash545 2002
[141] A Ferri M Cozzolino C Crosio et al ldquoFamilial ALS-superoxide dismutases associate with mitochondria and shifttheir redox potentialsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 37 pp13860ndash13865 2006
[142] K Aquilano P Vigilanza G Rotilio and M R CiriololdquoMitochondrial damage due to SOD1 deficiency in SH-SY5Yneuroblastoma cells a rationale for the redundancy of SOD1rdquoThe FASEB Journal vol 20 no 10 pp 1683ndash1685 2006
[143] E M OrsquoBrien R Dirmeier M Engle and R O PoytonldquoMitochondrial protein oxidation in yeast mutants lackingmanganese- (MnSOD) or copper- and zinc-containing super-oxide dismutase (CuZnSOD) evidence that mnsod and cuzn-sod have both unique and overlapping functions in protectingmitochondrial proteins from oxidative damagerdquo Journal ofBiological Chemistry vol 279 no 50 pp 51817ndash51827 2004
[144] S Pickles and C V Velde ldquoMisfolded SOD1 and ALS zeroingin on mitochondriardquo Amyotrophic Lateral Sclerosis vol 13 pp333ndash340 2012
[145] B Bandy and A J Davison ldquoMitochondrial mutations mayincrease oxidative stress implications for carcinogenesis andagingrdquo Free Radical Biology andMedicine vol 8 no 6 pp 523ndash539 1990
[146] F Zhang A L Strom K Fukada S Lee L J Hayward andH Zhu ldquoInteraction between familial Amyotrophic LateralSclerosis (ALS)-linked SOD1mutants and the dynein complexrdquoJournal of Biological Chemistry vol 282 no 22 pp 16691ndash166992007
[147] S Sasaki and S Maruyama ldquoUltrastructutal study of skein-like inclusions in anterior horn neurons of patients with motorneuron diseaserdquoNeuroscience Letters vol 147 no 2 pp 121ndash1241992
[148] D A Figlewicz A Krizus M G Martinoli et al ldquoVariantsof the heavy neurofilament subunit are associated with thedevelopment of amyotrophic lateral sclerosisrdquo Human Molec-ular Genetics vol 3 no 10 pp 1757ndash1761 1994
[149] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[150] S M Chou H S Wang and K Komai ldquoColocalization of NOSand SOD1 in neurofilament accumulation within motor neu-rons of amyotrophic lateral sclerosis an immunohistochemicalstudyrdquo Journal of Chemical Neuroanatomy vol 10 no 3-4 pp249ndash258 1996
[151] H Zhang X Kong J Kang et al ldquoOxidative stress inducesparallel autophagy and mitochondria dysfunction in humangliomaU251 cellsrdquoToxicological Sciences vol 110 no 2 pp 376ndash388 2009
[152] J Lee S Giordano and J Zhang ldquoAutophagymitochondria andoxidative stress cross-talk and redox signallingrdquo BiochemicalJournal vol 441 pp 523ndash540 2012
[153] A Li X Zhang and W Le ldquoAltered macroautophagy in thespinal cord of SOD1 mutant micerdquo Autophagy vol 4 no 3 pp290ndash293 2008
[154] Y Zhong Q J Wang X Li et al ldquoDistinct regulation ofautophagic activity by Atg14L and Rubicon associated withBeclin 1-phosphatidylinositol-3-kinase complexrdquo Nature CellBiology vol 11 no 4 pp 468ndash476 2009
[155] S Sasaki ldquoAutophagy in spinal cord motor neurons in sporadicamyotrophic lateral sclerosisrdquo Journal of Neuropathology andExperimental Neurology vol 70 no 5 pp 349ndash359 2011
[156] N Morimoto M Nagai Y Ohta et al ldquoIncreased autophagyin transgenic mice with a G93A mutant SOD1 generdquo BrainResearch vol 1167 no 1 pp 112ndash117 2007
[157] M Schroder ldquoEndoplasmic reticulum stress responsesrdquo Cellu-lar andMolecular Life Sciences vol 65 no 6 pp 862ndash894 2008
[158] J D Atkin M A Farg B J Turner et al ldquoInduction ofthe unfolded protein response in familial amyotrophic lateralsclerosis and association of protein-disulfide isomerase withsuperoxide dismutase 1rdquo Journal of Biological Chemistry vol281 no 40 pp 30152ndash30165 2006
[159] C M Haynes E A Titus and A A Cooper ldquoDegradation ofmisfolded proteins prevents ER-derived oxidative stress and celldeathrdquoMolecular Cell vol 15 no 5 pp 767ndash776 2004
[160] K Kanekura H Suzuki S Aiso and M Matsuoka ldquoER stressand unfolded protein response in amyotrophic lateral sclerosisrdquoMolecular Neurobiology vol 39 no 2 pp 81ndash89 2009
[161] M A Farg K Y Soo A K Walker et al ldquoMutant FUS inducesendoplasmic reticulum stress in amyotrophic lateral sclerosisand interacts with protein disulfide-isomeraserdquoNeurobiology ofAging vol 33 no 12 pp 2855ndash2868 2012
[162] E V Ilieva V Ayala M Jove et al ldquoOxidative and endoplas-mic reticulum stress interplay in sporadic amyotrophic lateralsclerosisrdquo Brain vol 130 no 12 pp 3111ndash3123 2007
[163] J D Malhotra and R J Kaufman ldquoEndoplasmic reticulumstress and oxidative stress a vicious cycle or a double-edgedswordrdquo Antioxidants and Redox Signaling vol 9 no 12 pp2277ndash2293 2007
[164] A K Walker and J D Atkin ldquoMechanisms of neuroprotectionby protein disulphide isomerase in amyotrophic lateral scle-rosisrdquo Neurology Research International vol 2011 Article ID317340 7 pages 2011
[165] R B Freedman T R Hirst andM F Tuite ldquoProtein disulphideisomerase building bridges in protein foldingrdquo Trends inBiochemical Sciences vol 19 no 8 pp 331ndash336 1994
[166] C I Andreu U Woehlbier M Torres and C Hetz ldquoProteindisulfide isomerases in neurodegeneration from disease mech-anisms to biomedical applicationsrdquo FEBS Letters vol 586 no18 pp 2826ndash2834 2012
[167] J J Galligan and D R Petersen ldquoThe human protein disulfideisomerase gene familyrdquoHuman Genomics vol 6 no 1 pp 1ndash152012
[168] L Ellgaard and L W Ruddock ldquoThe human protein disulphideisomerase family substrate interactions and functional proper-tiesrdquo EMBO Reports vol 6 no 1 pp 28ndash32 2005
12 Oxidative Medicine and Cellular Longevity
[169] B Wilkinson and H F Gilbert ldquoProtein disulfide isomeraserdquoBiochimica et Biophysica Acta vol 1699 no 1-2 pp 35ndash44 2004
[170] T Tanaka H Nakamura A Nishiyama et al ldquoRedox regulationby thioredoxin superfamily protection against oxidative stressand agingrdquo Free Radical Research vol 33 no 6 pp 851ndash8552000
[171] C Turano S Coppari F Altieri and A Ferraro ldquoProteins ofthe PDI family unpredicted non-ER locations and functionsrdquoJournal of Cellular Physiology vol 193 no 2 pp 154ndash163 2002
[172] D M Ferrari and H D Soling ldquoThe protein disulphide-isomerase family unravelling a string of foldsrdquo BiochemicalJournal vol 339 no 1 pp 1ndash10 1999
[173] G Tian S Xiang R Noiva W J Lennarz and H SchindelinldquoThe crystal structure of yeast protein disulfide isomerasesuggests cooperativity between its active sitesrdquo Cell vol 124 no1 pp 61ndash73 2006
[174] P Klappa LW Ruddock N J Darby and R B Freedman ldquoThebrsquo domain provides the principal peptide-binding site of proteindisulfide isomerase but all domains contribute to binding ofmisfolded proteinsrdquo EMBO Journal vol 17 no 4 pp 927ndash9351998
[175] A Pirneskoski P Klappa M Lobell et al ldquoMolecular char-acterization of the principal substrate binding site of theubiquitous folding catalyst protein disulfide isomeraserdquo Journalof Biological Chemistry vol 279 no 11 pp 10374ndash10381 2004
[176] G Kozlov P Maattanen D Y Thomas and K Gehring ldquoAstructural overview of the PDI family of proteinsrdquo FEBS Journalvol 277 no 19 pp 3924ndash3936 2010
[177] Y Dai and C C Wang ldquoA mutant truncated protein disulfideisomerase with no chaperone activityrdquo Journal of BiologicalChemistry vol 272 no 44 pp 27572ndash27576 1997
[178] C E Jessop R H Watkins J J Simmons M Tasab andN J Bulleid ldquoProtein disulphide isomerase family membersshow distinct substrate specificity P5 is targeted to BiP clientproteinsrdquo Journal of Cell Science vol 122 no 23 pp 4287ndash42952009
[179] C Appenzeller-Herzog J Riemer E Zito et al ldquoDisulphideproduction by Ero1120572-PDI relay is rapid and effectively regu-latedrdquo EMBO Journal vol 29 no 19 pp 3318ndash3329 2010
[180] F Hatahet and L W Ruddock ldquoProtein disulfide isomerase acritical evaluation of its function in disulfide bond formationrdquoAntioxidants and Redox Signaling vol 11 no 11 pp 2807ndash28502009
[181] N J Bulleid and L Ellgaard ldquoMultiple ways to make disulfidesrdquoTrends in Biochemical Sciences 2011
[182] S Chakravarthi C E Jessop and N J Bulleid ldquoThe role ofglutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stressrdquo EMBOReports vol 7 no3 pp 271ndash275 2006
[183] J Lundstrom and A Holmgren ldquoDetermination of thereduction-oxidation potential of the thioredoxin-like domainsof protein disulfide-isomerase from the equilibrium with glu-tathione and thioredoxinrdquo Biochemistry vol 32 no 26 pp6649ndash6655 1993
[184] E Gross C S Sevier N Heldman et al ldquoGenerating disulfidesenzymatically reaction products and electron acceptors of theendoplasmic reticulum thiol oxidase Ero1prdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 2 pp 299ndash304 2006
[185] P I Merksamer A Trusina and F R Papa ldquoReal-time redoxmeasurements during endoplasmic reticulum stress reveal
interlinked protein folding functionsrdquo Cell vol 135 no 5 pp933ndash947 2008
[186] J W Cuozzo and C A Kaiser ldquoCompetition between glu-tathione and protein thiols for disulphide-bond formationrdquoNature Cell Biology vol 1 no 3 pp 130ndash135 1999
[187] L A Rutkevich M F Cohen-Doyle U Brockmeier and DB Williams ldquoFunctional relationship between protein disulfideisomerase family members during the oxidative folding ofhuman secretory proteinsrdquoMolecular Biology of the Cell vol 21no 18 pp 3093ndash3105 2010
[188] Y Honjo S Kaneko H Ito et al ldquoProtein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateralsclerosisrdquo Amyotrophic Lateral Sclerosis vol 12 no 6 pp 444ndash450 2011
[189] H Tsuda S M Han Y Yang et al ldquoThe amyotrophic lateralsclerosis 8 proteinVAPB is cleaved secreted and acts as a ligandfor Eph receptorsrdquo Cell vol 133 no 6 pp 963ndash977 2008
[190] D M Townsend Y Manevich H Lin et al ldquoNitrosative stress-induced S-glutathionylation of protein disulfide isomerase leadsto activation of the unfolded protein responserdquoCancer Researchvol 69 no 19 pp 7626ndash7634 2009
[191] T Uehara T Nakamura D Yao et al ldquoS-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegen-erationrdquo Nature vol 441 no 7092 pp 513ndash517 2006
[192] X Chen C Li T Guan et al ldquoS-nitrosylated protein disul-phide isomerase contributes to mutant SOD1 aggregates inamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol124 no 1 pp 45ndash58 2012
[193] J D Rothstein ldquoTherapeutic horizons for amyotrophic lateralsclerosisrdquo Current Opinion in Neurobiology vol 6 no 5 pp679ndash687 1996
[194] D W Cleveland ldquoNeuronal growth and death order anddisorder in the axoplasmrdquoCell vol 84 no 5 pp 663ndash666 1996
Figure 2 Redox dysfunction and its relationship to other patholo-gies in ALS Alteration in the enzymatic activity of PDI due toredox dysregulation and oxidative stress can further increase theload of misfolded proteins ER stress oxidative stress autophagymitochondrial dysfunction and axonal impairment leading toneuronal cell death
apoptosis or indirectly to a range of cellular abnormalitiessuch as oxidative stress and protein misfolding which againlead to cell death [164 166] Hence the redox regulationof PDI is a crucial component in the maintenance of abalanced redox environment and inhibition of its enzymaticactivity will lead to important consequences for the cell(Figure 2)
Neurons are highly susceptible to redox dysregulationdue to their high metabolic requirements large size andlower ability to maintain the balance between antioxidantsand ROS [15] In disease states such as ALS oxidativestress and altered enzymatic activity of PDI which normallyreduces ROS and the burden of misfolded protein can causeserious damage to the neuron Since multiple mechanismsare involved in neurodegeneration any imbalance in redoxregulation can lead to an imbalance in the production offree radical species which consequently cause mitochondrialdamage and excitotoxicity thus elevating the levels of freeradicals [193] Furthermore an excess of free radicals canalso lead to DNA damage and may also result in aggregationof NF [194] and structural destabilization of other proteinsthus inducing ER stress and apoptosis Since ALS is a slowprogressive disorder it could be hypothesised that these cyclicevents due to loss of functional activity of PDImay graduallylead to neuronal degradation In such a scenario the redoxregulatory function of PDI may therefore have an importantprotective effect
5 Conclusion
Redox regulation is an important mechanism of homeostasisin eukaryotic cells especially neuronal cells where oxygen
levels are high [15] Many cellular processes rely on it includ-ing proper functioning of the mitochondria and ER calciumregulation axonal transport regulated autophagy and pro-tein folding Links between redox dysregulation and ALSare becoming well documented in the literature althoughthe directionality of these links and their underlying causeare still quite unknown One possible key player in redox reg-ulation in ALS is PDI whose role in ALS pathogenesis is thetopic of much new research As the critical protein involvedin thiol reduction any dysregulation of PDI activity can leadto oxidative stress and redox dysregulation Due to its activityPDI itself also contains an active site thiol group suggestingthat it can also be affected by oxidative stress leading to anescalating cycle that perpetuates redox dysregulation HowPDI becomes nonfunctional in the first place is still unclearalthough somepapers point to S-nitrosylation as having a role[20] Regardless of its exact role any mechanism to improvethe catalytic activity of PDI should have a reductive effect onoxidative stress levels in neurons It is therefore tempting tospeculate about PDI as a possible therapeutic target in thetreatment of ALS
Acknowledgments
This work was supported by the National Health and Med-ical Research Council of Australia (project Grants 4547491006141 and 1030513) Amyotrophic Lateral Sclerosis Asso-ciation (USA) MND Research Institute of Australia Beth-lehem Griffiths Research Council Henry H Roth CharitableFoundation Grant for MND Research Australian RotaryHealth and the Brain Foundation S Parakh holds a La TrobeUniversity Post Graduate Research Scholarship
References
[1] H Kamata and H Hirata ldquoRedox regulation of cellular sig-nallingrdquo Cellular Signalling vol 11 no 1 pp 1ndash14 1999
[2] A R Cross and O T G Jones ldquoEnzymic mechanisms ofsuperoxide productionrdquoBiochimica et BiophysicaActa vol 1057no 3 pp 281ndash298 1991
[3] VAdler Z YinKD Tew andZRonai ldquoRole of redox potentialand reactive oxygen species in stress signalingrdquo Oncogene vol18 no 45 pp 6104ndash6111 1999
[4] J Nordberg and E S J Arner ldquoReactive oxygen speciesantioxidants and the mammalian thioredoxin systemrdquo FreeRadical Biology andMedicine vol 31 no 11 pp 1287ndash1312 2001
[5] M G Espey K M Miranda D D Thomas et al ldquoA chemicalperspective on the interplay between NO reactive oxygenspecies and Reactive Nitrogen Oxide Speciesrdquo Annals of theNew York Academy of Sciences vol 962 pp 195ndash206 2002
[6] W A Pryor and G L Squadrito ldquoThe chemistry of per-oxynitrite a product from the reaction of nitric oxide withsuperoxiderdquo American Journal of Physiology-Lung Cellular andMolecular Physiology vol 268 no 5 pp L699ndashL722 1995
[7] K Abe L H Pan M Watanabe H Konno T Kato andY Itoyama ldquoUpregulation of protein-tyrosine nitration in theanterior horn cells of amyotrophic lateral sclerosisrdquo Neurologi-cal Research vol 19 no 2 pp 124ndash128 1997
Oxidative Medicine and Cellular Longevity 7
[8] J S Beckman M Carson C D Smith and W H KoppenolldquoALS SOD and peroxynitriterdquoNature vol 364 no 6438 p 5841993
[9] S C Barber and P J Shaw ldquoOxidative stress in ALS key rolein motor neuron injury and therapeutic targetrdquo Free RadicalBiology and Medicine vol 48 no 5 pp 629ndash641 2010
[10] M C Martınez and R Andriantsitohaina ldquoReactive nitrogenspecies molecular mechanisms and potential significance inhealth and diseaserdquo Antioxidants and Redox Signaling vol 11no 3 pp 669ndash702 2009
[11] D Trachootham W Lu M A Ogasawara N R D Valle andP Huang ldquoRedox regulation of cell survivalrdquo Antioxidants andRedox Signaling vol 10 no 8 pp 1343ndash1374 2008
[12] C E Cooper R P Patel P S Brookes and VM Darley-UsmarldquoNanotransducers in cellular redox signaling modification ofthiols by reactive oxygen and nitrogen speciesrdquo Trends inBiochemical Sciences vol 27 no 10 pp 489ndash492 2002
[13] H Nakamura K Nakamura and J Yodoi ldquoRedox regulation ofcellular activationrdquo Annual Review of Immunology vol 15 pp351ndash369 1997
[14] S A Lipton Y B Choi Z H Pan et al ldquoA redox-based mech-anism for the neuroprotective and neurodestructive effects ofnitric oxide and related nitroso-compoundsrdquo Nature vol 364no 6438 pp 626ndash632 1993
[15] B Halliwell ldquoOxidative stress and neurodegeneration whereare we nowrdquo Journal of Neurochemistry vol 97 no 6 pp 1634ndash1658 2006
[16] R P Guttmann and T J Powell ldquoRedox regulation of cysteine-dependent enzymes in neurodegenerationrdquo International Jour-nal of Cell Biology vol 2012 Article ID 703164 8 pages 2012
[17] H Tohgi T Abe K Yamazaki T Murata E Ishizaki and CIsobe ldquoIncrease in oxidized NO products and reduction inoxidized glutathione in cerebrospinal fluid from patients withsporadic form of amyotrophic lateral sclerosisrdquo NeuroscienceLetters vol 260 no 3 pp 204ndash206 1999
[18] D R Rosen T Siddique D Patterson et al ldquoMutations inCuZn superoxide dismutase gene are associated with familialamyotrophic lateral sclerosisrdquoNature vol 362 no 6415 pp 59ndash62 1993
[19] Y Ogawa H Kosaka T Nakanishi et al ldquoStability of mutantsuperoxide dismutase-1 associated with familial amyotrophiclateral sclerosis determines the manner of copper release andinduction of thioredoxin in erythrocytesrdquo Biochemical andBiophysical Research Communications vol 241 no 2 pp 251ndash257 1997
[20] A KWalker M A Farg C R Bye C AMcLeanM K Horneand J D Atkin ldquoProtein disulphide isomerase protects againstprotein aggregation and is S-nitrosylated in amyotrophic lateralsclerosisrdquo Brain vol 133 no 1 pp 105ndash116 2010
[21] M W Akhtar C R Sunico T Nakamura and S A Lip-ton ldquoRedox regulation of protein function via cysteine S-nitrosylation and its relevance to neurodegenerative diseasesrdquoInternational Journal of Cell Biology vol 2012 Article ID463756 9 pages 2012
[22] J D Rothstein ldquoCurrent hypotheses for the underlying biologyof amyotrophic lateral sclerosisrdquo Annals of Neurology vol 65no 1 pp S3ndashS9 2009
[23] J Mitchell and G Borasio ldquoAmyotrophic lateral sclerosisrdquoLancet vol 369 no 9578 pp 2031ndash2041 2007
[24] L CWijesekera and PN Leigh ldquoAmyotrophic lateral sclerosisrdquoOrphanet Journal of Rare Diseases vol 4 no 1 p 3 2009
[25] G Bensimon L Lacomblez and V Meininger ldquoA controlledtrial of riluzole in amyotrophic lateral sclerosisrdquo New EnglandJournal of Medicine vol 330 no 9 pp 585ndash591 1994
[26] R G Miller J D Mitchell M Lyon and D HMoore ldquoRiluzolefor amyotrophic lateral sclerosis (ALS)motor neuron disease(MND)rdquoCochraneDatabase of Systematic Reviews no 1 ArticleID CD001447 2007
[27] A Alonso G Logroscino S S Jick and M A HernanldquoAssociation of smoking with amyotrophic lateral sclerosis riskand survival in men and women a prospective studyrdquo BMCNeurology vol 10 no 1 p 6 2010
[28] A Verma and J R Berger ldquoALS syndrome in patients withHIV-1 infectionrdquo Journal of the Neurological Sciences vol 240 no 1-2pp 59ndash64 2006
[29] A Chio B J Traynor F Lombardo et al ldquoPrevalence of SOD1mutations in the Italian ALS populationrdquoNeurology vol 70 no7 pp 533ndash537 2008
[30] L Corrado R Del Bo B Castellotti et al ldquoMutations ofFUS gene in sporadic amyotrophic lateral sclerosisrdquo Journal ofMedical Genetics vol 47 no 3 pp 190ndash194 2010
[31] J Sreedharan I P Blair V B Tripathi et al ldquoTDP-43mutationsin familial and sporadic amyotrophic lateral sclerosisrdquo Sciencevol 319 no 5870 pp 1668ndash1672 2008
[32] E Pupillo P Messina G Logroscino et al ldquoTrauma andamyotrophic lateral sclerosis a case-control study from apopulation-based registryrdquo European Journal of Neurology vol19 no 12 pp 1509ndash1517 2012
[33] S Beretta M T Carrı E Beghi A Chio and C Ferrarese ldquoThesinister side of Italian soccerrdquo Lancet Neurology vol 2 no 11pp 656ndash657 2003
[34] M R Turner C Wotton K Talbot and M J GoldacreldquoCardiovascular fitness as a risk factor for amyotrophic lateralsclerosis indirect evidence from record linkage studyrdquo Journalof Neurology Neurosurgery amp Psychiatry vol 83 pp 395ndash3982012
[35] P A Dion H Daoud and G A Rouleau ldquoGenetics of motorneuron disorders new insights into pathogenic mechanismsrdquoNature Reviews Genetics vol 10 no 11 pp 769ndash782 2009
[36] T Arai M Hasegawa H Akiyama et al ldquoTDP-43 is a compo-nent of ubiquitin-positive tau-negative inclusions in frontotem-poral lobar degeneration and amyotrophic lateral sclerosisrdquoBiochemical and Biophysical Research Communications vol 351no 3 pp 602ndash611 2006
[37] M Neumann D M Sampathu L K Kwong et al ldquoUbiq-uitinated TDP-43 in frontotemporal lobar degeneration andamyotrophic lateral sclerosisrdquo Science vol 314 no 5796 pp130ndash133 2006
[38] C Vance B Rogelj T Hortobagyi et al ldquoMutations in FUSan RNA processing protein cause familial amyotrophic lateralsclerosis type 6rdquo Science vol 323 no 5918 pp 1208ndash1211 2009
[39] Y Yang A Hentati H X Deng et al ldquoThe gene encodingalsin a protein with three guanine-nucleotide exchange factordomains is mutated in a form of recessive amyotrophic lateralsclerosisrdquo Nature Genetics vol 29 pp 160ndash165 2001
[40] A L Nishimura M Mitne-Neto H C A Silva et al ldquoAmutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclero-sisrdquoAmerican Journal of HumanGenetics vol 75 no 5 pp 822ndash831 2004
8 Oxidative Medicine and Cellular Longevity
[41] T J Kwiatkowski Jr D A Bosco A L LeClerc et al ldquoMutationsin the FUSTLS gene on chromosome 16 cause familial amy-otrophic lateral sclerosisrdquo Science vol 323 no 5918 pp 1205ndash1208 2009
[42] HMaruyamaHMorinoH Ito et al ldquoMutations of optineurinin amyotrophic lateral sclerosisrdquo Nature vol 465 no 7295 pp223ndash226 2010
[43] H X Deng W Chen S T Hong et al ldquoMutations in UBQLN2cause dominant X-linked juvenile and adult-onset ALS andALSdementiardquo Nature vol 477 pp 211ndash215 2011
[44] M DeJesus-Hernandez I R Mackenzie B F Boeve et alldquoExpanded GGGGCC hexanucleotide repeat in noncodingregion of C9ORF72 causes chromosome 9p-linked FTD andALSrdquo Neuron vol 72 no 2 pp 245ndash256 2011
[45] L I Bruijn T M Miller and D W Cleveland ldquoUnraveling themechanisms involved in motor neuron degeneration in ALSrdquoAnnual Review of Neuroscience vol 27 pp 723ndash749 2004
[46] H D Durham J Roy L Dong and D A Figlewicz ldquoAggrega-tion of mutant CuZn superoxide dismutase proteins in a cul-turemodel ofALSrdquo Journal ofNeuropathology andExperimentalNeurology vol 56 no 5 pp 523ndash530 1997
[47] M Watanabe M Dykes-Hoberg V Cizewski Culotta D LPrice P C Wong and J D Rothstein ldquoHistological evidenceof protein aggregation in mutant SOD1 transgenic mice andin amyotrophic lateral sclerosis neural tissuesrdquo Neurobiology ofDisease vol 8 no 6 pp 933ndash941 2001
[48] C Soto ldquoUnfolding the role of protein misfolding in neurode-generative diseasesrdquo Nature Reviews Neuroscience vol 4 no 1pp 49ndash60 2003
[49] J Wang G Xu and D R Borchelt ldquoMapping superoxidedismutase 1 domains of non-native interaction roles of intra-and intermolecular disulfide bonding in aggregationrdquo Journalof Neurochemistry vol 96 no 5 pp 1277ndash1288 2006
[50] B S Johnson D Snead J J Lee J M McCaffery J Shorterand A D Gitler ldquoTDP-43 is intrinsically aggregation-proneand amyotrophic lateral sclerosis-linked mutations accelerateaggregation and increase toxicityrdquo Journal of Biological Chem-istry vol 284 pp 20329ndash20339 2009
[51] C Vance B Rogelj T Hortobagyi et al ldquoMutations in FUSan RNA processing protein cause familial amyotrophic lateralsclerosis type 6rdquo Science vol 323 no 5918 pp 1208ndash1211 2009
[52] T Arai M Hasegawa H Akiyama et al ldquoTDP-43 is a compo-nent of ubiquitin-positive tau-negative inclusions in frontotem-poral lobar degeneration and amyotrophic lateral sclerosisrdquoBiochemical and Biophysical Research Communications vol 351no 3 pp 602ndash611 2006
[53] N Shibata A Hirano M Kobayashi et al ldquoIntense super-oxide dismutase-1 immunoreactivity in intracytoplasmic hya-line inclusions of familial amyotrophic lateral sclerosis withposterior column involvementrdquo Journal of Neuropathology andExperimental Neurology vol 55 no 4 pp 481ndash490 1996
[54] J S Valentine P A Doucette and S Z Potter ldquoCopper-zinc superoxide dismutase and amyotrophic lateral sclerosisrdquoAnnual Review of Biochemistry vol 74 pp 563ndash593 2005
[55] F Arnesano L Banci I BertiniMMartinelli Y Furukawa andT V OrsquoHalloran ldquoThe unusually stable quaternary structureof human CuZn-superoxide dismutase 1 is controlled by bothmetal occupancy and disulfide statusrdquo Journal of BiologicalChemistry vol 279 no 46 pp 47998ndash48003 2004
[56] C Kayatekin J A Zitzewitz and C R Matthews ldquoDisulfide-Reduced ALS Variants of Cu Zn Superoxide Dismutase Exhibit
Increased Populations of Unfolded Speciesrdquo Journal of Molecu-lar Biology vol 398 no 2 pp 320ndash331 2010
[57] A E Svensson O Bilsel C Kayatekin J A Adefusika J AZitzewitz and C Robert Matthews ldquoMetal-free ALS variantsof dimeric human CuZn-superoxide dismutase have enhancedpopulations of monomeric speciesrdquo PLoS ONE vol 5 no 4Article ID e10064 2010
[58] M Cozzolino M G Pesaresi V Gerbino J Grosskreutzand M T Carr ldquoAmyotrophic lateral sclerosis new insightsinto underlying molecular mechanisms and opportunities fortherapeutic interventionrdquo Antioxidants amp Redox Signaling vol17 no 9 pp 1277ndash1330 2012
[59] O Spreux-Varoquaux G Bensimon L Lacomblez et al ldquoGlu-tamate levels in cerebrospinal fluid in amyotrophic lateralsclerosis a reappraisal using a new HPLC method with coulo-metric detection in a large cohort of patientsrdquo Journal of theNeurological Sciences vol 193 no 2 pp 73ndash78 2002
[60] I Puls C Jonnakuty B H LaMonte et al ldquoMutant dynactin inmotor neuron diseaserdquo Nature Genetics vol 33 no 4 pp 455ndash456 2003
[61] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[62] J Kong and Z Xu ldquoMassive mitochondrial degeneration inmotor neurons triggers the onset of amyotrophic lateral sclero-sis in mice expressing a mutant SOD1rdquo Journal of Neurosciencevol 18 no 9 pp 3241ndash3250 1998
[63] F R Wiedemann K Winkler A V Kuznetsov et al ldquoImpair-ment of mitochondrial function in skeletal muscle of patientswith amyotrophic lateral sclerosisrdquo Journal of the NeurologicalSciences vol 156 no 1 pp 65ndash72 1998
[64] AHiranoHDonnenfeld S Sasaki and I Nakano ldquoFine struc-tural observations of neurofilamentous changes in amyotrophiclateral sclerosisrdquo Journal of Neuropathology and ExperimentalNeurology vol 43 no 5 pp 461ndash470 1984
[65] J D Wood T P Beaujeux and P J Shaw ldquoProtein aggregationin motor neurone disordersrdquo Neuropathology and AppliedNeurobiology vol 29 no 6 pp 529ndash545 2003
[66] J D Atkin M A Farg A KWalker C McLean D Tomas andM K Horne ldquoEndoplasmic reticulum stress and induction ofthe unfolded protein response in human sporadic amyotrophiclateral sclerosisrdquoNeurobiology of Disease vol 30 no 3 pp 400ndash407 2008
[67] S Chen X Zhang L Song and W Le ldquoAutophagy dysregula-tion in amyotrophic lateral sclerosisrdquo Brain Pathology vol 22no 1 pp 110ndash116 2012
[68] R G Cutler W A Pedersen S Camandola J D Rothsteinand M P Mattson ldquoEvidence that accumulation of ceramidesand cholesterol esters mediates oxidative stress-induced deathof motor neurons in amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 52 no 4 pp 448ndash457 2002
[69] R J Ferrante S E Browne L A Shinobu et al ldquoEvidenceof increased oxidative damage in both sporadic and familialamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol69 no 5 pp 2064ndash2074 1997
[70] M Bogdanov R H Brown W Matson et al ldquoIncreasedoxidative damage to DNA in ALS patientsrdquo Free Radical Biologyand Medicine vol 29 no 7 pp 652ndash658 2000
[71] A W Girotti ldquoLipid hydroperoxide generation turnover andeffector action in biological systemsrdquo Journal of Lipid Researchvol 39 no 8 pp 1529ndash1542 1998
Oxidative Medicine and Cellular Longevity 9
[72] P J Shaw P G Ince G Falkous and D Mantle ldquoOxidativedamage to protein in sporadic motor neuron disease spinalcordrdquo Annals of Neurology vol 38 no 4 pp 691ndash695 1995
[73] D Liu J Wen J Liu and L Li ldquoThe roles of free radicalsin amyotrophic lateral sclerosis reactive oxygen species andelevated oxidation of protein DNA and membrane phospho-lipidsrdquo FASEB Journal vol 13 no 15 pp 2318ndash2328 1999
[74] B J Carter P Anklesaria S Choi and J F Engelhardt ldquoRedoxmodifier genes and pathways in amyotrophic lateral sclerosisrdquoAntioxidants and Redox Signaling vol 11 no 7 pp 1569ndash15862009
[75] H F Poon K Hensley V Thongboonkerd et al ldquoRedoxproteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice-a model of familial amyotrophic lateralsclerosisrdquo Free Radical Biology and Medicine vol 39 no 4 pp453ndash462 2005
[76] J J Haddad ldquoAntioxidant and prooxidant mechanisms in theregulation of redox(y)-sensitive transcription factorsrdquo CellularSignalling vol 14 no 11 pp 879ndash897 2002
[77] K T Turpaev ldquoReactive oxygen species and regulation of geneexpressionrdquo Biochemistry vol 67 no 3 pp 281ndash292 2002
[78] C Iaccarino M E Mura S Esposito et al ldquoBcl2-A1 interactswith pro-caspase-3 implications for amyotrophic lateral scle-rosisrdquo Neurobiology of Disease vol 43 no 3 pp 642ndash650 2011
[79] C Moreau P Gosset J Kluza et al ldquoDeregulation of thehypoxia inducible factor-1120572 pathway in monocytes from spo-radic amyotrophic lateral sclerosis patientsrdquo Neuroscience vol172 pp 110ndash117 2011
[80] C M Karch M Prudencio D D Winkler P J Hart andD R Borchelt ldquoRole of mutant SOD1 disulfide oxidation andaggregation in the pathogenesis of familial ALSrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 106 no 19 pp 7774ndash7779 2009
[81] J B ProescherM Son J L Elliott andV C Culotta ldquoBiologicaleffects of CCS in the absence of SOD1 enzyme activationimplications for disease in a mouse model for ALSrdquo HumanMolecular Genetics vol 17 no 12 pp 1728ndash1737 2008
[82] J M McCord and I Fridovich ldquoSuperoxide dismutase Anenzymic function for erythrocuprein (hemocuprein)rdquo Journalof Biological Chemistry vol 244 no 22 pp 6049ndash6055 1969
[83] D Sau S De Biasi L Vitellaro-Zuccarello et al ldquoMutation ofSOD1 in ALS a gain of a loss of functionrdquo Human MolecularGenetics vol 16 no 13 pp 1604ndash1618 2007
[84] J S Beckman M Carson C D Smith and W H KoppenolldquoALS SOD and peroxynitriterdquoNature vol 364 no 6438 p 5841993
[85] N V Blough and O C Zafiriou ldquoReaction of superoxide withnitric oxide to form peroxonitrite in alkaline aqueous solutionrdquoInorganic Chemistry vol 24 no 22 pp 3502ndash3504 1985
[86] M F Beal R J Ferrante S E Browne Jr R T Matthews NW Kowall and R H Brown ldquoIncreased 3-nitrotyrosine in bothsporadic and familial amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 42 no 4 pp 644ndash654 1997
[87] H Tohgi T Abe K Yamazaki T Murata E Ishizaki andC Isobe ldquoRemarkable increase in cerebrospinal fluid 3-nitrotyrosine in patients with sporadic amyotrophic lateralsclerosisrdquo Annals of Neurology vol 46 pp 129ndash131 1999
[88] F Casoni M Basso T Massignan et al ldquoProtein nitration in amouse model of familial amyotrophic lateral sclerosis possiblemultifunctional role in the pathogenesisrdquo Journal of BiologicalChemistry vol 280 no 16 pp 16295ndash16304 2005
[89] S Guareschi E Cova C Cereda et al ldquoAn over-oxidizedform of superoxide dismutase found in sporadic amyotrophiclateral sclerosiswith bulbar onset shares a toxicmechanismwithmutant SOD1rdquo Proceedings of the National Academy of Sciencesvol 109 no 13 pp 5074ndash5079 2012
[90] RW Orrell R J M Lane andM Ross ldquoA systematic review ofantioxidant treatment for amyotrophic lateral sclerosismotorneuron diseaserdquo Amyotrophic Lateral Sclerosis vol 9 no 4 pp195ndash211 2008
[91] S A Ezzi M Urushitani and J P Julien ldquoWild-type superoxidedismutase acquires binding and toxic properties of ALS-linkedmutant forms through oxidationrdquo Journal of Neurochemistryvol 102 no 1 pp 170ndash178 2007
[92] R L Redler K C Wilcox E A Proctor L Fee M Caplowand N V Dokholyan ldquoGlutathionylation at Cys-111 inducesdissociation of wild type and FALS mutant SOD1 dimersrdquoBiochemistry vol 50 no 32 pp 7057ndash7066 2011
[93] K Forsberg P A Jonsson P M Andersen et al ldquoNovelantibodies reveal inclusions containing non-native SOD1 insporadic ALS patientsrdquo PloS One vol 5 no 7 Article ID e115522010
[94] D A Bosco G Morfini N M Karabacak et al ldquoWild-type andmutant SOD1 share an aberrant conformation and a commonpathogenic pathway in ALSrdquo Nature Neuroscience vol 13 no11 pp 1396ndash1403 2010
[95] A C Estevez J P Crow J B Sampson et al ldquoInduction of nitricoxide-dependent apoptosis in motor neurons by zinc- deficientsuperoxide dismutaserdquo Science vol 286 no 5449 pp 2498ndash2500 1999
[96] Y Furukawa R Fu H X Deng T Siddique and T VOrsquoHalloran ldquoDisulfide cross-linked protein represents a signif-icant fraction of ALS-associated Cu Zn-superoxide dismutaseaggregates in spinal cords of model micerdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 18 pp 7148ndash7153 2006
[97] T J Cohen AWHwang T Unger J Q Trojanowski and VMY Lee ldquoRedox signalling directly regulates TDP-43 via cysteineoxidation and disulphide cross-linkingrdquo The EMBO Journalvol 31 no 5 pp 1241ndash1252 2011
[98] DDormann R Rodde D Edbauer et al ldquoALS-associated fusedin sarcoma (FUS) mutations disrupt transportin-mediatednuclear importrdquo EMBO Journal vol 29 no 16 pp 2841ndash28572010
[99] S P Butcher andAHamberger ldquoIn vivo studies on the extracel-lular and veratrine-releasable pools of endogenous amino acidsin the rat striatum effects of corticostriatal deafferentiation andkainic acid lesionrdquo Journal of Neurochemistry vol 48 no 3 pp713ndash721 1987
[100] I Sen A Nalini N B Joshi and P G Joshi ldquoCerebrospinalfluid from amyotrophic lateral sclerosis patients preferentiallyelevates intracellular calcium and toxicity in motor neurons viaAMPAkainate receptorrdquo Journal of the Neurological Sciencesvol 235 no 1-2 pp 45ndash54 2005
[101] A Plaitakis and J T Caroscio ldquoAbnormal glutamatemetabolism in amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 22 no 5 pp 575ndash579 1987
[102] L Van Den Bosch and W Robberecht ldquoDifferent receptorsmediate motor neuron death induced by short and long expo-sures to excitotoxicityrdquo Brain Research Bulletin vol 53 no 4 pp383ndash388 2000
10 Oxidative Medicine and Cellular Longevity
[103] D Trotti ldquoNeuronal and glial glutamate transporters possessan SH-based redox regulatory mechanismrdquo European Journalof Neuroscience vol 9 no 6 pp 1236ndash1243 1997
[104] A Plaitakis and E Constantakakis ldquoAlteredmetabolism of exci-tatory amino acids N-acetyl-aspartate and N- acetyl-aspartyl-glutamate in amyotrophic lateral sclerosisrdquo Brain ResearchBulletin vol 30 no 3-4 pp 381ndash386 1993
[105] J D Rothstein L J Martin and R W Kuncl ldquoDecreasedglutamate transport by the brain and spinal cord in amyotrophiclateral sclerosisrdquo New England Journal of Medicine vol 326 no22 pp 1464ndash1468 1992
[106] J D Rothstein M Van Kammen A I Levey L J Martin andRW Kuncl ldquoSelective loss of glial glutamate transporter GLT-1amyotrophic lateral sclerosisrdquo Annals of Neurology vol 38 no1 pp 73ndash84 1995
[107] A Volterra D Trotti C Tromba S Floridi and G RacagnildquoGlutamate uptake inhibition by oxygen free radicals in ratcortical astrocytesrdquo Journal of Neuroscience vol 14 no 5 pp2924ndash2932 1994
[108] P J Shaw ldquoGlutamate excitotoxicity and amyotrophic lateralsclerosisrdquo Journal of Neurology vol 244 no 2 pp S3ndashS14 1997
[109] W L Miller ldquoMinireview regulation of steroidogenesis byelectron transferrdquo Endocrinology vol 146 no 6 pp 2544ndash25502005
[110] S Jin F Zhou F Katirai and P L Li ldquoLipid raft redox signalingmolecular mechanisms in health and diseaserdquoAntioxidants andRedox Signaling vol 15 no 4 pp 1043ndash1083 2011
[111] W A Pedersen W Fu J N Keller et al ldquoProtein modificationby the lipid peroxidation product 4-hydroxynonenal in thespinal cords of amyotrophic lateral sclerosis patientsrdquo Annals ofNeurology vol 44 no 5 pp 819ndash824 1998
[112] L Dupuis P Corcia A Fergani et al ldquoDyslipidemia is aprotective factor in amyotrophic lateral sclerosisrdquo Neurologyvol 70 no 13 pp 1004ndash1009 2008
[113] L Dupuis and J P Loeffler ldquoNeuromuscular junction destruc-tion during amyotrophic lateral sclerosis insights from trans-genic modelsrdquo Current Opinion in Pharmacology vol 9 no 3pp 341ndash346 2009
[114] I Choi H D Song S Lee et al ldquoDirect observation ofdefects and increased ion permeability of a membrane inducedby structurally disordered CuZn-superoxide dismutase aggre-gatesrdquo PloS One vol 6 no 12 pp e28982ndashe28982 2011
[115] C Taghibiglou J Lu I R Mackenzie Y T Wang and NR Cashman ldquoSterol regulatory element binding protein-1(SREBP1) activation in motor neurons in excitotoxicity andamyotrophic lateral sclerosis (ALS) indip a potential therapeu-tic peptiderdquo Biochemical and Biophysical Research Communica-tions vol 413 no 2 pp 159ndash163 2011
[116] E Colman A Szarfman J Wyeth et al ldquoAn evaluation of adata mining signal for amyotrophic lateral sclerosis and statinsdetected in FDArsquos spontaneous adverse event reporting systemrdquoPharmacoepidemiology and Drug Safety vol 17 no 11 pp 1068ndash1076 2008
[117] I R Edwards K Star and A Kiuru ldquoStatins neuromusculardegenerative disease and an amyotrophic lateral sclerosis-likesyndrome an analysis of individual case safety reports fromvigibaserdquo Drug Safety vol 30 no 6 pp 515ndash525 2007
[118] L Zinman R Sadeghi M Gawel D Patton and A Kiss ldquoArestatin medications safe in patients with ALSrdquo AmyotrophicLateral Sclerosis vol 9 no 4 pp 223ndash228 2008
[119] HToftSoslashrensen andT L Lash ldquoStatins and amyotrophic lateralsclerosis-the level of evidence for an associationrdquo Journal ofInternal Medicine vol 266 no 6 pp 520ndash526 2009
[120] J Zhai A L Strom R Kilty et al ldquoProteomic characterizationof lipid raft proteins in amyotrophic lateral sclerosis mousespinal cordrdquo FEBS Journal vol 276 no 12 pp 3308ndash3323 2009
[121] M F Beal ldquoAging energy and oxidative stress in neurodegen-erative diseasesrdquoAnnals of Neurology vol 38 no 3 pp 357ndash3661995
[122] F RWiedemann GManfredi CMawrinM Flint Beal and EA Schon ldquoMitochondrial DNA and respiratory chain functionin spinal cords of ALS patientsrdquo Journal of Neurochemistry vol80 no 4 pp 616ndash625 2002
[123] G M Borthwick M A Johnson P G Ince P J Shaw and DM Turnbull ldquoMitochondrial enzyme activity in amyotrophiclateral sclerosis implications for the role of mitochondria inneuronal cell deathrdquoAnnals of Neurology vol 46 no 5 pp 787ndash790 2001
[124] P M Keeney and J P Bennett ldquoALS spinal neurons show variedand reducedmtDNAgene copy numbers and increasedmtDNAgene deletionsrdquoMolecular Neurodegeneration vol 5 no 1 p 212010
[125] M B Graeber E Grasbon-Frodl U V Eitzen and S K KoselldquoNeurodegeneration and aging role of the second genomerdquoJournal of Neuroscience Research vol 52 no 1 pp 1ndash6 1998
[126] K C Zimmermann C Bonzon andD R Green ldquoThemachin-ery of programmed cell deathrdquo Pharmacology andTherapeuticsvol 92 no 1 pp 57ndash70 2001
[127] P Nagley G C Higgins J D Atkin and P M Beart ldquoMul-tifaceted deaths orchestrated by mitochondria in neuronesrdquoBiochimica et Biophysica Acta vol 1802 no 1 pp 167ndash185 2010
[128] C GueganM Vila G Rosoklija A P Hays and S PrzedborskildquoRecruitment of the mitochondria-dependent apoptotic path-way in amyotrophic lateral sclerosisrdquo Journal of Neurosciencevol 21 no 17 pp 6569ndash6576 2001
[129] L J Martin Z Liu K Chen et al ldquoMotor neuron degenerationin amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice mechanisms of mitochondriopathy and celldeathrdquo Journal of Comparative Neurology vol 500 no 1 pp 20ndash46 2007
[130] P C Wong C A Pardo D R Borchelt et al ldquoAn adverseproperty of a familial ALS-linked SOD1 mutation causes motorneuron disease characterized by vacuolar degeneration ofmito-chondriardquo Neuron vol 14 no 6 pp 1105ndash1116 1995
[131] F M Menzies M R Cookson R W Taylor et al ldquoMitochon-drial dysfunction in a cell culturemodel of familial amyotrophiclateral sclerosisrdquo Brain vol 125 no 7 pp 1522ndash1533 2002
[132] M T Carrı A Ferri A Battistoni et al ldquoExpression of aCuZn superoxide dismutase typical of familial amyotrophiclateral sclerosis induces mitochondrial alteration and increaseof cytosolic Ca2+ concentration in transfected neuroblastomaSH-SY5Y cellsrdquo FEBS Letters vol 414 no 2 pp 365ndash368 1997
[133] S Sasaki and M Iwata ldquoUltrastructural study of synapses inthe anterior horn neurons of patients with amyotrophic lateralsclerosisrdquoNeuroscience Letters vol 204 no 1-2 pp 53ndash56 1996
[134] L Siklos J Engelhardt Y Harati R G Smith F Joo andS H Appel ldquoUltrastructural evidence for altered calcium inmotor nerve terminals in amyotrophic lateral sclerosisrdquo Annalsof Neurology vol 39 no 2 pp 203ndash216 1996
[135] M Cozzolino and M T Carrı ldquoMitochondrial dysfunction inALSrdquo Progress in Neurobiology vol 97 no 2 pp 54ndash66 2012
Oxidative Medicine and Cellular Longevity 11
[136] K Y Soo J D Atkin M Farg A K Walker M K Horne andP Nagley ldquoBim links ER stress and apoptosis in cells expressingmutant SOD1 associated with amyotrophic lateral sclerosisrdquoPloS One vol 7 no 4 Article ID e35413 2012
[137] K Hong Y Li W Duan et al ldquoFull-length TDP-43 and itsC-terminal fragments activate mitophagy in NSC34 cell linerdquoNeuroscience Letters vol 530 no 2 pp 144ndash149 2012
[138] R J Braun and B Westermann ldquoMitochondrial dynamics inyeast cell death and agingrdquo Biochemical Society Transactionsvol 39 pp 1520ndash1526 2011
[139] W Duan X Li J Shi Y Guo Z Li and C Li ldquoMutant TARDNA-binding protein-43 induces oxidative injury in motorneuron-like cellrdquo Neuroscience vol 169 no 4 pp 1621ndash16292010
[140] C Jung C M J Higgins and Z Xu ldquoMitochondrial electrontransport chain complex dysfunction in a transgenic mousemodel for amyotrophic lateral sclerosisrdquo Journal of Neurochem-istry vol 83 no 3 pp 535ndash545 2002
[141] A Ferri M Cozzolino C Crosio et al ldquoFamilial ALS-superoxide dismutases associate with mitochondria and shifttheir redox potentialsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 37 pp13860ndash13865 2006
[142] K Aquilano P Vigilanza G Rotilio and M R CiriololdquoMitochondrial damage due to SOD1 deficiency in SH-SY5Yneuroblastoma cells a rationale for the redundancy of SOD1rdquoThe FASEB Journal vol 20 no 10 pp 1683ndash1685 2006
[143] E M OrsquoBrien R Dirmeier M Engle and R O PoytonldquoMitochondrial protein oxidation in yeast mutants lackingmanganese- (MnSOD) or copper- and zinc-containing super-oxide dismutase (CuZnSOD) evidence that mnsod and cuzn-sod have both unique and overlapping functions in protectingmitochondrial proteins from oxidative damagerdquo Journal ofBiological Chemistry vol 279 no 50 pp 51817ndash51827 2004
[144] S Pickles and C V Velde ldquoMisfolded SOD1 and ALS zeroingin on mitochondriardquo Amyotrophic Lateral Sclerosis vol 13 pp333ndash340 2012
[145] B Bandy and A J Davison ldquoMitochondrial mutations mayincrease oxidative stress implications for carcinogenesis andagingrdquo Free Radical Biology andMedicine vol 8 no 6 pp 523ndash539 1990
[146] F Zhang A L Strom K Fukada S Lee L J Hayward andH Zhu ldquoInteraction between familial Amyotrophic LateralSclerosis (ALS)-linked SOD1mutants and the dynein complexrdquoJournal of Biological Chemistry vol 282 no 22 pp 16691ndash166992007
[147] S Sasaki and S Maruyama ldquoUltrastructutal study of skein-like inclusions in anterior horn neurons of patients with motorneuron diseaserdquoNeuroscience Letters vol 147 no 2 pp 121ndash1241992
[148] D A Figlewicz A Krizus M G Martinoli et al ldquoVariantsof the heavy neurofilament subunit are associated with thedevelopment of amyotrophic lateral sclerosisrdquo Human Molec-ular Genetics vol 3 no 10 pp 1757ndash1761 1994
[149] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[150] S M Chou H S Wang and K Komai ldquoColocalization of NOSand SOD1 in neurofilament accumulation within motor neu-rons of amyotrophic lateral sclerosis an immunohistochemicalstudyrdquo Journal of Chemical Neuroanatomy vol 10 no 3-4 pp249ndash258 1996
[151] H Zhang X Kong J Kang et al ldquoOxidative stress inducesparallel autophagy and mitochondria dysfunction in humangliomaU251 cellsrdquoToxicological Sciences vol 110 no 2 pp 376ndash388 2009
[152] J Lee S Giordano and J Zhang ldquoAutophagymitochondria andoxidative stress cross-talk and redox signallingrdquo BiochemicalJournal vol 441 pp 523ndash540 2012
[153] A Li X Zhang and W Le ldquoAltered macroautophagy in thespinal cord of SOD1 mutant micerdquo Autophagy vol 4 no 3 pp290ndash293 2008
[154] Y Zhong Q J Wang X Li et al ldquoDistinct regulation ofautophagic activity by Atg14L and Rubicon associated withBeclin 1-phosphatidylinositol-3-kinase complexrdquo Nature CellBiology vol 11 no 4 pp 468ndash476 2009
[155] S Sasaki ldquoAutophagy in spinal cord motor neurons in sporadicamyotrophic lateral sclerosisrdquo Journal of Neuropathology andExperimental Neurology vol 70 no 5 pp 349ndash359 2011
[156] N Morimoto M Nagai Y Ohta et al ldquoIncreased autophagyin transgenic mice with a G93A mutant SOD1 generdquo BrainResearch vol 1167 no 1 pp 112ndash117 2007
[157] M Schroder ldquoEndoplasmic reticulum stress responsesrdquo Cellu-lar andMolecular Life Sciences vol 65 no 6 pp 862ndash894 2008
[158] J D Atkin M A Farg B J Turner et al ldquoInduction ofthe unfolded protein response in familial amyotrophic lateralsclerosis and association of protein-disulfide isomerase withsuperoxide dismutase 1rdquo Journal of Biological Chemistry vol281 no 40 pp 30152ndash30165 2006
[159] C M Haynes E A Titus and A A Cooper ldquoDegradation ofmisfolded proteins prevents ER-derived oxidative stress and celldeathrdquoMolecular Cell vol 15 no 5 pp 767ndash776 2004
[160] K Kanekura H Suzuki S Aiso and M Matsuoka ldquoER stressand unfolded protein response in amyotrophic lateral sclerosisrdquoMolecular Neurobiology vol 39 no 2 pp 81ndash89 2009
[161] M A Farg K Y Soo A K Walker et al ldquoMutant FUS inducesendoplasmic reticulum stress in amyotrophic lateral sclerosisand interacts with protein disulfide-isomeraserdquoNeurobiology ofAging vol 33 no 12 pp 2855ndash2868 2012
[162] E V Ilieva V Ayala M Jove et al ldquoOxidative and endoplas-mic reticulum stress interplay in sporadic amyotrophic lateralsclerosisrdquo Brain vol 130 no 12 pp 3111ndash3123 2007
[163] J D Malhotra and R J Kaufman ldquoEndoplasmic reticulumstress and oxidative stress a vicious cycle or a double-edgedswordrdquo Antioxidants and Redox Signaling vol 9 no 12 pp2277ndash2293 2007
[164] A K Walker and J D Atkin ldquoMechanisms of neuroprotectionby protein disulphide isomerase in amyotrophic lateral scle-rosisrdquo Neurology Research International vol 2011 Article ID317340 7 pages 2011
[165] R B Freedman T R Hirst andM F Tuite ldquoProtein disulphideisomerase building bridges in protein foldingrdquo Trends inBiochemical Sciences vol 19 no 8 pp 331ndash336 1994
[166] C I Andreu U Woehlbier M Torres and C Hetz ldquoProteindisulfide isomerases in neurodegeneration from disease mech-anisms to biomedical applicationsrdquo FEBS Letters vol 586 no18 pp 2826ndash2834 2012
[167] J J Galligan and D R Petersen ldquoThe human protein disulfideisomerase gene familyrdquoHuman Genomics vol 6 no 1 pp 1ndash152012
[168] L Ellgaard and L W Ruddock ldquoThe human protein disulphideisomerase family substrate interactions and functional proper-tiesrdquo EMBO Reports vol 6 no 1 pp 28ndash32 2005
12 Oxidative Medicine and Cellular Longevity
[169] B Wilkinson and H F Gilbert ldquoProtein disulfide isomeraserdquoBiochimica et Biophysica Acta vol 1699 no 1-2 pp 35ndash44 2004
[170] T Tanaka H Nakamura A Nishiyama et al ldquoRedox regulationby thioredoxin superfamily protection against oxidative stressand agingrdquo Free Radical Research vol 33 no 6 pp 851ndash8552000
[171] C Turano S Coppari F Altieri and A Ferraro ldquoProteins ofthe PDI family unpredicted non-ER locations and functionsrdquoJournal of Cellular Physiology vol 193 no 2 pp 154ndash163 2002
[172] D M Ferrari and H D Soling ldquoThe protein disulphide-isomerase family unravelling a string of foldsrdquo BiochemicalJournal vol 339 no 1 pp 1ndash10 1999
[173] G Tian S Xiang R Noiva W J Lennarz and H SchindelinldquoThe crystal structure of yeast protein disulfide isomerasesuggests cooperativity between its active sitesrdquo Cell vol 124 no1 pp 61ndash73 2006
[174] P Klappa LW Ruddock N J Darby and R B Freedman ldquoThebrsquo domain provides the principal peptide-binding site of proteindisulfide isomerase but all domains contribute to binding ofmisfolded proteinsrdquo EMBO Journal vol 17 no 4 pp 927ndash9351998
[175] A Pirneskoski P Klappa M Lobell et al ldquoMolecular char-acterization of the principal substrate binding site of theubiquitous folding catalyst protein disulfide isomeraserdquo Journalof Biological Chemistry vol 279 no 11 pp 10374ndash10381 2004
[176] G Kozlov P Maattanen D Y Thomas and K Gehring ldquoAstructural overview of the PDI family of proteinsrdquo FEBS Journalvol 277 no 19 pp 3924ndash3936 2010
[177] Y Dai and C C Wang ldquoA mutant truncated protein disulfideisomerase with no chaperone activityrdquo Journal of BiologicalChemistry vol 272 no 44 pp 27572ndash27576 1997
[178] C E Jessop R H Watkins J J Simmons M Tasab andN J Bulleid ldquoProtein disulphide isomerase family membersshow distinct substrate specificity P5 is targeted to BiP clientproteinsrdquo Journal of Cell Science vol 122 no 23 pp 4287ndash42952009
[179] C Appenzeller-Herzog J Riemer E Zito et al ldquoDisulphideproduction by Ero1120572-PDI relay is rapid and effectively regu-latedrdquo EMBO Journal vol 29 no 19 pp 3318ndash3329 2010
[180] F Hatahet and L W Ruddock ldquoProtein disulfide isomerase acritical evaluation of its function in disulfide bond formationrdquoAntioxidants and Redox Signaling vol 11 no 11 pp 2807ndash28502009
[181] N J Bulleid and L Ellgaard ldquoMultiple ways to make disulfidesrdquoTrends in Biochemical Sciences 2011
[182] S Chakravarthi C E Jessop and N J Bulleid ldquoThe role ofglutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stressrdquo EMBOReports vol 7 no3 pp 271ndash275 2006
[183] J Lundstrom and A Holmgren ldquoDetermination of thereduction-oxidation potential of the thioredoxin-like domainsof protein disulfide-isomerase from the equilibrium with glu-tathione and thioredoxinrdquo Biochemistry vol 32 no 26 pp6649ndash6655 1993
[184] E Gross C S Sevier N Heldman et al ldquoGenerating disulfidesenzymatically reaction products and electron acceptors of theendoplasmic reticulum thiol oxidase Ero1prdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 2 pp 299ndash304 2006
[185] P I Merksamer A Trusina and F R Papa ldquoReal-time redoxmeasurements during endoplasmic reticulum stress reveal
interlinked protein folding functionsrdquo Cell vol 135 no 5 pp933ndash947 2008
[186] J W Cuozzo and C A Kaiser ldquoCompetition between glu-tathione and protein thiols for disulphide-bond formationrdquoNature Cell Biology vol 1 no 3 pp 130ndash135 1999
[187] L A Rutkevich M F Cohen-Doyle U Brockmeier and DB Williams ldquoFunctional relationship between protein disulfideisomerase family members during the oxidative folding ofhuman secretory proteinsrdquoMolecular Biology of the Cell vol 21no 18 pp 3093ndash3105 2010
[188] Y Honjo S Kaneko H Ito et al ldquoProtein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateralsclerosisrdquo Amyotrophic Lateral Sclerosis vol 12 no 6 pp 444ndash450 2011
[189] H Tsuda S M Han Y Yang et al ldquoThe amyotrophic lateralsclerosis 8 proteinVAPB is cleaved secreted and acts as a ligandfor Eph receptorsrdquo Cell vol 133 no 6 pp 963ndash977 2008
[190] D M Townsend Y Manevich H Lin et al ldquoNitrosative stress-induced S-glutathionylation of protein disulfide isomerase leadsto activation of the unfolded protein responserdquoCancer Researchvol 69 no 19 pp 7626ndash7634 2009
[191] T Uehara T Nakamura D Yao et al ldquoS-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegen-erationrdquo Nature vol 441 no 7092 pp 513ndash517 2006
[192] X Chen C Li T Guan et al ldquoS-nitrosylated protein disul-phide isomerase contributes to mutant SOD1 aggregates inamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol124 no 1 pp 45ndash58 2012
[193] J D Rothstein ldquoTherapeutic horizons for amyotrophic lateralsclerosisrdquo Current Opinion in Neurobiology vol 6 no 5 pp679ndash687 1996
[194] D W Cleveland ldquoNeuronal growth and death order anddisorder in the axoplasmrdquoCell vol 84 no 5 pp 663ndash666 1996
[8] J S Beckman M Carson C D Smith and W H KoppenolldquoALS SOD and peroxynitriterdquoNature vol 364 no 6438 p 5841993
[9] S C Barber and P J Shaw ldquoOxidative stress in ALS key rolein motor neuron injury and therapeutic targetrdquo Free RadicalBiology and Medicine vol 48 no 5 pp 629ndash641 2010
[10] M C Martınez and R Andriantsitohaina ldquoReactive nitrogenspecies molecular mechanisms and potential significance inhealth and diseaserdquo Antioxidants and Redox Signaling vol 11no 3 pp 669ndash702 2009
[11] D Trachootham W Lu M A Ogasawara N R D Valle andP Huang ldquoRedox regulation of cell survivalrdquo Antioxidants andRedox Signaling vol 10 no 8 pp 1343ndash1374 2008
[12] C E Cooper R P Patel P S Brookes and VM Darley-UsmarldquoNanotransducers in cellular redox signaling modification ofthiols by reactive oxygen and nitrogen speciesrdquo Trends inBiochemical Sciences vol 27 no 10 pp 489ndash492 2002
[13] H Nakamura K Nakamura and J Yodoi ldquoRedox regulation ofcellular activationrdquo Annual Review of Immunology vol 15 pp351ndash369 1997
[14] S A Lipton Y B Choi Z H Pan et al ldquoA redox-based mech-anism for the neuroprotective and neurodestructive effects ofnitric oxide and related nitroso-compoundsrdquo Nature vol 364no 6438 pp 626ndash632 1993
[15] B Halliwell ldquoOxidative stress and neurodegeneration whereare we nowrdquo Journal of Neurochemistry vol 97 no 6 pp 1634ndash1658 2006
[16] R P Guttmann and T J Powell ldquoRedox regulation of cysteine-dependent enzymes in neurodegenerationrdquo International Jour-nal of Cell Biology vol 2012 Article ID 703164 8 pages 2012
[17] H Tohgi T Abe K Yamazaki T Murata E Ishizaki and CIsobe ldquoIncrease in oxidized NO products and reduction inoxidized glutathione in cerebrospinal fluid from patients withsporadic form of amyotrophic lateral sclerosisrdquo NeuroscienceLetters vol 260 no 3 pp 204ndash206 1999
[18] D R Rosen T Siddique D Patterson et al ldquoMutations inCuZn superoxide dismutase gene are associated with familialamyotrophic lateral sclerosisrdquoNature vol 362 no 6415 pp 59ndash62 1993
[19] Y Ogawa H Kosaka T Nakanishi et al ldquoStability of mutantsuperoxide dismutase-1 associated with familial amyotrophiclateral sclerosis determines the manner of copper release andinduction of thioredoxin in erythrocytesrdquo Biochemical andBiophysical Research Communications vol 241 no 2 pp 251ndash257 1997
[20] A KWalker M A Farg C R Bye C AMcLeanM K Horneand J D Atkin ldquoProtein disulphide isomerase protects againstprotein aggregation and is S-nitrosylated in amyotrophic lateralsclerosisrdquo Brain vol 133 no 1 pp 105ndash116 2010
[21] M W Akhtar C R Sunico T Nakamura and S A Lip-ton ldquoRedox regulation of protein function via cysteine S-nitrosylation and its relevance to neurodegenerative diseasesrdquoInternational Journal of Cell Biology vol 2012 Article ID463756 9 pages 2012
[22] J D Rothstein ldquoCurrent hypotheses for the underlying biologyof amyotrophic lateral sclerosisrdquo Annals of Neurology vol 65no 1 pp S3ndashS9 2009
[23] J Mitchell and G Borasio ldquoAmyotrophic lateral sclerosisrdquoLancet vol 369 no 9578 pp 2031ndash2041 2007
[24] L CWijesekera and PN Leigh ldquoAmyotrophic lateral sclerosisrdquoOrphanet Journal of Rare Diseases vol 4 no 1 p 3 2009
[25] G Bensimon L Lacomblez and V Meininger ldquoA controlledtrial of riluzole in amyotrophic lateral sclerosisrdquo New EnglandJournal of Medicine vol 330 no 9 pp 585ndash591 1994
[26] R G Miller J D Mitchell M Lyon and D HMoore ldquoRiluzolefor amyotrophic lateral sclerosis (ALS)motor neuron disease(MND)rdquoCochraneDatabase of Systematic Reviews no 1 ArticleID CD001447 2007
[27] A Alonso G Logroscino S S Jick and M A HernanldquoAssociation of smoking with amyotrophic lateral sclerosis riskand survival in men and women a prospective studyrdquo BMCNeurology vol 10 no 1 p 6 2010
[28] A Verma and J R Berger ldquoALS syndrome in patients withHIV-1 infectionrdquo Journal of the Neurological Sciences vol 240 no 1-2pp 59ndash64 2006
[29] A Chio B J Traynor F Lombardo et al ldquoPrevalence of SOD1mutations in the Italian ALS populationrdquoNeurology vol 70 no7 pp 533ndash537 2008
[30] L Corrado R Del Bo B Castellotti et al ldquoMutations ofFUS gene in sporadic amyotrophic lateral sclerosisrdquo Journal ofMedical Genetics vol 47 no 3 pp 190ndash194 2010
[31] J Sreedharan I P Blair V B Tripathi et al ldquoTDP-43mutationsin familial and sporadic amyotrophic lateral sclerosisrdquo Sciencevol 319 no 5870 pp 1668ndash1672 2008
[32] E Pupillo P Messina G Logroscino et al ldquoTrauma andamyotrophic lateral sclerosis a case-control study from apopulation-based registryrdquo European Journal of Neurology vol19 no 12 pp 1509ndash1517 2012
[33] S Beretta M T Carrı E Beghi A Chio and C Ferrarese ldquoThesinister side of Italian soccerrdquo Lancet Neurology vol 2 no 11pp 656ndash657 2003
[34] M R Turner C Wotton K Talbot and M J GoldacreldquoCardiovascular fitness as a risk factor for amyotrophic lateralsclerosis indirect evidence from record linkage studyrdquo Journalof Neurology Neurosurgery amp Psychiatry vol 83 pp 395ndash3982012
[35] P A Dion H Daoud and G A Rouleau ldquoGenetics of motorneuron disorders new insights into pathogenic mechanismsrdquoNature Reviews Genetics vol 10 no 11 pp 769ndash782 2009
[36] T Arai M Hasegawa H Akiyama et al ldquoTDP-43 is a compo-nent of ubiquitin-positive tau-negative inclusions in frontotem-poral lobar degeneration and amyotrophic lateral sclerosisrdquoBiochemical and Biophysical Research Communications vol 351no 3 pp 602ndash611 2006
[37] M Neumann D M Sampathu L K Kwong et al ldquoUbiq-uitinated TDP-43 in frontotemporal lobar degeneration andamyotrophic lateral sclerosisrdquo Science vol 314 no 5796 pp130ndash133 2006
[38] C Vance B Rogelj T Hortobagyi et al ldquoMutations in FUSan RNA processing protein cause familial amyotrophic lateralsclerosis type 6rdquo Science vol 323 no 5918 pp 1208ndash1211 2009
[39] Y Yang A Hentati H X Deng et al ldquoThe gene encodingalsin a protein with three guanine-nucleotide exchange factordomains is mutated in a form of recessive amyotrophic lateralsclerosisrdquo Nature Genetics vol 29 pp 160ndash165 2001
[40] A L Nishimura M Mitne-Neto H C A Silva et al ldquoAmutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclero-sisrdquoAmerican Journal of HumanGenetics vol 75 no 5 pp 822ndash831 2004
8 Oxidative Medicine and Cellular Longevity
[41] T J Kwiatkowski Jr D A Bosco A L LeClerc et al ldquoMutationsin the FUSTLS gene on chromosome 16 cause familial amy-otrophic lateral sclerosisrdquo Science vol 323 no 5918 pp 1205ndash1208 2009
[42] HMaruyamaHMorinoH Ito et al ldquoMutations of optineurinin amyotrophic lateral sclerosisrdquo Nature vol 465 no 7295 pp223ndash226 2010
[43] H X Deng W Chen S T Hong et al ldquoMutations in UBQLN2cause dominant X-linked juvenile and adult-onset ALS andALSdementiardquo Nature vol 477 pp 211ndash215 2011
[44] M DeJesus-Hernandez I R Mackenzie B F Boeve et alldquoExpanded GGGGCC hexanucleotide repeat in noncodingregion of C9ORF72 causes chromosome 9p-linked FTD andALSrdquo Neuron vol 72 no 2 pp 245ndash256 2011
[45] L I Bruijn T M Miller and D W Cleveland ldquoUnraveling themechanisms involved in motor neuron degeneration in ALSrdquoAnnual Review of Neuroscience vol 27 pp 723ndash749 2004
[46] H D Durham J Roy L Dong and D A Figlewicz ldquoAggrega-tion of mutant CuZn superoxide dismutase proteins in a cul-turemodel ofALSrdquo Journal ofNeuropathology andExperimentalNeurology vol 56 no 5 pp 523ndash530 1997
[47] M Watanabe M Dykes-Hoberg V Cizewski Culotta D LPrice P C Wong and J D Rothstein ldquoHistological evidenceof protein aggregation in mutant SOD1 transgenic mice andin amyotrophic lateral sclerosis neural tissuesrdquo Neurobiology ofDisease vol 8 no 6 pp 933ndash941 2001
[48] C Soto ldquoUnfolding the role of protein misfolding in neurode-generative diseasesrdquo Nature Reviews Neuroscience vol 4 no 1pp 49ndash60 2003
[49] J Wang G Xu and D R Borchelt ldquoMapping superoxidedismutase 1 domains of non-native interaction roles of intra-and intermolecular disulfide bonding in aggregationrdquo Journalof Neurochemistry vol 96 no 5 pp 1277ndash1288 2006
[50] B S Johnson D Snead J J Lee J M McCaffery J Shorterand A D Gitler ldquoTDP-43 is intrinsically aggregation-proneand amyotrophic lateral sclerosis-linked mutations accelerateaggregation and increase toxicityrdquo Journal of Biological Chem-istry vol 284 pp 20329ndash20339 2009
[51] C Vance B Rogelj T Hortobagyi et al ldquoMutations in FUSan RNA processing protein cause familial amyotrophic lateralsclerosis type 6rdquo Science vol 323 no 5918 pp 1208ndash1211 2009
[52] T Arai M Hasegawa H Akiyama et al ldquoTDP-43 is a compo-nent of ubiquitin-positive tau-negative inclusions in frontotem-poral lobar degeneration and amyotrophic lateral sclerosisrdquoBiochemical and Biophysical Research Communications vol 351no 3 pp 602ndash611 2006
[53] N Shibata A Hirano M Kobayashi et al ldquoIntense super-oxide dismutase-1 immunoreactivity in intracytoplasmic hya-line inclusions of familial amyotrophic lateral sclerosis withposterior column involvementrdquo Journal of Neuropathology andExperimental Neurology vol 55 no 4 pp 481ndash490 1996
[54] J S Valentine P A Doucette and S Z Potter ldquoCopper-zinc superoxide dismutase and amyotrophic lateral sclerosisrdquoAnnual Review of Biochemistry vol 74 pp 563ndash593 2005
[55] F Arnesano L Banci I BertiniMMartinelli Y Furukawa andT V OrsquoHalloran ldquoThe unusually stable quaternary structureof human CuZn-superoxide dismutase 1 is controlled by bothmetal occupancy and disulfide statusrdquo Journal of BiologicalChemistry vol 279 no 46 pp 47998ndash48003 2004
[56] C Kayatekin J A Zitzewitz and C R Matthews ldquoDisulfide-Reduced ALS Variants of Cu Zn Superoxide Dismutase Exhibit
Increased Populations of Unfolded Speciesrdquo Journal of Molecu-lar Biology vol 398 no 2 pp 320ndash331 2010
[57] A E Svensson O Bilsel C Kayatekin J A Adefusika J AZitzewitz and C Robert Matthews ldquoMetal-free ALS variantsof dimeric human CuZn-superoxide dismutase have enhancedpopulations of monomeric speciesrdquo PLoS ONE vol 5 no 4Article ID e10064 2010
[58] M Cozzolino M G Pesaresi V Gerbino J Grosskreutzand M T Carr ldquoAmyotrophic lateral sclerosis new insightsinto underlying molecular mechanisms and opportunities fortherapeutic interventionrdquo Antioxidants amp Redox Signaling vol17 no 9 pp 1277ndash1330 2012
[59] O Spreux-Varoquaux G Bensimon L Lacomblez et al ldquoGlu-tamate levels in cerebrospinal fluid in amyotrophic lateralsclerosis a reappraisal using a new HPLC method with coulo-metric detection in a large cohort of patientsrdquo Journal of theNeurological Sciences vol 193 no 2 pp 73ndash78 2002
[60] I Puls C Jonnakuty B H LaMonte et al ldquoMutant dynactin inmotor neuron diseaserdquo Nature Genetics vol 33 no 4 pp 455ndash456 2003
[61] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[62] J Kong and Z Xu ldquoMassive mitochondrial degeneration inmotor neurons triggers the onset of amyotrophic lateral sclero-sis in mice expressing a mutant SOD1rdquo Journal of Neurosciencevol 18 no 9 pp 3241ndash3250 1998
[63] F R Wiedemann K Winkler A V Kuznetsov et al ldquoImpair-ment of mitochondrial function in skeletal muscle of patientswith amyotrophic lateral sclerosisrdquo Journal of the NeurologicalSciences vol 156 no 1 pp 65ndash72 1998
[64] AHiranoHDonnenfeld S Sasaki and I Nakano ldquoFine struc-tural observations of neurofilamentous changes in amyotrophiclateral sclerosisrdquo Journal of Neuropathology and ExperimentalNeurology vol 43 no 5 pp 461ndash470 1984
[65] J D Wood T P Beaujeux and P J Shaw ldquoProtein aggregationin motor neurone disordersrdquo Neuropathology and AppliedNeurobiology vol 29 no 6 pp 529ndash545 2003
[66] J D Atkin M A Farg A KWalker C McLean D Tomas andM K Horne ldquoEndoplasmic reticulum stress and induction ofthe unfolded protein response in human sporadic amyotrophiclateral sclerosisrdquoNeurobiology of Disease vol 30 no 3 pp 400ndash407 2008
[67] S Chen X Zhang L Song and W Le ldquoAutophagy dysregula-tion in amyotrophic lateral sclerosisrdquo Brain Pathology vol 22no 1 pp 110ndash116 2012
[68] R G Cutler W A Pedersen S Camandola J D Rothsteinand M P Mattson ldquoEvidence that accumulation of ceramidesand cholesterol esters mediates oxidative stress-induced deathof motor neurons in amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 52 no 4 pp 448ndash457 2002
[69] R J Ferrante S E Browne L A Shinobu et al ldquoEvidenceof increased oxidative damage in both sporadic and familialamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol69 no 5 pp 2064ndash2074 1997
[70] M Bogdanov R H Brown W Matson et al ldquoIncreasedoxidative damage to DNA in ALS patientsrdquo Free Radical Biologyand Medicine vol 29 no 7 pp 652ndash658 2000
[71] A W Girotti ldquoLipid hydroperoxide generation turnover andeffector action in biological systemsrdquo Journal of Lipid Researchvol 39 no 8 pp 1529ndash1542 1998
Oxidative Medicine and Cellular Longevity 9
[72] P J Shaw P G Ince G Falkous and D Mantle ldquoOxidativedamage to protein in sporadic motor neuron disease spinalcordrdquo Annals of Neurology vol 38 no 4 pp 691ndash695 1995
[73] D Liu J Wen J Liu and L Li ldquoThe roles of free radicalsin amyotrophic lateral sclerosis reactive oxygen species andelevated oxidation of protein DNA and membrane phospho-lipidsrdquo FASEB Journal vol 13 no 15 pp 2318ndash2328 1999
[74] B J Carter P Anklesaria S Choi and J F Engelhardt ldquoRedoxmodifier genes and pathways in amyotrophic lateral sclerosisrdquoAntioxidants and Redox Signaling vol 11 no 7 pp 1569ndash15862009
[75] H F Poon K Hensley V Thongboonkerd et al ldquoRedoxproteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice-a model of familial amyotrophic lateralsclerosisrdquo Free Radical Biology and Medicine vol 39 no 4 pp453ndash462 2005
[76] J J Haddad ldquoAntioxidant and prooxidant mechanisms in theregulation of redox(y)-sensitive transcription factorsrdquo CellularSignalling vol 14 no 11 pp 879ndash897 2002
[77] K T Turpaev ldquoReactive oxygen species and regulation of geneexpressionrdquo Biochemistry vol 67 no 3 pp 281ndash292 2002
[78] C Iaccarino M E Mura S Esposito et al ldquoBcl2-A1 interactswith pro-caspase-3 implications for amyotrophic lateral scle-rosisrdquo Neurobiology of Disease vol 43 no 3 pp 642ndash650 2011
[79] C Moreau P Gosset J Kluza et al ldquoDeregulation of thehypoxia inducible factor-1120572 pathway in monocytes from spo-radic amyotrophic lateral sclerosis patientsrdquo Neuroscience vol172 pp 110ndash117 2011
[80] C M Karch M Prudencio D D Winkler P J Hart andD R Borchelt ldquoRole of mutant SOD1 disulfide oxidation andaggregation in the pathogenesis of familial ALSrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 106 no 19 pp 7774ndash7779 2009
[81] J B ProescherM Son J L Elliott andV C Culotta ldquoBiologicaleffects of CCS in the absence of SOD1 enzyme activationimplications for disease in a mouse model for ALSrdquo HumanMolecular Genetics vol 17 no 12 pp 1728ndash1737 2008
[82] J M McCord and I Fridovich ldquoSuperoxide dismutase Anenzymic function for erythrocuprein (hemocuprein)rdquo Journalof Biological Chemistry vol 244 no 22 pp 6049ndash6055 1969
[83] D Sau S De Biasi L Vitellaro-Zuccarello et al ldquoMutation ofSOD1 in ALS a gain of a loss of functionrdquo Human MolecularGenetics vol 16 no 13 pp 1604ndash1618 2007
[84] J S Beckman M Carson C D Smith and W H KoppenolldquoALS SOD and peroxynitriterdquoNature vol 364 no 6438 p 5841993
[85] N V Blough and O C Zafiriou ldquoReaction of superoxide withnitric oxide to form peroxonitrite in alkaline aqueous solutionrdquoInorganic Chemistry vol 24 no 22 pp 3502ndash3504 1985
[86] M F Beal R J Ferrante S E Browne Jr R T Matthews NW Kowall and R H Brown ldquoIncreased 3-nitrotyrosine in bothsporadic and familial amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 42 no 4 pp 644ndash654 1997
[87] H Tohgi T Abe K Yamazaki T Murata E Ishizaki andC Isobe ldquoRemarkable increase in cerebrospinal fluid 3-nitrotyrosine in patients with sporadic amyotrophic lateralsclerosisrdquo Annals of Neurology vol 46 pp 129ndash131 1999
[88] F Casoni M Basso T Massignan et al ldquoProtein nitration in amouse model of familial amyotrophic lateral sclerosis possiblemultifunctional role in the pathogenesisrdquo Journal of BiologicalChemistry vol 280 no 16 pp 16295ndash16304 2005
[89] S Guareschi E Cova C Cereda et al ldquoAn over-oxidizedform of superoxide dismutase found in sporadic amyotrophiclateral sclerosiswith bulbar onset shares a toxicmechanismwithmutant SOD1rdquo Proceedings of the National Academy of Sciencesvol 109 no 13 pp 5074ndash5079 2012
[90] RW Orrell R J M Lane andM Ross ldquoA systematic review ofantioxidant treatment for amyotrophic lateral sclerosismotorneuron diseaserdquo Amyotrophic Lateral Sclerosis vol 9 no 4 pp195ndash211 2008
[91] S A Ezzi M Urushitani and J P Julien ldquoWild-type superoxidedismutase acquires binding and toxic properties of ALS-linkedmutant forms through oxidationrdquo Journal of Neurochemistryvol 102 no 1 pp 170ndash178 2007
[92] R L Redler K C Wilcox E A Proctor L Fee M Caplowand N V Dokholyan ldquoGlutathionylation at Cys-111 inducesdissociation of wild type and FALS mutant SOD1 dimersrdquoBiochemistry vol 50 no 32 pp 7057ndash7066 2011
[93] K Forsberg P A Jonsson P M Andersen et al ldquoNovelantibodies reveal inclusions containing non-native SOD1 insporadic ALS patientsrdquo PloS One vol 5 no 7 Article ID e115522010
[94] D A Bosco G Morfini N M Karabacak et al ldquoWild-type andmutant SOD1 share an aberrant conformation and a commonpathogenic pathway in ALSrdquo Nature Neuroscience vol 13 no11 pp 1396ndash1403 2010
[95] A C Estevez J P Crow J B Sampson et al ldquoInduction of nitricoxide-dependent apoptosis in motor neurons by zinc- deficientsuperoxide dismutaserdquo Science vol 286 no 5449 pp 2498ndash2500 1999
[96] Y Furukawa R Fu H X Deng T Siddique and T VOrsquoHalloran ldquoDisulfide cross-linked protein represents a signif-icant fraction of ALS-associated Cu Zn-superoxide dismutaseaggregates in spinal cords of model micerdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 18 pp 7148ndash7153 2006
[97] T J Cohen AWHwang T Unger J Q Trojanowski and VMY Lee ldquoRedox signalling directly regulates TDP-43 via cysteineoxidation and disulphide cross-linkingrdquo The EMBO Journalvol 31 no 5 pp 1241ndash1252 2011
[98] DDormann R Rodde D Edbauer et al ldquoALS-associated fusedin sarcoma (FUS) mutations disrupt transportin-mediatednuclear importrdquo EMBO Journal vol 29 no 16 pp 2841ndash28572010
[99] S P Butcher andAHamberger ldquoIn vivo studies on the extracel-lular and veratrine-releasable pools of endogenous amino acidsin the rat striatum effects of corticostriatal deafferentiation andkainic acid lesionrdquo Journal of Neurochemistry vol 48 no 3 pp713ndash721 1987
[100] I Sen A Nalini N B Joshi and P G Joshi ldquoCerebrospinalfluid from amyotrophic lateral sclerosis patients preferentiallyelevates intracellular calcium and toxicity in motor neurons viaAMPAkainate receptorrdquo Journal of the Neurological Sciencesvol 235 no 1-2 pp 45ndash54 2005
[101] A Plaitakis and J T Caroscio ldquoAbnormal glutamatemetabolism in amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 22 no 5 pp 575ndash579 1987
[102] L Van Den Bosch and W Robberecht ldquoDifferent receptorsmediate motor neuron death induced by short and long expo-sures to excitotoxicityrdquo Brain Research Bulletin vol 53 no 4 pp383ndash388 2000
10 Oxidative Medicine and Cellular Longevity
[103] D Trotti ldquoNeuronal and glial glutamate transporters possessan SH-based redox regulatory mechanismrdquo European Journalof Neuroscience vol 9 no 6 pp 1236ndash1243 1997
[104] A Plaitakis and E Constantakakis ldquoAlteredmetabolism of exci-tatory amino acids N-acetyl-aspartate and N- acetyl-aspartyl-glutamate in amyotrophic lateral sclerosisrdquo Brain ResearchBulletin vol 30 no 3-4 pp 381ndash386 1993
[105] J D Rothstein L J Martin and R W Kuncl ldquoDecreasedglutamate transport by the brain and spinal cord in amyotrophiclateral sclerosisrdquo New England Journal of Medicine vol 326 no22 pp 1464ndash1468 1992
[106] J D Rothstein M Van Kammen A I Levey L J Martin andRW Kuncl ldquoSelective loss of glial glutamate transporter GLT-1amyotrophic lateral sclerosisrdquo Annals of Neurology vol 38 no1 pp 73ndash84 1995
[107] A Volterra D Trotti C Tromba S Floridi and G RacagnildquoGlutamate uptake inhibition by oxygen free radicals in ratcortical astrocytesrdquo Journal of Neuroscience vol 14 no 5 pp2924ndash2932 1994
[108] P J Shaw ldquoGlutamate excitotoxicity and amyotrophic lateralsclerosisrdquo Journal of Neurology vol 244 no 2 pp S3ndashS14 1997
[109] W L Miller ldquoMinireview regulation of steroidogenesis byelectron transferrdquo Endocrinology vol 146 no 6 pp 2544ndash25502005
[110] S Jin F Zhou F Katirai and P L Li ldquoLipid raft redox signalingmolecular mechanisms in health and diseaserdquoAntioxidants andRedox Signaling vol 15 no 4 pp 1043ndash1083 2011
[111] W A Pedersen W Fu J N Keller et al ldquoProtein modificationby the lipid peroxidation product 4-hydroxynonenal in thespinal cords of amyotrophic lateral sclerosis patientsrdquo Annals ofNeurology vol 44 no 5 pp 819ndash824 1998
[112] L Dupuis P Corcia A Fergani et al ldquoDyslipidemia is aprotective factor in amyotrophic lateral sclerosisrdquo Neurologyvol 70 no 13 pp 1004ndash1009 2008
[113] L Dupuis and J P Loeffler ldquoNeuromuscular junction destruc-tion during amyotrophic lateral sclerosis insights from trans-genic modelsrdquo Current Opinion in Pharmacology vol 9 no 3pp 341ndash346 2009
[114] I Choi H D Song S Lee et al ldquoDirect observation ofdefects and increased ion permeability of a membrane inducedby structurally disordered CuZn-superoxide dismutase aggre-gatesrdquo PloS One vol 6 no 12 pp e28982ndashe28982 2011
[115] C Taghibiglou J Lu I R Mackenzie Y T Wang and NR Cashman ldquoSterol regulatory element binding protein-1(SREBP1) activation in motor neurons in excitotoxicity andamyotrophic lateral sclerosis (ALS) indip a potential therapeu-tic peptiderdquo Biochemical and Biophysical Research Communica-tions vol 413 no 2 pp 159ndash163 2011
[116] E Colman A Szarfman J Wyeth et al ldquoAn evaluation of adata mining signal for amyotrophic lateral sclerosis and statinsdetected in FDArsquos spontaneous adverse event reporting systemrdquoPharmacoepidemiology and Drug Safety vol 17 no 11 pp 1068ndash1076 2008
[117] I R Edwards K Star and A Kiuru ldquoStatins neuromusculardegenerative disease and an amyotrophic lateral sclerosis-likesyndrome an analysis of individual case safety reports fromvigibaserdquo Drug Safety vol 30 no 6 pp 515ndash525 2007
[118] L Zinman R Sadeghi M Gawel D Patton and A Kiss ldquoArestatin medications safe in patients with ALSrdquo AmyotrophicLateral Sclerosis vol 9 no 4 pp 223ndash228 2008
[119] HToftSoslashrensen andT L Lash ldquoStatins and amyotrophic lateralsclerosis-the level of evidence for an associationrdquo Journal ofInternal Medicine vol 266 no 6 pp 520ndash526 2009
[120] J Zhai A L Strom R Kilty et al ldquoProteomic characterizationof lipid raft proteins in amyotrophic lateral sclerosis mousespinal cordrdquo FEBS Journal vol 276 no 12 pp 3308ndash3323 2009
[121] M F Beal ldquoAging energy and oxidative stress in neurodegen-erative diseasesrdquoAnnals of Neurology vol 38 no 3 pp 357ndash3661995
[122] F RWiedemann GManfredi CMawrinM Flint Beal and EA Schon ldquoMitochondrial DNA and respiratory chain functionin spinal cords of ALS patientsrdquo Journal of Neurochemistry vol80 no 4 pp 616ndash625 2002
[123] G M Borthwick M A Johnson P G Ince P J Shaw and DM Turnbull ldquoMitochondrial enzyme activity in amyotrophiclateral sclerosis implications for the role of mitochondria inneuronal cell deathrdquoAnnals of Neurology vol 46 no 5 pp 787ndash790 2001
[124] P M Keeney and J P Bennett ldquoALS spinal neurons show variedand reducedmtDNAgene copy numbers and increasedmtDNAgene deletionsrdquoMolecular Neurodegeneration vol 5 no 1 p 212010
[125] M B Graeber E Grasbon-Frodl U V Eitzen and S K KoselldquoNeurodegeneration and aging role of the second genomerdquoJournal of Neuroscience Research vol 52 no 1 pp 1ndash6 1998
[126] K C Zimmermann C Bonzon andD R Green ldquoThemachin-ery of programmed cell deathrdquo Pharmacology andTherapeuticsvol 92 no 1 pp 57ndash70 2001
[127] P Nagley G C Higgins J D Atkin and P M Beart ldquoMul-tifaceted deaths orchestrated by mitochondria in neuronesrdquoBiochimica et Biophysica Acta vol 1802 no 1 pp 167ndash185 2010
[128] C GueganM Vila G Rosoklija A P Hays and S PrzedborskildquoRecruitment of the mitochondria-dependent apoptotic path-way in amyotrophic lateral sclerosisrdquo Journal of Neurosciencevol 21 no 17 pp 6569ndash6576 2001
[129] L J Martin Z Liu K Chen et al ldquoMotor neuron degenerationin amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice mechanisms of mitochondriopathy and celldeathrdquo Journal of Comparative Neurology vol 500 no 1 pp 20ndash46 2007
[130] P C Wong C A Pardo D R Borchelt et al ldquoAn adverseproperty of a familial ALS-linked SOD1 mutation causes motorneuron disease characterized by vacuolar degeneration ofmito-chondriardquo Neuron vol 14 no 6 pp 1105ndash1116 1995
[131] F M Menzies M R Cookson R W Taylor et al ldquoMitochon-drial dysfunction in a cell culturemodel of familial amyotrophiclateral sclerosisrdquo Brain vol 125 no 7 pp 1522ndash1533 2002
[132] M T Carrı A Ferri A Battistoni et al ldquoExpression of aCuZn superoxide dismutase typical of familial amyotrophiclateral sclerosis induces mitochondrial alteration and increaseof cytosolic Ca2+ concentration in transfected neuroblastomaSH-SY5Y cellsrdquo FEBS Letters vol 414 no 2 pp 365ndash368 1997
[133] S Sasaki and M Iwata ldquoUltrastructural study of synapses inthe anterior horn neurons of patients with amyotrophic lateralsclerosisrdquoNeuroscience Letters vol 204 no 1-2 pp 53ndash56 1996
[134] L Siklos J Engelhardt Y Harati R G Smith F Joo andS H Appel ldquoUltrastructural evidence for altered calcium inmotor nerve terminals in amyotrophic lateral sclerosisrdquo Annalsof Neurology vol 39 no 2 pp 203ndash216 1996
[135] M Cozzolino and M T Carrı ldquoMitochondrial dysfunction inALSrdquo Progress in Neurobiology vol 97 no 2 pp 54ndash66 2012
Oxidative Medicine and Cellular Longevity 11
[136] K Y Soo J D Atkin M Farg A K Walker M K Horne andP Nagley ldquoBim links ER stress and apoptosis in cells expressingmutant SOD1 associated with amyotrophic lateral sclerosisrdquoPloS One vol 7 no 4 Article ID e35413 2012
[137] K Hong Y Li W Duan et al ldquoFull-length TDP-43 and itsC-terminal fragments activate mitophagy in NSC34 cell linerdquoNeuroscience Letters vol 530 no 2 pp 144ndash149 2012
[138] R J Braun and B Westermann ldquoMitochondrial dynamics inyeast cell death and agingrdquo Biochemical Society Transactionsvol 39 pp 1520ndash1526 2011
[139] W Duan X Li J Shi Y Guo Z Li and C Li ldquoMutant TARDNA-binding protein-43 induces oxidative injury in motorneuron-like cellrdquo Neuroscience vol 169 no 4 pp 1621ndash16292010
[140] C Jung C M J Higgins and Z Xu ldquoMitochondrial electrontransport chain complex dysfunction in a transgenic mousemodel for amyotrophic lateral sclerosisrdquo Journal of Neurochem-istry vol 83 no 3 pp 535ndash545 2002
[141] A Ferri M Cozzolino C Crosio et al ldquoFamilial ALS-superoxide dismutases associate with mitochondria and shifttheir redox potentialsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 37 pp13860ndash13865 2006
[142] K Aquilano P Vigilanza G Rotilio and M R CiriololdquoMitochondrial damage due to SOD1 deficiency in SH-SY5Yneuroblastoma cells a rationale for the redundancy of SOD1rdquoThe FASEB Journal vol 20 no 10 pp 1683ndash1685 2006
[143] E M OrsquoBrien R Dirmeier M Engle and R O PoytonldquoMitochondrial protein oxidation in yeast mutants lackingmanganese- (MnSOD) or copper- and zinc-containing super-oxide dismutase (CuZnSOD) evidence that mnsod and cuzn-sod have both unique and overlapping functions in protectingmitochondrial proteins from oxidative damagerdquo Journal ofBiological Chemistry vol 279 no 50 pp 51817ndash51827 2004
[144] S Pickles and C V Velde ldquoMisfolded SOD1 and ALS zeroingin on mitochondriardquo Amyotrophic Lateral Sclerosis vol 13 pp333ndash340 2012
[145] B Bandy and A J Davison ldquoMitochondrial mutations mayincrease oxidative stress implications for carcinogenesis andagingrdquo Free Radical Biology andMedicine vol 8 no 6 pp 523ndash539 1990
[146] F Zhang A L Strom K Fukada S Lee L J Hayward andH Zhu ldquoInteraction between familial Amyotrophic LateralSclerosis (ALS)-linked SOD1mutants and the dynein complexrdquoJournal of Biological Chemistry vol 282 no 22 pp 16691ndash166992007
[147] S Sasaki and S Maruyama ldquoUltrastructutal study of skein-like inclusions in anterior horn neurons of patients with motorneuron diseaserdquoNeuroscience Letters vol 147 no 2 pp 121ndash1241992
[148] D A Figlewicz A Krizus M G Martinoli et al ldquoVariantsof the heavy neurofilament subunit are associated with thedevelopment of amyotrophic lateral sclerosisrdquo Human Molec-ular Genetics vol 3 no 10 pp 1757ndash1761 1994
[149] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[150] S M Chou H S Wang and K Komai ldquoColocalization of NOSand SOD1 in neurofilament accumulation within motor neu-rons of amyotrophic lateral sclerosis an immunohistochemicalstudyrdquo Journal of Chemical Neuroanatomy vol 10 no 3-4 pp249ndash258 1996
[151] H Zhang X Kong J Kang et al ldquoOxidative stress inducesparallel autophagy and mitochondria dysfunction in humangliomaU251 cellsrdquoToxicological Sciences vol 110 no 2 pp 376ndash388 2009
[152] J Lee S Giordano and J Zhang ldquoAutophagymitochondria andoxidative stress cross-talk and redox signallingrdquo BiochemicalJournal vol 441 pp 523ndash540 2012
[153] A Li X Zhang and W Le ldquoAltered macroautophagy in thespinal cord of SOD1 mutant micerdquo Autophagy vol 4 no 3 pp290ndash293 2008
[154] Y Zhong Q J Wang X Li et al ldquoDistinct regulation ofautophagic activity by Atg14L and Rubicon associated withBeclin 1-phosphatidylinositol-3-kinase complexrdquo Nature CellBiology vol 11 no 4 pp 468ndash476 2009
[155] S Sasaki ldquoAutophagy in spinal cord motor neurons in sporadicamyotrophic lateral sclerosisrdquo Journal of Neuropathology andExperimental Neurology vol 70 no 5 pp 349ndash359 2011
[156] N Morimoto M Nagai Y Ohta et al ldquoIncreased autophagyin transgenic mice with a G93A mutant SOD1 generdquo BrainResearch vol 1167 no 1 pp 112ndash117 2007
[157] M Schroder ldquoEndoplasmic reticulum stress responsesrdquo Cellu-lar andMolecular Life Sciences vol 65 no 6 pp 862ndash894 2008
[158] J D Atkin M A Farg B J Turner et al ldquoInduction ofthe unfolded protein response in familial amyotrophic lateralsclerosis and association of protein-disulfide isomerase withsuperoxide dismutase 1rdquo Journal of Biological Chemistry vol281 no 40 pp 30152ndash30165 2006
[159] C M Haynes E A Titus and A A Cooper ldquoDegradation ofmisfolded proteins prevents ER-derived oxidative stress and celldeathrdquoMolecular Cell vol 15 no 5 pp 767ndash776 2004
[160] K Kanekura H Suzuki S Aiso and M Matsuoka ldquoER stressand unfolded protein response in amyotrophic lateral sclerosisrdquoMolecular Neurobiology vol 39 no 2 pp 81ndash89 2009
[161] M A Farg K Y Soo A K Walker et al ldquoMutant FUS inducesendoplasmic reticulum stress in amyotrophic lateral sclerosisand interacts with protein disulfide-isomeraserdquoNeurobiology ofAging vol 33 no 12 pp 2855ndash2868 2012
[162] E V Ilieva V Ayala M Jove et al ldquoOxidative and endoplas-mic reticulum stress interplay in sporadic amyotrophic lateralsclerosisrdquo Brain vol 130 no 12 pp 3111ndash3123 2007
[163] J D Malhotra and R J Kaufman ldquoEndoplasmic reticulumstress and oxidative stress a vicious cycle or a double-edgedswordrdquo Antioxidants and Redox Signaling vol 9 no 12 pp2277ndash2293 2007
[164] A K Walker and J D Atkin ldquoMechanisms of neuroprotectionby protein disulphide isomerase in amyotrophic lateral scle-rosisrdquo Neurology Research International vol 2011 Article ID317340 7 pages 2011
[165] R B Freedman T R Hirst andM F Tuite ldquoProtein disulphideisomerase building bridges in protein foldingrdquo Trends inBiochemical Sciences vol 19 no 8 pp 331ndash336 1994
[166] C I Andreu U Woehlbier M Torres and C Hetz ldquoProteindisulfide isomerases in neurodegeneration from disease mech-anisms to biomedical applicationsrdquo FEBS Letters vol 586 no18 pp 2826ndash2834 2012
[167] J J Galligan and D R Petersen ldquoThe human protein disulfideisomerase gene familyrdquoHuman Genomics vol 6 no 1 pp 1ndash152012
[168] L Ellgaard and L W Ruddock ldquoThe human protein disulphideisomerase family substrate interactions and functional proper-tiesrdquo EMBO Reports vol 6 no 1 pp 28ndash32 2005
12 Oxidative Medicine and Cellular Longevity
[169] B Wilkinson and H F Gilbert ldquoProtein disulfide isomeraserdquoBiochimica et Biophysica Acta vol 1699 no 1-2 pp 35ndash44 2004
[170] T Tanaka H Nakamura A Nishiyama et al ldquoRedox regulationby thioredoxin superfamily protection against oxidative stressand agingrdquo Free Radical Research vol 33 no 6 pp 851ndash8552000
[171] C Turano S Coppari F Altieri and A Ferraro ldquoProteins ofthe PDI family unpredicted non-ER locations and functionsrdquoJournal of Cellular Physiology vol 193 no 2 pp 154ndash163 2002
[172] D M Ferrari and H D Soling ldquoThe protein disulphide-isomerase family unravelling a string of foldsrdquo BiochemicalJournal vol 339 no 1 pp 1ndash10 1999
[173] G Tian S Xiang R Noiva W J Lennarz and H SchindelinldquoThe crystal structure of yeast protein disulfide isomerasesuggests cooperativity between its active sitesrdquo Cell vol 124 no1 pp 61ndash73 2006
[174] P Klappa LW Ruddock N J Darby and R B Freedman ldquoThebrsquo domain provides the principal peptide-binding site of proteindisulfide isomerase but all domains contribute to binding ofmisfolded proteinsrdquo EMBO Journal vol 17 no 4 pp 927ndash9351998
[175] A Pirneskoski P Klappa M Lobell et al ldquoMolecular char-acterization of the principal substrate binding site of theubiquitous folding catalyst protein disulfide isomeraserdquo Journalof Biological Chemistry vol 279 no 11 pp 10374ndash10381 2004
[176] G Kozlov P Maattanen D Y Thomas and K Gehring ldquoAstructural overview of the PDI family of proteinsrdquo FEBS Journalvol 277 no 19 pp 3924ndash3936 2010
[177] Y Dai and C C Wang ldquoA mutant truncated protein disulfideisomerase with no chaperone activityrdquo Journal of BiologicalChemistry vol 272 no 44 pp 27572ndash27576 1997
[178] C E Jessop R H Watkins J J Simmons M Tasab andN J Bulleid ldquoProtein disulphide isomerase family membersshow distinct substrate specificity P5 is targeted to BiP clientproteinsrdquo Journal of Cell Science vol 122 no 23 pp 4287ndash42952009
[179] C Appenzeller-Herzog J Riemer E Zito et al ldquoDisulphideproduction by Ero1120572-PDI relay is rapid and effectively regu-latedrdquo EMBO Journal vol 29 no 19 pp 3318ndash3329 2010
[180] F Hatahet and L W Ruddock ldquoProtein disulfide isomerase acritical evaluation of its function in disulfide bond formationrdquoAntioxidants and Redox Signaling vol 11 no 11 pp 2807ndash28502009
[181] N J Bulleid and L Ellgaard ldquoMultiple ways to make disulfidesrdquoTrends in Biochemical Sciences 2011
[182] S Chakravarthi C E Jessop and N J Bulleid ldquoThe role ofglutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stressrdquo EMBOReports vol 7 no3 pp 271ndash275 2006
[183] J Lundstrom and A Holmgren ldquoDetermination of thereduction-oxidation potential of the thioredoxin-like domainsof protein disulfide-isomerase from the equilibrium with glu-tathione and thioredoxinrdquo Biochemistry vol 32 no 26 pp6649ndash6655 1993
[184] E Gross C S Sevier N Heldman et al ldquoGenerating disulfidesenzymatically reaction products and electron acceptors of theendoplasmic reticulum thiol oxidase Ero1prdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 2 pp 299ndash304 2006
[185] P I Merksamer A Trusina and F R Papa ldquoReal-time redoxmeasurements during endoplasmic reticulum stress reveal
interlinked protein folding functionsrdquo Cell vol 135 no 5 pp933ndash947 2008
[186] J W Cuozzo and C A Kaiser ldquoCompetition between glu-tathione and protein thiols for disulphide-bond formationrdquoNature Cell Biology vol 1 no 3 pp 130ndash135 1999
[187] L A Rutkevich M F Cohen-Doyle U Brockmeier and DB Williams ldquoFunctional relationship between protein disulfideisomerase family members during the oxidative folding ofhuman secretory proteinsrdquoMolecular Biology of the Cell vol 21no 18 pp 3093ndash3105 2010
[188] Y Honjo S Kaneko H Ito et al ldquoProtein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateralsclerosisrdquo Amyotrophic Lateral Sclerosis vol 12 no 6 pp 444ndash450 2011
[189] H Tsuda S M Han Y Yang et al ldquoThe amyotrophic lateralsclerosis 8 proteinVAPB is cleaved secreted and acts as a ligandfor Eph receptorsrdquo Cell vol 133 no 6 pp 963ndash977 2008
[190] D M Townsend Y Manevich H Lin et al ldquoNitrosative stress-induced S-glutathionylation of protein disulfide isomerase leadsto activation of the unfolded protein responserdquoCancer Researchvol 69 no 19 pp 7626ndash7634 2009
[191] T Uehara T Nakamura D Yao et al ldquoS-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegen-erationrdquo Nature vol 441 no 7092 pp 513ndash517 2006
[192] X Chen C Li T Guan et al ldquoS-nitrosylated protein disul-phide isomerase contributes to mutant SOD1 aggregates inamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol124 no 1 pp 45ndash58 2012
[193] J D Rothstein ldquoTherapeutic horizons for amyotrophic lateralsclerosisrdquo Current Opinion in Neurobiology vol 6 no 5 pp679ndash687 1996
[194] D W Cleveland ldquoNeuronal growth and death order anddisorder in the axoplasmrdquoCell vol 84 no 5 pp 663ndash666 1996
[41] T J Kwiatkowski Jr D A Bosco A L LeClerc et al ldquoMutationsin the FUSTLS gene on chromosome 16 cause familial amy-otrophic lateral sclerosisrdquo Science vol 323 no 5918 pp 1205ndash1208 2009
[42] HMaruyamaHMorinoH Ito et al ldquoMutations of optineurinin amyotrophic lateral sclerosisrdquo Nature vol 465 no 7295 pp223ndash226 2010
[43] H X Deng W Chen S T Hong et al ldquoMutations in UBQLN2cause dominant X-linked juvenile and adult-onset ALS andALSdementiardquo Nature vol 477 pp 211ndash215 2011
[44] M DeJesus-Hernandez I R Mackenzie B F Boeve et alldquoExpanded GGGGCC hexanucleotide repeat in noncodingregion of C9ORF72 causes chromosome 9p-linked FTD andALSrdquo Neuron vol 72 no 2 pp 245ndash256 2011
[45] L I Bruijn T M Miller and D W Cleveland ldquoUnraveling themechanisms involved in motor neuron degeneration in ALSrdquoAnnual Review of Neuroscience vol 27 pp 723ndash749 2004
[46] H D Durham J Roy L Dong and D A Figlewicz ldquoAggrega-tion of mutant CuZn superoxide dismutase proteins in a cul-turemodel ofALSrdquo Journal ofNeuropathology andExperimentalNeurology vol 56 no 5 pp 523ndash530 1997
[47] M Watanabe M Dykes-Hoberg V Cizewski Culotta D LPrice P C Wong and J D Rothstein ldquoHistological evidenceof protein aggregation in mutant SOD1 transgenic mice andin amyotrophic lateral sclerosis neural tissuesrdquo Neurobiology ofDisease vol 8 no 6 pp 933ndash941 2001
[48] C Soto ldquoUnfolding the role of protein misfolding in neurode-generative diseasesrdquo Nature Reviews Neuroscience vol 4 no 1pp 49ndash60 2003
[49] J Wang G Xu and D R Borchelt ldquoMapping superoxidedismutase 1 domains of non-native interaction roles of intra-and intermolecular disulfide bonding in aggregationrdquo Journalof Neurochemistry vol 96 no 5 pp 1277ndash1288 2006
[50] B S Johnson D Snead J J Lee J M McCaffery J Shorterand A D Gitler ldquoTDP-43 is intrinsically aggregation-proneand amyotrophic lateral sclerosis-linked mutations accelerateaggregation and increase toxicityrdquo Journal of Biological Chem-istry vol 284 pp 20329ndash20339 2009
[51] C Vance B Rogelj T Hortobagyi et al ldquoMutations in FUSan RNA processing protein cause familial amyotrophic lateralsclerosis type 6rdquo Science vol 323 no 5918 pp 1208ndash1211 2009
[52] T Arai M Hasegawa H Akiyama et al ldquoTDP-43 is a compo-nent of ubiquitin-positive tau-negative inclusions in frontotem-poral lobar degeneration and amyotrophic lateral sclerosisrdquoBiochemical and Biophysical Research Communications vol 351no 3 pp 602ndash611 2006
[53] N Shibata A Hirano M Kobayashi et al ldquoIntense super-oxide dismutase-1 immunoreactivity in intracytoplasmic hya-line inclusions of familial amyotrophic lateral sclerosis withposterior column involvementrdquo Journal of Neuropathology andExperimental Neurology vol 55 no 4 pp 481ndash490 1996
[54] J S Valentine P A Doucette and S Z Potter ldquoCopper-zinc superoxide dismutase and amyotrophic lateral sclerosisrdquoAnnual Review of Biochemistry vol 74 pp 563ndash593 2005
[55] F Arnesano L Banci I BertiniMMartinelli Y Furukawa andT V OrsquoHalloran ldquoThe unusually stable quaternary structureof human CuZn-superoxide dismutase 1 is controlled by bothmetal occupancy and disulfide statusrdquo Journal of BiologicalChemistry vol 279 no 46 pp 47998ndash48003 2004
[56] C Kayatekin J A Zitzewitz and C R Matthews ldquoDisulfide-Reduced ALS Variants of Cu Zn Superoxide Dismutase Exhibit
Increased Populations of Unfolded Speciesrdquo Journal of Molecu-lar Biology vol 398 no 2 pp 320ndash331 2010
[57] A E Svensson O Bilsel C Kayatekin J A Adefusika J AZitzewitz and C Robert Matthews ldquoMetal-free ALS variantsof dimeric human CuZn-superoxide dismutase have enhancedpopulations of monomeric speciesrdquo PLoS ONE vol 5 no 4Article ID e10064 2010
[58] M Cozzolino M G Pesaresi V Gerbino J Grosskreutzand M T Carr ldquoAmyotrophic lateral sclerosis new insightsinto underlying molecular mechanisms and opportunities fortherapeutic interventionrdquo Antioxidants amp Redox Signaling vol17 no 9 pp 1277ndash1330 2012
[59] O Spreux-Varoquaux G Bensimon L Lacomblez et al ldquoGlu-tamate levels in cerebrospinal fluid in amyotrophic lateralsclerosis a reappraisal using a new HPLC method with coulo-metric detection in a large cohort of patientsrdquo Journal of theNeurological Sciences vol 193 no 2 pp 73ndash78 2002
[60] I Puls C Jonnakuty B H LaMonte et al ldquoMutant dynactin inmotor neuron diseaserdquo Nature Genetics vol 33 no 4 pp 455ndash456 2003
[61] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[62] J Kong and Z Xu ldquoMassive mitochondrial degeneration inmotor neurons triggers the onset of amyotrophic lateral sclero-sis in mice expressing a mutant SOD1rdquo Journal of Neurosciencevol 18 no 9 pp 3241ndash3250 1998
[63] F R Wiedemann K Winkler A V Kuznetsov et al ldquoImpair-ment of mitochondrial function in skeletal muscle of patientswith amyotrophic lateral sclerosisrdquo Journal of the NeurologicalSciences vol 156 no 1 pp 65ndash72 1998
[64] AHiranoHDonnenfeld S Sasaki and I Nakano ldquoFine struc-tural observations of neurofilamentous changes in amyotrophiclateral sclerosisrdquo Journal of Neuropathology and ExperimentalNeurology vol 43 no 5 pp 461ndash470 1984
[65] J D Wood T P Beaujeux and P J Shaw ldquoProtein aggregationin motor neurone disordersrdquo Neuropathology and AppliedNeurobiology vol 29 no 6 pp 529ndash545 2003
[66] J D Atkin M A Farg A KWalker C McLean D Tomas andM K Horne ldquoEndoplasmic reticulum stress and induction ofthe unfolded protein response in human sporadic amyotrophiclateral sclerosisrdquoNeurobiology of Disease vol 30 no 3 pp 400ndash407 2008
[67] S Chen X Zhang L Song and W Le ldquoAutophagy dysregula-tion in amyotrophic lateral sclerosisrdquo Brain Pathology vol 22no 1 pp 110ndash116 2012
[68] R G Cutler W A Pedersen S Camandola J D Rothsteinand M P Mattson ldquoEvidence that accumulation of ceramidesand cholesterol esters mediates oxidative stress-induced deathof motor neurons in amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 52 no 4 pp 448ndash457 2002
[69] R J Ferrante S E Browne L A Shinobu et al ldquoEvidenceof increased oxidative damage in both sporadic and familialamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol69 no 5 pp 2064ndash2074 1997
[70] M Bogdanov R H Brown W Matson et al ldquoIncreasedoxidative damage to DNA in ALS patientsrdquo Free Radical Biologyand Medicine vol 29 no 7 pp 652ndash658 2000
[71] A W Girotti ldquoLipid hydroperoxide generation turnover andeffector action in biological systemsrdquo Journal of Lipid Researchvol 39 no 8 pp 1529ndash1542 1998
Oxidative Medicine and Cellular Longevity 9
[72] P J Shaw P G Ince G Falkous and D Mantle ldquoOxidativedamage to protein in sporadic motor neuron disease spinalcordrdquo Annals of Neurology vol 38 no 4 pp 691ndash695 1995
[73] D Liu J Wen J Liu and L Li ldquoThe roles of free radicalsin amyotrophic lateral sclerosis reactive oxygen species andelevated oxidation of protein DNA and membrane phospho-lipidsrdquo FASEB Journal vol 13 no 15 pp 2318ndash2328 1999
[74] B J Carter P Anklesaria S Choi and J F Engelhardt ldquoRedoxmodifier genes and pathways in amyotrophic lateral sclerosisrdquoAntioxidants and Redox Signaling vol 11 no 7 pp 1569ndash15862009
[75] H F Poon K Hensley V Thongboonkerd et al ldquoRedoxproteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice-a model of familial amyotrophic lateralsclerosisrdquo Free Radical Biology and Medicine vol 39 no 4 pp453ndash462 2005
[76] J J Haddad ldquoAntioxidant and prooxidant mechanisms in theregulation of redox(y)-sensitive transcription factorsrdquo CellularSignalling vol 14 no 11 pp 879ndash897 2002
[77] K T Turpaev ldquoReactive oxygen species and regulation of geneexpressionrdquo Biochemistry vol 67 no 3 pp 281ndash292 2002
[78] C Iaccarino M E Mura S Esposito et al ldquoBcl2-A1 interactswith pro-caspase-3 implications for amyotrophic lateral scle-rosisrdquo Neurobiology of Disease vol 43 no 3 pp 642ndash650 2011
[79] C Moreau P Gosset J Kluza et al ldquoDeregulation of thehypoxia inducible factor-1120572 pathway in monocytes from spo-radic amyotrophic lateral sclerosis patientsrdquo Neuroscience vol172 pp 110ndash117 2011
[80] C M Karch M Prudencio D D Winkler P J Hart andD R Borchelt ldquoRole of mutant SOD1 disulfide oxidation andaggregation in the pathogenesis of familial ALSrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 106 no 19 pp 7774ndash7779 2009
[81] J B ProescherM Son J L Elliott andV C Culotta ldquoBiologicaleffects of CCS in the absence of SOD1 enzyme activationimplications for disease in a mouse model for ALSrdquo HumanMolecular Genetics vol 17 no 12 pp 1728ndash1737 2008
[82] J M McCord and I Fridovich ldquoSuperoxide dismutase Anenzymic function for erythrocuprein (hemocuprein)rdquo Journalof Biological Chemistry vol 244 no 22 pp 6049ndash6055 1969
[83] D Sau S De Biasi L Vitellaro-Zuccarello et al ldquoMutation ofSOD1 in ALS a gain of a loss of functionrdquo Human MolecularGenetics vol 16 no 13 pp 1604ndash1618 2007
[84] J S Beckman M Carson C D Smith and W H KoppenolldquoALS SOD and peroxynitriterdquoNature vol 364 no 6438 p 5841993
[85] N V Blough and O C Zafiriou ldquoReaction of superoxide withnitric oxide to form peroxonitrite in alkaline aqueous solutionrdquoInorganic Chemistry vol 24 no 22 pp 3502ndash3504 1985
[86] M F Beal R J Ferrante S E Browne Jr R T Matthews NW Kowall and R H Brown ldquoIncreased 3-nitrotyrosine in bothsporadic and familial amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 42 no 4 pp 644ndash654 1997
[87] H Tohgi T Abe K Yamazaki T Murata E Ishizaki andC Isobe ldquoRemarkable increase in cerebrospinal fluid 3-nitrotyrosine in patients with sporadic amyotrophic lateralsclerosisrdquo Annals of Neurology vol 46 pp 129ndash131 1999
[88] F Casoni M Basso T Massignan et al ldquoProtein nitration in amouse model of familial amyotrophic lateral sclerosis possiblemultifunctional role in the pathogenesisrdquo Journal of BiologicalChemistry vol 280 no 16 pp 16295ndash16304 2005
[89] S Guareschi E Cova C Cereda et al ldquoAn over-oxidizedform of superoxide dismutase found in sporadic amyotrophiclateral sclerosiswith bulbar onset shares a toxicmechanismwithmutant SOD1rdquo Proceedings of the National Academy of Sciencesvol 109 no 13 pp 5074ndash5079 2012
[90] RW Orrell R J M Lane andM Ross ldquoA systematic review ofantioxidant treatment for amyotrophic lateral sclerosismotorneuron diseaserdquo Amyotrophic Lateral Sclerosis vol 9 no 4 pp195ndash211 2008
[91] S A Ezzi M Urushitani and J P Julien ldquoWild-type superoxidedismutase acquires binding and toxic properties of ALS-linkedmutant forms through oxidationrdquo Journal of Neurochemistryvol 102 no 1 pp 170ndash178 2007
[92] R L Redler K C Wilcox E A Proctor L Fee M Caplowand N V Dokholyan ldquoGlutathionylation at Cys-111 inducesdissociation of wild type and FALS mutant SOD1 dimersrdquoBiochemistry vol 50 no 32 pp 7057ndash7066 2011
[93] K Forsberg P A Jonsson P M Andersen et al ldquoNovelantibodies reveal inclusions containing non-native SOD1 insporadic ALS patientsrdquo PloS One vol 5 no 7 Article ID e115522010
[94] D A Bosco G Morfini N M Karabacak et al ldquoWild-type andmutant SOD1 share an aberrant conformation and a commonpathogenic pathway in ALSrdquo Nature Neuroscience vol 13 no11 pp 1396ndash1403 2010
[95] A C Estevez J P Crow J B Sampson et al ldquoInduction of nitricoxide-dependent apoptosis in motor neurons by zinc- deficientsuperoxide dismutaserdquo Science vol 286 no 5449 pp 2498ndash2500 1999
[96] Y Furukawa R Fu H X Deng T Siddique and T VOrsquoHalloran ldquoDisulfide cross-linked protein represents a signif-icant fraction of ALS-associated Cu Zn-superoxide dismutaseaggregates in spinal cords of model micerdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 18 pp 7148ndash7153 2006
[97] T J Cohen AWHwang T Unger J Q Trojanowski and VMY Lee ldquoRedox signalling directly regulates TDP-43 via cysteineoxidation and disulphide cross-linkingrdquo The EMBO Journalvol 31 no 5 pp 1241ndash1252 2011
[98] DDormann R Rodde D Edbauer et al ldquoALS-associated fusedin sarcoma (FUS) mutations disrupt transportin-mediatednuclear importrdquo EMBO Journal vol 29 no 16 pp 2841ndash28572010
[99] S P Butcher andAHamberger ldquoIn vivo studies on the extracel-lular and veratrine-releasable pools of endogenous amino acidsin the rat striatum effects of corticostriatal deafferentiation andkainic acid lesionrdquo Journal of Neurochemistry vol 48 no 3 pp713ndash721 1987
[100] I Sen A Nalini N B Joshi and P G Joshi ldquoCerebrospinalfluid from amyotrophic lateral sclerosis patients preferentiallyelevates intracellular calcium and toxicity in motor neurons viaAMPAkainate receptorrdquo Journal of the Neurological Sciencesvol 235 no 1-2 pp 45ndash54 2005
[101] A Plaitakis and J T Caroscio ldquoAbnormal glutamatemetabolism in amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 22 no 5 pp 575ndash579 1987
[102] L Van Den Bosch and W Robberecht ldquoDifferent receptorsmediate motor neuron death induced by short and long expo-sures to excitotoxicityrdquo Brain Research Bulletin vol 53 no 4 pp383ndash388 2000
10 Oxidative Medicine and Cellular Longevity
[103] D Trotti ldquoNeuronal and glial glutamate transporters possessan SH-based redox regulatory mechanismrdquo European Journalof Neuroscience vol 9 no 6 pp 1236ndash1243 1997
[104] A Plaitakis and E Constantakakis ldquoAlteredmetabolism of exci-tatory amino acids N-acetyl-aspartate and N- acetyl-aspartyl-glutamate in amyotrophic lateral sclerosisrdquo Brain ResearchBulletin vol 30 no 3-4 pp 381ndash386 1993
[105] J D Rothstein L J Martin and R W Kuncl ldquoDecreasedglutamate transport by the brain and spinal cord in amyotrophiclateral sclerosisrdquo New England Journal of Medicine vol 326 no22 pp 1464ndash1468 1992
[106] J D Rothstein M Van Kammen A I Levey L J Martin andRW Kuncl ldquoSelective loss of glial glutamate transporter GLT-1amyotrophic lateral sclerosisrdquo Annals of Neurology vol 38 no1 pp 73ndash84 1995
[107] A Volterra D Trotti C Tromba S Floridi and G RacagnildquoGlutamate uptake inhibition by oxygen free radicals in ratcortical astrocytesrdquo Journal of Neuroscience vol 14 no 5 pp2924ndash2932 1994
[108] P J Shaw ldquoGlutamate excitotoxicity and amyotrophic lateralsclerosisrdquo Journal of Neurology vol 244 no 2 pp S3ndashS14 1997
[109] W L Miller ldquoMinireview regulation of steroidogenesis byelectron transferrdquo Endocrinology vol 146 no 6 pp 2544ndash25502005
[110] S Jin F Zhou F Katirai and P L Li ldquoLipid raft redox signalingmolecular mechanisms in health and diseaserdquoAntioxidants andRedox Signaling vol 15 no 4 pp 1043ndash1083 2011
[111] W A Pedersen W Fu J N Keller et al ldquoProtein modificationby the lipid peroxidation product 4-hydroxynonenal in thespinal cords of amyotrophic lateral sclerosis patientsrdquo Annals ofNeurology vol 44 no 5 pp 819ndash824 1998
[112] L Dupuis P Corcia A Fergani et al ldquoDyslipidemia is aprotective factor in amyotrophic lateral sclerosisrdquo Neurologyvol 70 no 13 pp 1004ndash1009 2008
[113] L Dupuis and J P Loeffler ldquoNeuromuscular junction destruc-tion during amyotrophic lateral sclerosis insights from trans-genic modelsrdquo Current Opinion in Pharmacology vol 9 no 3pp 341ndash346 2009
[114] I Choi H D Song S Lee et al ldquoDirect observation ofdefects and increased ion permeability of a membrane inducedby structurally disordered CuZn-superoxide dismutase aggre-gatesrdquo PloS One vol 6 no 12 pp e28982ndashe28982 2011
[115] C Taghibiglou J Lu I R Mackenzie Y T Wang and NR Cashman ldquoSterol regulatory element binding protein-1(SREBP1) activation in motor neurons in excitotoxicity andamyotrophic lateral sclerosis (ALS) indip a potential therapeu-tic peptiderdquo Biochemical and Biophysical Research Communica-tions vol 413 no 2 pp 159ndash163 2011
[116] E Colman A Szarfman J Wyeth et al ldquoAn evaluation of adata mining signal for amyotrophic lateral sclerosis and statinsdetected in FDArsquos spontaneous adverse event reporting systemrdquoPharmacoepidemiology and Drug Safety vol 17 no 11 pp 1068ndash1076 2008
[117] I R Edwards K Star and A Kiuru ldquoStatins neuromusculardegenerative disease and an amyotrophic lateral sclerosis-likesyndrome an analysis of individual case safety reports fromvigibaserdquo Drug Safety vol 30 no 6 pp 515ndash525 2007
[118] L Zinman R Sadeghi M Gawel D Patton and A Kiss ldquoArestatin medications safe in patients with ALSrdquo AmyotrophicLateral Sclerosis vol 9 no 4 pp 223ndash228 2008
[119] HToftSoslashrensen andT L Lash ldquoStatins and amyotrophic lateralsclerosis-the level of evidence for an associationrdquo Journal ofInternal Medicine vol 266 no 6 pp 520ndash526 2009
[120] J Zhai A L Strom R Kilty et al ldquoProteomic characterizationof lipid raft proteins in amyotrophic lateral sclerosis mousespinal cordrdquo FEBS Journal vol 276 no 12 pp 3308ndash3323 2009
[121] M F Beal ldquoAging energy and oxidative stress in neurodegen-erative diseasesrdquoAnnals of Neurology vol 38 no 3 pp 357ndash3661995
[122] F RWiedemann GManfredi CMawrinM Flint Beal and EA Schon ldquoMitochondrial DNA and respiratory chain functionin spinal cords of ALS patientsrdquo Journal of Neurochemistry vol80 no 4 pp 616ndash625 2002
[123] G M Borthwick M A Johnson P G Ince P J Shaw and DM Turnbull ldquoMitochondrial enzyme activity in amyotrophiclateral sclerosis implications for the role of mitochondria inneuronal cell deathrdquoAnnals of Neurology vol 46 no 5 pp 787ndash790 2001
[124] P M Keeney and J P Bennett ldquoALS spinal neurons show variedand reducedmtDNAgene copy numbers and increasedmtDNAgene deletionsrdquoMolecular Neurodegeneration vol 5 no 1 p 212010
[125] M B Graeber E Grasbon-Frodl U V Eitzen and S K KoselldquoNeurodegeneration and aging role of the second genomerdquoJournal of Neuroscience Research vol 52 no 1 pp 1ndash6 1998
[126] K C Zimmermann C Bonzon andD R Green ldquoThemachin-ery of programmed cell deathrdquo Pharmacology andTherapeuticsvol 92 no 1 pp 57ndash70 2001
[127] P Nagley G C Higgins J D Atkin and P M Beart ldquoMul-tifaceted deaths orchestrated by mitochondria in neuronesrdquoBiochimica et Biophysica Acta vol 1802 no 1 pp 167ndash185 2010
[128] C GueganM Vila G Rosoklija A P Hays and S PrzedborskildquoRecruitment of the mitochondria-dependent apoptotic path-way in amyotrophic lateral sclerosisrdquo Journal of Neurosciencevol 21 no 17 pp 6569ndash6576 2001
[129] L J Martin Z Liu K Chen et al ldquoMotor neuron degenerationin amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice mechanisms of mitochondriopathy and celldeathrdquo Journal of Comparative Neurology vol 500 no 1 pp 20ndash46 2007
[130] P C Wong C A Pardo D R Borchelt et al ldquoAn adverseproperty of a familial ALS-linked SOD1 mutation causes motorneuron disease characterized by vacuolar degeneration ofmito-chondriardquo Neuron vol 14 no 6 pp 1105ndash1116 1995
[131] F M Menzies M R Cookson R W Taylor et al ldquoMitochon-drial dysfunction in a cell culturemodel of familial amyotrophiclateral sclerosisrdquo Brain vol 125 no 7 pp 1522ndash1533 2002
[132] M T Carrı A Ferri A Battistoni et al ldquoExpression of aCuZn superoxide dismutase typical of familial amyotrophiclateral sclerosis induces mitochondrial alteration and increaseof cytosolic Ca2+ concentration in transfected neuroblastomaSH-SY5Y cellsrdquo FEBS Letters vol 414 no 2 pp 365ndash368 1997
[133] S Sasaki and M Iwata ldquoUltrastructural study of synapses inthe anterior horn neurons of patients with amyotrophic lateralsclerosisrdquoNeuroscience Letters vol 204 no 1-2 pp 53ndash56 1996
[134] L Siklos J Engelhardt Y Harati R G Smith F Joo andS H Appel ldquoUltrastructural evidence for altered calcium inmotor nerve terminals in amyotrophic lateral sclerosisrdquo Annalsof Neurology vol 39 no 2 pp 203ndash216 1996
[135] M Cozzolino and M T Carrı ldquoMitochondrial dysfunction inALSrdquo Progress in Neurobiology vol 97 no 2 pp 54ndash66 2012
Oxidative Medicine and Cellular Longevity 11
[136] K Y Soo J D Atkin M Farg A K Walker M K Horne andP Nagley ldquoBim links ER stress and apoptosis in cells expressingmutant SOD1 associated with amyotrophic lateral sclerosisrdquoPloS One vol 7 no 4 Article ID e35413 2012
[137] K Hong Y Li W Duan et al ldquoFull-length TDP-43 and itsC-terminal fragments activate mitophagy in NSC34 cell linerdquoNeuroscience Letters vol 530 no 2 pp 144ndash149 2012
[138] R J Braun and B Westermann ldquoMitochondrial dynamics inyeast cell death and agingrdquo Biochemical Society Transactionsvol 39 pp 1520ndash1526 2011
[139] W Duan X Li J Shi Y Guo Z Li and C Li ldquoMutant TARDNA-binding protein-43 induces oxidative injury in motorneuron-like cellrdquo Neuroscience vol 169 no 4 pp 1621ndash16292010
[140] C Jung C M J Higgins and Z Xu ldquoMitochondrial electrontransport chain complex dysfunction in a transgenic mousemodel for amyotrophic lateral sclerosisrdquo Journal of Neurochem-istry vol 83 no 3 pp 535ndash545 2002
[141] A Ferri M Cozzolino C Crosio et al ldquoFamilial ALS-superoxide dismutases associate with mitochondria and shifttheir redox potentialsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 37 pp13860ndash13865 2006
[142] K Aquilano P Vigilanza G Rotilio and M R CiriololdquoMitochondrial damage due to SOD1 deficiency in SH-SY5Yneuroblastoma cells a rationale for the redundancy of SOD1rdquoThe FASEB Journal vol 20 no 10 pp 1683ndash1685 2006
[143] E M OrsquoBrien R Dirmeier M Engle and R O PoytonldquoMitochondrial protein oxidation in yeast mutants lackingmanganese- (MnSOD) or copper- and zinc-containing super-oxide dismutase (CuZnSOD) evidence that mnsod and cuzn-sod have both unique and overlapping functions in protectingmitochondrial proteins from oxidative damagerdquo Journal ofBiological Chemistry vol 279 no 50 pp 51817ndash51827 2004
[144] S Pickles and C V Velde ldquoMisfolded SOD1 and ALS zeroingin on mitochondriardquo Amyotrophic Lateral Sclerosis vol 13 pp333ndash340 2012
[145] B Bandy and A J Davison ldquoMitochondrial mutations mayincrease oxidative stress implications for carcinogenesis andagingrdquo Free Radical Biology andMedicine vol 8 no 6 pp 523ndash539 1990
[146] F Zhang A L Strom K Fukada S Lee L J Hayward andH Zhu ldquoInteraction between familial Amyotrophic LateralSclerosis (ALS)-linked SOD1mutants and the dynein complexrdquoJournal of Biological Chemistry vol 282 no 22 pp 16691ndash166992007
[147] S Sasaki and S Maruyama ldquoUltrastructutal study of skein-like inclusions in anterior horn neurons of patients with motorneuron diseaserdquoNeuroscience Letters vol 147 no 2 pp 121ndash1241992
[148] D A Figlewicz A Krizus M G Martinoli et al ldquoVariantsof the heavy neurofilament subunit are associated with thedevelopment of amyotrophic lateral sclerosisrdquo Human Molec-ular Genetics vol 3 no 10 pp 1757ndash1761 1994
[149] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[150] S M Chou H S Wang and K Komai ldquoColocalization of NOSand SOD1 in neurofilament accumulation within motor neu-rons of amyotrophic lateral sclerosis an immunohistochemicalstudyrdquo Journal of Chemical Neuroanatomy vol 10 no 3-4 pp249ndash258 1996
[151] H Zhang X Kong J Kang et al ldquoOxidative stress inducesparallel autophagy and mitochondria dysfunction in humangliomaU251 cellsrdquoToxicological Sciences vol 110 no 2 pp 376ndash388 2009
[152] J Lee S Giordano and J Zhang ldquoAutophagymitochondria andoxidative stress cross-talk and redox signallingrdquo BiochemicalJournal vol 441 pp 523ndash540 2012
[153] A Li X Zhang and W Le ldquoAltered macroautophagy in thespinal cord of SOD1 mutant micerdquo Autophagy vol 4 no 3 pp290ndash293 2008
[154] Y Zhong Q J Wang X Li et al ldquoDistinct regulation ofautophagic activity by Atg14L and Rubicon associated withBeclin 1-phosphatidylinositol-3-kinase complexrdquo Nature CellBiology vol 11 no 4 pp 468ndash476 2009
[155] S Sasaki ldquoAutophagy in spinal cord motor neurons in sporadicamyotrophic lateral sclerosisrdquo Journal of Neuropathology andExperimental Neurology vol 70 no 5 pp 349ndash359 2011
[156] N Morimoto M Nagai Y Ohta et al ldquoIncreased autophagyin transgenic mice with a G93A mutant SOD1 generdquo BrainResearch vol 1167 no 1 pp 112ndash117 2007
[157] M Schroder ldquoEndoplasmic reticulum stress responsesrdquo Cellu-lar andMolecular Life Sciences vol 65 no 6 pp 862ndash894 2008
[158] J D Atkin M A Farg B J Turner et al ldquoInduction ofthe unfolded protein response in familial amyotrophic lateralsclerosis and association of protein-disulfide isomerase withsuperoxide dismutase 1rdquo Journal of Biological Chemistry vol281 no 40 pp 30152ndash30165 2006
[159] C M Haynes E A Titus and A A Cooper ldquoDegradation ofmisfolded proteins prevents ER-derived oxidative stress and celldeathrdquoMolecular Cell vol 15 no 5 pp 767ndash776 2004
[160] K Kanekura H Suzuki S Aiso and M Matsuoka ldquoER stressand unfolded protein response in amyotrophic lateral sclerosisrdquoMolecular Neurobiology vol 39 no 2 pp 81ndash89 2009
[161] M A Farg K Y Soo A K Walker et al ldquoMutant FUS inducesendoplasmic reticulum stress in amyotrophic lateral sclerosisand interacts with protein disulfide-isomeraserdquoNeurobiology ofAging vol 33 no 12 pp 2855ndash2868 2012
[162] E V Ilieva V Ayala M Jove et al ldquoOxidative and endoplas-mic reticulum stress interplay in sporadic amyotrophic lateralsclerosisrdquo Brain vol 130 no 12 pp 3111ndash3123 2007
[163] J D Malhotra and R J Kaufman ldquoEndoplasmic reticulumstress and oxidative stress a vicious cycle or a double-edgedswordrdquo Antioxidants and Redox Signaling vol 9 no 12 pp2277ndash2293 2007
[164] A K Walker and J D Atkin ldquoMechanisms of neuroprotectionby protein disulphide isomerase in amyotrophic lateral scle-rosisrdquo Neurology Research International vol 2011 Article ID317340 7 pages 2011
[165] R B Freedman T R Hirst andM F Tuite ldquoProtein disulphideisomerase building bridges in protein foldingrdquo Trends inBiochemical Sciences vol 19 no 8 pp 331ndash336 1994
[166] C I Andreu U Woehlbier M Torres and C Hetz ldquoProteindisulfide isomerases in neurodegeneration from disease mech-anisms to biomedical applicationsrdquo FEBS Letters vol 586 no18 pp 2826ndash2834 2012
[167] J J Galligan and D R Petersen ldquoThe human protein disulfideisomerase gene familyrdquoHuman Genomics vol 6 no 1 pp 1ndash152012
[168] L Ellgaard and L W Ruddock ldquoThe human protein disulphideisomerase family substrate interactions and functional proper-tiesrdquo EMBO Reports vol 6 no 1 pp 28ndash32 2005
12 Oxidative Medicine and Cellular Longevity
[169] B Wilkinson and H F Gilbert ldquoProtein disulfide isomeraserdquoBiochimica et Biophysica Acta vol 1699 no 1-2 pp 35ndash44 2004
[170] T Tanaka H Nakamura A Nishiyama et al ldquoRedox regulationby thioredoxin superfamily protection against oxidative stressand agingrdquo Free Radical Research vol 33 no 6 pp 851ndash8552000
[171] C Turano S Coppari F Altieri and A Ferraro ldquoProteins ofthe PDI family unpredicted non-ER locations and functionsrdquoJournal of Cellular Physiology vol 193 no 2 pp 154ndash163 2002
[172] D M Ferrari and H D Soling ldquoThe protein disulphide-isomerase family unravelling a string of foldsrdquo BiochemicalJournal vol 339 no 1 pp 1ndash10 1999
[173] G Tian S Xiang R Noiva W J Lennarz and H SchindelinldquoThe crystal structure of yeast protein disulfide isomerasesuggests cooperativity between its active sitesrdquo Cell vol 124 no1 pp 61ndash73 2006
[174] P Klappa LW Ruddock N J Darby and R B Freedman ldquoThebrsquo domain provides the principal peptide-binding site of proteindisulfide isomerase but all domains contribute to binding ofmisfolded proteinsrdquo EMBO Journal vol 17 no 4 pp 927ndash9351998
[175] A Pirneskoski P Klappa M Lobell et al ldquoMolecular char-acterization of the principal substrate binding site of theubiquitous folding catalyst protein disulfide isomeraserdquo Journalof Biological Chemistry vol 279 no 11 pp 10374ndash10381 2004
[176] G Kozlov P Maattanen D Y Thomas and K Gehring ldquoAstructural overview of the PDI family of proteinsrdquo FEBS Journalvol 277 no 19 pp 3924ndash3936 2010
[177] Y Dai and C C Wang ldquoA mutant truncated protein disulfideisomerase with no chaperone activityrdquo Journal of BiologicalChemistry vol 272 no 44 pp 27572ndash27576 1997
[178] C E Jessop R H Watkins J J Simmons M Tasab andN J Bulleid ldquoProtein disulphide isomerase family membersshow distinct substrate specificity P5 is targeted to BiP clientproteinsrdquo Journal of Cell Science vol 122 no 23 pp 4287ndash42952009
[179] C Appenzeller-Herzog J Riemer E Zito et al ldquoDisulphideproduction by Ero1120572-PDI relay is rapid and effectively regu-latedrdquo EMBO Journal vol 29 no 19 pp 3318ndash3329 2010
[180] F Hatahet and L W Ruddock ldquoProtein disulfide isomerase acritical evaluation of its function in disulfide bond formationrdquoAntioxidants and Redox Signaling vol 11 no 11 pp 2807ndash28502009
[181] N J Bulleid and L Ellgaard ldquoMultiple ways to make disulfidesrdquoTrends in Biochemical Sciences 2011
[182] S Chakravarthi C E Jessop and N J Bulleid ldquoThe role ofglutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stressrdquo EMBOReports vol 7 no3 pp 271ndash275 2006
[183] J Lundstrom and A Holmgren ldquoDetermination of thereduction-oxidation potential of the thioredoxin-like domainsof protein disulfide-isomerase from the equilibrium with glu-tathione and thioredoxinrdquo Biochemistry vol 32 no 26 pp6649ndash6655 1993
[184] E Gross C S Sevier N Heldman et al ldquoGenerating disulfidesenzymatically reaction products and electron acceptors of theendoplasmic reticulum thiol oxidase Ero1prdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 2 pp 299ndash304 2006
[185] P I Merksamer A Trusina and F R Papa ldquoReal-time redoxmeasurements during endoplasmic reticulum stress reveal
interlinked protein folding functionsrdquo Cell vol 135 no 5 pp933ndash947 2008
[186] J W Cuozzo and C A Kaiser ldquoCompetition between glu-tathione and protein thiols for disulphide-bond formationrdquoNature Cell Biology vol 1 no 3 pp 130ndash135 1999
[187] L A Rutkevich M F Cohen-Doyle U Brockmeier and DB Williams ldquoFunctional relationship between protein disulfideisomerase family members during the oxidative folding ofhuman secretory proteinsrdquoMolecular Biology of the Cell vol 21no 18 pp 3093ndash3105 2010
[188] Y Honjo S Kaneko H Ito et al ldquoProtein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateralsclerosisrdquo Amyotrophic Lateral Sclerosis vol 12 no 6 pp 444ndash450 2011
[189] H Tsuda S M Han Y Yang et al ldquoThe amyotrophic lateralsclerosis 8 proteinVAPB is cleaved secreted and acts as a ligandfor Eph receptorsrdquo Cell vol 133 no 6 pp 963ndash977 2008
[190] D M Townsend Y Manevich H Lin et al ldquoNitrosative stress-induced S-glutathionylation of protein disulfide isomerase leadsto activation of the unfolded protein responserdquoCancer Researchvol 69 no 19 pp 7626ndash7634 2009
[191] T Uehara T Nakamura D Yao et al ldquoS-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegen-erationrdquo Nature vol 441 no 7092 pp 513ndash517 2006
[192] X Chen C Li T Guan et al ldquoS-nitrosylated protein disul-phide isomerase contributes to mutant SOD1 aggregates inamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol124 no 1 pp 45ndash58 2012
[193] J D Rothstein ldquoTherapeutic horizons for amyotrophic lateralsclerosisrdquo Current Opinion in Neurobiology vol 6 no 5 pp679ndash687 1996
[194] D W Cleveland ldquoNeuronal growth and death order anddisorder in the axoplasmrdquoCell vol 84 no 5 pp 663ndash666 1996
[72] P J Shaw P G Ince G Falkous and D Mantle ldquoOxidativedamage to protein in sporadic motor neuron disease spinalcordrdquo Annals of Neurology vol 38 no 4 pp 691ndash695 1995
[73] D Liu J Wen J Liu and L Li ldquoThe roles of free radicalsin amyotrophic lateral sclerosis reactive oxygen species andelevated oxidation of protein DNA and membrane phospho-lipidsrdquo FASEB Journal vol 13 no 15 pp 2318ndash2328 1999
[74] B J Carter P Anklesaria S Choi and J F Engelhardt ldquoRedoxmodifier genes and pathways in amyotrophic lateral sclerosisrdquoAntioxidants and Redox Signaling vol 11 no 7 pp 1569ndash15862009
[75] H F Poon K Hensley V Thongboonkerd et al ldquoRedoxproteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice-a model of familial amyotrophic lateralsclerosisrdquo Free Radical Biology and Medicine vol 39 no 4 pp453ndash462 2005
[76] J J Haddad ldquoAntioxidant and prooxidant mechanisms in theregulation of redox(y)-sensitive transcription factorsrdquo CellularSignalling vol 14 no 11 pp 879ndash897 2002
[77] K T Turpaev ldquoReactive oxygen species and regulation of geneexpressionrdquo Biochemistry vol 67 no 3 pp 281ndash292 2002
[78] C Iaccarino M E Mura S Esposito et al ldquoBcl2-A1 interactswith pro-caspase-3 implications for amyotrophic lateral scle-rosisrdquo Neurobiology of Disease vol 43 no 3 pp 642ndash650 2011
[79] C Moreau P Gosset J Kluza et al ldquoDeregulation of thehypoxia inducible factor-1120572 pathway in monocytes from spo-radic amyotrophic lateral sclerosis patientsrdquo Neuroscience vol172 pp 110ndash117 2011
[80] C M Karch M Prudencio D D Winkler P J Hart andD R Borchelt ldquoRole of mutant SOD1 disulfide oxidation andaggregation in the pathogenesis of familial ALSrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 106 no 19 pp 7774ndash7779 2009
[81] J B ProescherM Son J L Elliott andV C Culotta ldquoBiologicaleffects of CCS in the absence of SOD1 enzyme activationimplications for disease in a mouse model for ALSrdquo HumanMolecular Genetics vol 17 no 12 pp 1728ndash1737 2008
[82] J M McCord and I Fridovich ldquoSuperoxide dismutase Anenzymic function for erythrocuprein (hemocuprein)rdquo Journalof Biological Chemistry vol 244 no 22 pp 6049ndash6055 1969
[83] D Sau S De Biasi L Vitellaro-Zuccarello et al ldquoMutation ofSOD1 in ALS a gain of a loss of functionrdquo Human MolecularGenetics vol 16 no 13 pp 1604ndash1618 2007
[84] J S Beckman M Carson C D Smith and W H KoppenolldquoALS SOD and peroxynitriterdquoNature vol 364 no 6438 p 5841993
[85] N V Blough and O C Zafiriou ldquoReaction of superoxide withnitric oxide to form peroxonitrite in alkaline aqueous solutionrdquoInorganic Chemistry vol 24 no 22 pp 3502ndash3504 1985
[86] M F Beal R J Ferrante S E Browne Jr R T Matthews NW Kowall and R H Brown ldquoIncreased 3-nitrotyrosine in bothsporadic and familial amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 42 no 4 pp 644ndash654 1997
[87] H Tohgi T Abe K Yamazaki T Murata E Ishizaki andC Isobe ldquoRemarkable increase in cerebrospinal fluid 3-nitrotyrosine in patients with sporadic amyotrophic lateralsclerosisrdquo Annals of Neurology vol 46 pp 129ndash131 1999
[88] F Casoni M Basso T Massignan et al ldquoProtein nitration in amouse model of familial amyotrophic lateral sclerosis possiblemultifunctional role in the pathogenesisrdquo Journal of BiologicalChemistry vol 280 no 16 pp 16295ndash16304 2005
[89] S Guareschi E Cova C Cereda et al ldquoAn over-oxidizedform of superoxide dismutase found in sporadic amyotrophiclateral sclerosiswith bulbar onset shares a toxicmechanismwithmutant SOD1rdquo Proceedings of the National Academy of Sciencesvol 109 no 13 pp 5074ndash5079 2012
[90] RW Orrell R J M Lane andM Ross ldquoA systematic review ofantioxidant treatment for amyotrophic lateral sclerosismotorneuron diseaserdquo Amyotrophic Lateral Sclerosis vol 9 no 4 pp195ndash211 2008
[91] S A Ezzi M Urushitani and J P Julien ldquoWild-type superoxidedismutase acquires binding and toxic properties of ALS-linkedmutant forms through oxidationrdquo Journal of Neurochemistryvol 102 no 1 pp 170ndash178 2007
[92] R L Redler K C Wilcox E A Proctor L Fee M Caplowand N V Dokholyan ldquoGlutathionylation at Cys-111 inducesdissociation of wild type and FALS mutant SOD1 dimersrdquoBiochemistry vol 50 no 32 pp 7057ndash7066 2011
[93] K Forsberg P A Jonsson P M Andersen et al ldquoNovelantibodies reveal inclusions containing non-native SOD1 insporadic ALS patientsrdquo PloS One vol 5 no 7 Article ID e115522010
[94] D A Bosco G Morfini N M Karabacak et al ldquoWild-type andmutant SOD1 share an aberrant conformation and a commonpathogenic pathway in ALSrdquo Nature Neuroscience vol 13 no11 pp 1396ndash1403 2010
[95] A C Estevez J P Crow J B Sampson et al ldquoInduction of nitricoxide-dependent apoptosis in motor neurons by zinc- deficientsuperoxide dismutaserdquo Science vol 286 no 5449 pp 2498ndash2500 1999
[96] Y Furukawa R Fu H X Deng T Siddique and T VOrsquoHalloran ldquoDisulfide cross-linked protein represents a signif-icant fraction of ALS-associated Cu Zn-superoxide dismutaseaggregates in spinal cords of model micerdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 18 pp 7148ndash7153 2006
[97] T J Cohen AWHwang T Unger J Q Trojanowski and VMY Lee ldquoRedox signalling directly regulates TDP-43 via cysteineoxidation and disulphide cross-linkingrdquo The EMBO Journalvol 31 no 5 pp 1241ndash1252 2011
[98] DDormann R Rodde D Edbauer et al ldquoALS-associated fusedin sarcoma (FUS) mutations disrupt transportin-mediatednuclear importrdquo EMBO Journal vol 29 no 16 pp 2841ndash28572010
[99] S P Butcher andAHamberger ldquoIn vivo studies on the extracel-lular and veratrine-releasable pools of endogenous amino acidsin the rat striatum effects of corticostriatal deafferentiation andkainic acid lesionrdquo Journal of Neurochemistry vol 48 no 3 pp713ndash721 1987
[100] I Sen A Nalini N B Joshi and P G Joshi ldquoCerebrospinalfluid from amyotrophic lateral sclerosis patients preferentiallyelevates intracellular calcium and toxicity in motor neurons viaAMPAkainate receptorrdquo Journal of the Neurological Sciencesvol 235 no 1-2 pp 45ndash54 2005
[101] A Plaitakis and J T Caroscio ldquoAbnormal glutamatemetabolism in amyotrophic lateral sclerosisrdquo Annals ofNeurology vol 22 no 5 pp 575ndash579 1987
[102] L Van Den Bosch and W Robberecht ldquoDifferent receptorsmediate motor neuron death induced by short and long expo-sures to excitotoxicityrdquo Brain Research Bulletin vol 53 no 4 pp383ndash388 2000
10 Oxidative Medicine and Cellular Longevity
[103] D Trotti ldquoNeuronal and glial glutamate transporters possessan SH-based redox regulatory mechanismrdquo European Journalof Neuroscience vol 9 no 6 pp 1236ndash1243 1997
[104] A Plaitakis and E Constantakakis ldquoAlteredmetabolism of exci-tatory amino acids N-acetyl-aspartate and N- acetyl-aspartyl-glutamate in amyotrophic lateral sclerosisrdquo Brain ResearchBulletin vol 30 no 3-4 pp 381ndash386 1993
[105] J D Rothstein L J Martin and R W Kuncl ldquoDecreasedglutamate transport by the brain and spinal cord in amyotrophiclateral sclerosisrdquo New England Journal of Medicine vol 326 no22 pp 1464ndash1468 1992
[106] J D Rothstein M Van Kammen A I Levey L J Martin andRW Kuncl ldquoSelective loss of glial glutamate transporter GLT-1amyotrophic lateral sclerosisrdquo Annals of Neurology vol 38 no1 pp 73ndash84 1995
[107] A Volterra D Trotti C Tromba S Floridi and G RacagnildquoGlutamate uptake inhibition by oxygen free radicals in ratcortical astrocytesrdquo Journal of Neuroscience vol 14 no 5 pp2924ndash2932 1994
[108] P J Shaw ldquoGlutamate excitotoxicity and amyotrophic lateralsclerosisrdquo Journal of Neurology vol 244 no 2 pp S3ndashS14 1997
[109] W L Miller ldquoMinireview regulation of steroidogenesis byelectron transferrdquo Endocrinology vol 146 no 6 pp 2544ndash25502005
[110] S Jin F Zhou F Katirai and P L Li ldquoLipid raft redox signalingmolecular mechanisms in health and diseaserdquoAntioxidants andRedox Signaling vol 15 no 4 pp 1043ndash1083 2011
[111] W A Pedersen W Fu J N Keller et al ldquoProtein modificationby the lipid peroxidation product 4-hydroxynonenal in thespinal cords of amyotrophic lateral sclerosis patientsrdquo Annals ofNeurology vol 44 no 5 pp 819ndash824 1998
[112] L Dupuis P Corcia A Fergani et al ldquoDyslipidemia is aprotective factor in amyotrophic lateral sclerosisrdquo Neurologyvol 70 no 13 pp 1004ndash1009 2008
[113] L Dupuis and J P Loeffler ldquoNeuromuscular junction destruc-tion during amyotrophic lateral sclerosis insights from trans-genic modelsrdquo Current Opinion in Pharmacology vol 9 no 3pp 341ndash346 2009
[114] I Choi H D Song S Lee et al ldquoDirect observation ofdefects and increased ion permeability of a membrane inducedby structurally disordered CuZn-superoxide dismutase aggre-gatesrdquo PloS One vol 6 no 12 pp e28982ndashe28982 2011
[115] C Taghibiglou J Lu I R Mackenzie Y T Wang and NR Cashman ldquoSterol regulatory element binding protein-1(SREBP1) activation in motor neurons in excitotoxicity andamyotrophic lateral sclerosis (ALS) indip a potential therapeu-tic peptiderdquo Biochemical and Biophysical Research Communica-tions vol 413 no 2 pp 159ndash163 2011
[116] E Colman A Szarfman J Wyeth et al ldquoAn evaluation of adata mining signal for amyotrophic lateral sclerosis and statinsdetected in FDArsquos spontaneous adverse event reporting systemrdquoPharmacoepidemiology and Drug Safety vol 17 no 11 pp 1068ndash1076 2008
[117] I R Edwards K Star and A Kiuru ldquoStatins neuromusculardegenerative disease and an amyotrophic lateral sclerosis-likesyndrome an analysis of individual case safety reports fromvigibaserdquo Drug Safety vol 30 no 6 pp 515ndash525 2007
[118] L Zinman R Sadeghi M Gawel D Patton and A Kiss ldquoArestatin medications safe in patients with ALSrdquo AmyotrophicLateral Sclerosis vol 9 no 4 pp 223ndash228 2008
[119] HToftSoslashrensen andT L Lash ldquoStatins and amyotrophic lateralsclerosis-the level of evidence for an associationrdquo Journal ofInternal Medicine vol 266 no 6 pp 520ndash526 2009
[120] J Zhai A L Strom R Kilty et al ldquoProteomic characterizationof lipid raft proteins in amyotrophic lateral sclerosis mousespinal cordrdquo FEBS Journal vol 276 no 12 pp 3308ndash3323 2009
[121] M F Beal ldquoAging energy and oxidative stress in neurodegen-erative diseasesrdquoAnnals of Neurology vol 38 no 3 pp 357ndash3661995
[122] F RWiedemann GManfredi CMawrinM Flint Beal and EA Schon ldquoMitochondrial DNA and respiratory chain functionin spinal cords of ALS patientsrdquo Journal of Neurochemistry vol80 no 4 pp 616ndash625 2002
[123] G M Borthwick M A Johnson P G Ince P J Shaw and DM Turnbull ldquoMitochondrial enzyme activity in amyotrophiclateral sclerosis implications for the role of mitochondria inneuronal cell deathrdquoAnnals of Neurology vol 46 no 5 pp 787ndash790 2001
[124] P M Keeney and J P Bennett ldquoALS spinal neurons show variedand reducedmtDNAgene copy numbers and increasedmtDNAgene deletionsrdquoMolecular Neurodegeneration vol 5 no 1 p 212010
[125] M B Graeber E Grasbon-Frodl U V Eitzen and S K KoselldquoNeurodegeneration and aging role of the second genomerdquoJournal of Neuroscience Research vol 52 no 1 pp 1ndash6 1998
[126] K C Zimmermann C Bonzon andD R Green ldquoThemachin-ery of programmed cell deathrdquo Pharmacology andTherapeuticsvol 92 no 1 pp 57ndash70 2001
[127] P Nagley G C Higgins J D Atkin and P M Beart ldquoMul-tifaceted deaths orchestrated by mitochondria in neuronesrdquoBiochimica et Biophysica Acta vol 1802 no 1 pp 167ndash185 2010
[128] C GueganM Vila G Rosoklija A P Hays and S PrzedborskildquoRecruitment of the mitochondria-dependent apoptotic path-way in amyotrophic lateral sclerosisrdquo Journal of Neurosciencevol 21 no 17 pp 6569ndash6576 2001
[129] L J Martin Z Liu K Chen et al ldquoMotor neuron degenerationin amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice mechanisms of mitochondriopathy and celldeathrdquo Journal of Comparative Neurology vol 500 no 1 pp 20ndash46 2007
[130] P C Wong C A Pardo D R Borchelt et al ldquoAn adverseproperty of a familial ALS-linked SOD1 mutation causes motorneuron disease characterized by vacuolar degeneration ofmito-chondriardquo Neuron vol 14 no 6 pp 1105ndash1116 1995
[131] F M Menzies M R Cookson R W Taylor et al ldquoMitochon-drial dysfunction in a cell culturemodel of familial amyotrophiclateral sclerosisrdquo Brain vol 125 no 7 pp 1522ndash1533 2002
[132] M T Carrı A Ferri A Battistoni et al ldquoExpression of aCuZn superoxide dismutase typical of familial amyotrophiclateral sclerosis induces mitochondrial alteration and increaseof cytosolic Ca2+ concentration in transfected neuroblastomaSH-SY5Y cellsrdquo FEBS Letters vol 414 no 2 pp 365ndash368 1997
[133] S Sasaki and M Iwata ldquoUltrastructural study of synapses inthe anterior horn neurons of patients with amyotrophic lateralsclerosisrdquoNeuroscience Letters vol 204 no 1-2 pp 53ndash56 1996
[134] L Siklos J Engelhardt Y Harati R G Smith F Joo andS H Appel ldquoUltrastructural evidence for altered calcium inmotor nerve terminals in amyotrophic lateral sclerosisrdquo Annalsof Neurology vol 39 no 2 pp 203ndash216 1996
[135] M Cozzolino and M T Carrı ldquoMitochondrial dysfunction inALSrdquo Progress in Neurobiology vol 97 no 2 pp 54ndash66 2012
Oxidative Medicine and Cellular Longevity 11
[136] K Y Soo J D Atkin M Farg A K Walker M K Horne andP Nagley ldquoBim links ER stress and apoptosis in cells expressingmutant SOD1 associated with amyotrophic lateral sclerosisrdquoPloS One vol 7 no 4 Article ID e35413 2012
[137] K Hong Y Li W Duan et al ldquoFull-length TDP-43 and itsC-terminal fragments activate mitophagy in NSC34 cell linerdquoNeuroscience Letters vol 530 no 2 pp 144ndash149 2012
[138] R J Braun and B Westermann ldquoMitochondrial dynamics inyeast cell death and agingrdquo Biochemical Society Transactionsvol 39 pp 1520ndash1526 2011
[139] W Duan X Li J Shi Y Guo Z Li and C Li ldquoMutant TARDNA-binding protein-43 induces oxidative injury in motorneuron-like cellrdquo Neuroscience vol 169 no 4 pp 1621ndash16292010
[140] C Jung C M J Higgins and Z Xu ldquoMitochondrial electrontransport chain complex dysfunction in a transgenic mousemodel for amyotrophic lateral sclerosisrdquo Journal of Neurochem-istry vol 83 no 3 pp 535ndash545 2002
[141] A Ferri M Cozzolino C Crosio et al ldquoFamilial ALS-superoxide dismutases associate with mitochondria and shifttheir redox potentialsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 37 pp13860ndash13865 2006
[142] K Aquilano P Vigilanza G Rotilio and M R CiriololdquoMitochondrial damage due to SOD1 deficiency in SH-SY5Yneuroblastoma cells a rationale for the redundancy of SOD1rdquoThe FASEB Journal vol 20 no 10 pp 1683ndash1685 2006
[143] E M OrsquoBrien R Dirmeier M Engle and R O PoytonldquoMitochondrial protein oxidation in yeast mutants lackingmanganese- (MnSOD) or copper- and zinc-containing super-oxide dismutase (CuZnSOD) evidence that mnsod and cuzn-sod have both unique and overlapping functions in protectingmitochondrial proteins from oxidative damagerdquo Journal ofBiological Chemistry vol 279 no 50 pp 51817ndash51827 2004
[144] S Pickles and C V Velde ldquoMisfolded SOD1 and ALS zeroingin on mitochondriardquo Amyotrophic Lateral Sclerosis vol 13 pp333ndash340 2012
[145] B Bandy and A J Davison ldquoMitochondrial mutations mayincrease oxidative stress implications for carcinogenesis andagingrdquo Free Radical Biology andMedicine vol 8 no 6 pp 523ndash539 1990
[146] F Zhang A L Strom K Fukada S Lee L J Hayward andH Zhu ldquoInteraction between familial Amyotrophic LateralSclerosis (ALS)-linked SOD1mutants and the dynein complexrdquoJournal of Biological Chemistry vol 282 no 22 pp 16691ndash166992007
[147] S Sasaki and S Maruyama ldquoUltrastructutal study of skein-like inclusions in anterior horn neurons of patients with motorneuron diseaserdquoNeuroscience Letters vol 147 no 2 pp 121ndash1241992
[148] D A Figlewicz A Krizus M G Martinoli et al ldquoVariantsof the heavy neurofilament subunit are associated with thedevelopment of amyotrophic lateral sclerosisrdquo Human Molec-ular Genetics vol 3 no 10 pp 1757ndash1761 1994
[149] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[150] S M Chou H S Wang and K Komai ldquoColocalization of NOSand SOD1 in neurofilament accumulation within motor neu-rons of amyotrophic lateral sclerosis an immunohistochemicalstudyrdquo Journal of Chemical Neuroanatomy vol 10 no 3-4 pp249ndash258 1996
[151] H Zhang X Kong J Kang et al ldquoOxidative stress inducesparallel autophagy and mitochondria dysfunction in humangliomaU251 cellsrdquoToxicological Sciences vol 110 no 2 pp 376ndash388 2009
[152] J Lee S Giordano and J Zhang ldquoAutophagymitochondria andoxidative stress cross-talk and redox signallingrdquo BiochemicalJournal vol 441 pp 523ndash540 2012
[153] A Li X Zhang and W Le ldquoAltered macroautophagy in thespinal cord of SOD1 mutant micerdquo Autophagy vol 4 no 3 pp290ndash293 2008
[154] Y Zhong Q J Wang X Li et al ldquoDistinct regulation ofautophagic activity by Atg14L and Rubicon associated withBeclin 1-phosphatidylinositol-3-kinase complexrdquo Nature CellBiology vol 11 no 4 pp 468ndash476 2009
[155] S Sasaki ldquoAutophagy in spinal cord motor neurons in sporadicamyotrophic lateral sclerosisrdquo Journal of Neuropathology andExperimental Neurology vol 70 no 5 pp 349ndash359 2011
[156] N Morimoto M Nagai Y Ohta et al ldquoIncreased autophagyin transgenic mice with a G93A mutant SOD1 generdquo BrainResearch vol 1167 no 1 pp 112ndash117 2007
[157] M Schroder ldquoEndoplasmic reticulum stress responsesrdquo Cellu-lar andMolecular Life Sciences vol 65 no 6 pp 862ndash894 2008
[158] J D Atkin M A Farg B J Turner et al ldquoInduction ofthe unfolded protein response in familial amyotrophic lateralsclerosis and association of protein-disulfide isomerase withsuperoxide dismutase 1rdquo Journal of Biological Chemistry vol281 no 40 pp 30152ndash30165 2006
[159] C M Haynes E A Titus and A A Cooper ldquoDegradation ofmisfolded proteins prevents ER-derived oxidative stress and celldeathrdquoMolecular Cell vol 15 no 5 pp 767ndash776 2004
[160] K Kanekura H Suzuki S Aiso and M Matsuoka ldquoER stressand unfolded protein response in amyotrophic lateral sclerosisrdquoMolecular Neurobiology vol 39 no 2 pp 81ndash89 2009
[161] M A Farg K Y Soo A K Walker et al ldquoMutant FUS inducesendoplasmic reticulum stress in amyotrophic lateral sclerosisand interacts with protein disulfide-isomeraserdquoNeurobiology ofAging vol 33 no 12 pp 2855ndash2868 2012
[162] E V Ilieva V Ayala M Jove et al ldquoOxidative and endoplas-mic reticulum stress interplay in sporadic amyotrophic lateralsclerosisrdquo Brain vol 130 no 12 pp 3111ndash3123 2007
[163] J D Malhotra and R J Kaufman ldquoEndoplasmic reticulumstress and oxidative stress a vicious cycle or a double-edgedswordrdquo Antioxidants and Redox Signaling vol 9 no 12 pp2277ndash2293 2007
[164] A K Walker and J D Atkin ldquoMechanisms of neuroprotectionby protein disulphide isomerase in amyotrophic lateral scle-rosisrdquo Neurology Research International vol 2011 Article ID317340 7 pages 2011
[165] R B Freedman T R Hirst andM F Tuite ldquoProtein disulphideisomerase building bridges in protein foldingrdquo Trends inBiochemical Sciences vol 19 no 8 pp 331ndash336 1994
[166] C I Andreu U Woehlbier M Torres and C Hetz ldquoProteindisulfide isomerases in neurodegeneration from disease mech-anisms to biomedical applicationsrdquo FEBS Letters vol 586 no18 pp 2826ndash2834 2012
[167] J J Galligan and D R Petersen ldquoThe human protein disulfideisomerase gene familyrdquoHuman Genomics vol 6 no 1 pp 1ndash152012
[168] L Ellgaard and L W Ruddock ldquoThe human protein disulphideisomerase family substrate interactions and functional proper-tiesrdquo EMBO Reports vol 6 no 1 pp 28ndash32 2005
12 Oxidative Medicine and Cellular Longevity
[169] B Wilkinson and H F Gilbert ldquoProtein disulfide isomeraserdquoBiochimica et Biophysica Acta vol 1699 no 1-2 pp 35ndash44 2004
[170] T Tanaka H Nakamura A Nishiyama et al ldquoRedox regulationby thioredoxin superfamily protection against oxidative stressand agingrdquo Free Radical Research vol 33 no 6 pp 851ndash8552000
[171] C Turano S Coppari F Altieri and A Ferraro ldquoProteins ofthe PDI family unpredicted non-ER locations and functionsrdquoJournal of Cellular Physiology vol 193 no 2 pp 154ndash163 2002
[172] D M Ferrari and H D Soling ldquoThe protein disulphide-isomerase family unravelling a string of foldsrdquo BiochemicalJournal vol 339 no 1 pp 1ndash10 1999
[173] G Tian S Xiang R Noiva W J Lennarz and H SchindelinldquoThe crystal structure of yeast protein disulfide isomerasesuggests cooperativity between its active sitesrdquo Cell vol 124 no1 pp 61ndash73 2006
[174] P Klappa LW Ruddock N J Darby and R B Freedman ldquoThebrsquo domain provides the principal peptide-binding site of proteindisulfide isomerase but all domains contribute to binding ofmisfolded proteinsrdquo EMBO Journal vol 17 no 4 pp 927ndash9351998
[175] A Pirneskoski P Klappa M Lobell et al ldquoMolecular char-acterization of the principal substrate binding site of theubiquitous folding catalyst protein disulfide isomeraserdquo Journalof Biological Chemistry vol 279 no 11 pp 10374ndash10381 2004
[176] G Kozlov P Maattanen D Y Thomas and K Gehring ldquoAstructural overview of the PDI family of proteinsrdquo FEBS Journalvol 277 no 19 pp 3924ndash3936 2010
[177] Y Dai and C C Wang ldquoA mutant truncated protein disulfideisomerase with no chaperone activityrdquo Journal of BiologicalChemistry vol 272 no 44 pp 27572ndash27576 1997
[178] C E Jessop R H Watkins J J Simmons M Tasab andN J Bulleid ldquoProtein disulphide isomerase family membersshow distinct substrate specificity P5 is targeted to BiP clientproteinsrdquo Journal of Cell Science vol 122 no 23 pp 4287ndash42952009
[179] C Appenzeller-Herzog J Riemer E Zito et al ldquoDisulphideproduction by Ero1120572-PDI relay is rapid and effectively regu-latedrdquo EMBO Journal vol 29 no 19 pp 3318ndash3329 2010
[180] F Hatahet and L W Ruddock ldquoProtein disulfide isomerase acritical evaluation of its function in disulfide bond formationrdquoAntioxidants and Redox Signaling vol 11 no 11 pp 2807ndash28502009
[181] N J Bulleid and L Ellgaard ldquoMultiple ways to make disulfidesrdquoTrends in Biochemical Sciences 2011
[182] S Chakravarthi C E Jessop and N J Bulleid ldquoThe role ofglutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stressrdquo EMBOReports vol 7 no3 pp 271ndash275 2006
[183] J Lundstrom and A Holmgren ldquoDetermination of thereduction-oxidation potential of the thioredoxin-like domainsof protein disulfide-isomerase from the equilibrium with glu-tathione and thioredoxinrdquo Biochemistry vol 32 no 26 pp6649ndash6655 1993
[184] E Gross C S Sevier N Heldman et al ldquoGenerating disulfidesenzymatically reaction products and electron acceptors of theendoplasmic reticulum thiol oxidase Ero1prdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 2 pp 299ndash304 2006
[185] P I Merksamer A Trusina and F R Papa ldquoReal-time redoxmeasurements during endoplasmic reticulum stress reveal
interlinked protein folding functionsrdquo Cell vol 135 no 5 pp933ndash947 2008
[186] J W Cuozzo and C A Kaiser ldquoCompetition between glu-tathione and protein thiols for disulphide-bond formationrdquoNature Cell Biology vol 1 no 3 pp 130ndash135 1999
[187] L A Rutkevich M F Cohen-Doyle U Brockmeier and DB Williams ldquoFunctional relationship between protein disulfideisomerase family members during the oxidative folding ofhuman secretory proteinsrdquoMolecular Biology of the Cell vol 21no 18 pp 3093ndash3105 2010
[188] Y Honjo S Kaneko H Ito et al ldquoProtein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateralsclerosisrdquo Amyotrophic Lateral Sclerosis vol 12 no 6 pp 444ndash450 2011
[189] H Tsuda S M Han Y Yang et al ldquoThe amyotrophic lateralsclerosis 8 proteinVAPB is cleaved secreted and acts as a ligandfor Eph receptorsrdquo Cell vol 133 no 6 pp 963ndash977 2008
[190] D M Townsend Y Manevich H Lin et al ldquoNitrosative stress-induced S-glutathionylation of protein disulfide isomerase leadsto activation of the unfolded protein responserdquoCancer Researchvol 69 no 19 pp 7626ndash7634 2009
[191] T Uehara T Nakamura D Yao et al ldquoS-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegen-erationrdquo Nature vol 441 no 7092 pp 513ndash517 2006
[192] X Chen C Li T Guan et al ldquoS-nitrosylated protein disul-phide isomerase contributes to mutant SOD1 aggregates inamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol124 no 1 pp 45ndash58 2012
[193] J D Rothstein ldquoTherapeutic horizons for amyotrophic lateralsclerosisrdquo Current Opinion in Neurobiology vol 6 no 5 pp679ndash687 1996
[194] D W Cleveland ldquoNeuronal growth and death order anddisorder in the axoplasmrdquoCell vol 84 no 5 pp 663ndash666 1996
[103] D Trotti ldquoNeuronal and glial glutamate transporters possessan SH-based redox regulatory mechanismrdquo European Journalof Neuroscience vol 9 no 6 pp 1236ndash1243 1997
[104] A Plaitakis and E Constantakakis ldquoAlteredmetabolism of exci-tatory amino acids N-acetyl-aspartate and N- acetyl-aspartyl-glutamate in amyotrophic lateral sclerosisrdquo Brain ResearchBulletin vol 30 no 3-4 pp 381ndash386 1993
[105] J D Rothstein L J Martin and R W Kuncl ldquoDecreasedglutamate transport by the brain and spinal cord in amyotrophiclateral sclerosisrdquo New England Journal of Medicine vol 326 no22 pp 1464ndash1468 1992
[106] J D Rothstein M Van Kammen A I Levey L J Martin andRW Kuncl ldquoSelective loss of glial glutamate transporter GLT-1amyotrophic lateral sclerosisrdquo Annals of Neurology vol 38 no1 pp 73ndash84 1995
[107] A Volterra D Trotti C Tromba S Floridi and G RacagnildquoGlutamate uptake inhibition by oxygen free radicals in ratcortical astrocytesrdquo Journal of Neuroscience vol 14 no 5 pp2924ndash2932 1994
[108] P J Shaw ldquoGlutamate excitotoxicity and amyotrophic lateralsclerosisrdquo Journal of Neurology vol 244 no 2 pp S3ndashS14 1997
[109] W L Miller ldquoMinireview regulation of steroidogenesis byelectron transferrdquo Endocrinology vol 146 no 6 pp 2544ndash25502005
[110] S Jin F Zhou F Katirai and P L Li ldquoLipid raft redox signalingmolecular mechanisms in health and diseaserdquoAntioxidants andRedox Signaling vol 15 no 4 pp 1043ndash1083 2011
[111] W A Pedersen W Fu J N Keller et al ldquoProtein modificationby the lipid peroxidation product 4-hydroxynonenal in thespinal cords of amyotrophic lateral sclerosis patientsrdquo Annals ofNeurology vol 44 no 5 pp 819ndash824 1998
[112] L Dupuis P Corcia A Fergani et al ldquoDyslipidemia is aprotective factor in amyotrophic lateral sclerosisrdquo Neurologyvol 70 no 13 pp 1004ndash1009 2008
[113] L Dupuis and J P Loeffler ldquoNeuromuscular junction destruc-tion during amyotrophic lateral sclerosis insights from trans-genic modelsrdquo Current Opinion in Pharmacology vol 9 no 3pp 341ndash346 2009
[114] I Choi H D Song S Lee et al ldquoDirect observation ofdefects and increased ion permeability of a membrane inducedby structurally disordered CuZn-superoxide dismutase aggre-gatesrdquo PloS One vol 6 no 12 pp e28982ndashe28982 2011
[115] C Taghibiglou J Lu I R Mackenzie Y T Wang and NR Cashman ldquoSterol regulatory element binding protein-1(SREBP1) activation in motor neurons in excitotoxicity andamyotrophic lateral sclerosis (ALS) indip a potential therapeu-tic peptiderdquo Biochemical and Biophysical Research Communica-tions vol 413 no 2 pp 159ndash163 2011
[116] E Colman A Szarfman J Wyeth et al ldquoAn evaluation of adata mining signal for amyotrophic lateral sclerosis and statinsdetected in FDArsquos spontaneous adverse event reporting systemrdquoPharmacoepidemiology and Drug Safety vol 17 no 11 pp 1068ndash1076 2008
[117] I R Edwards K Star and A Kiuru ldquoStatins neuromusculardegenerative disease and an amyotrophic lateral sclerosis-likesyndrome an analysis of individual case safety reports fromvigibaserdquo Drug Safety vol 30 no 6 pp 515ndash525 2007
[118] L Zinman R Sadeghi M Gawel D Patton and A Kiss ldquoArestatin medications safe in patients with ALSrdquo AmyotrophicLateral Sclerosis vol 9 no 4 pp 223ndash228 2008
[119] HToftSoslashrensen andT L Lash ldquoStatins and amyotrophic lateralsclerosis-the level of evidence for an associationrdquo Journal ofInternal Medicine vol 266 no 6 pp 520ndash526 2009
[120] J Zhai A L Strom R Kilty et al ldquoProteomic characterizationof lipid raft proteins in amyotrophic lateral sclerosis mousespinal cordrdquo FEBS Journal vol 276 no 12 pp 3308ndash3323 2009
[121] M F Beal ldquoAging energy and oxidative stress in neurodegen-erative diseasesrdquoAnnals of Neurology vol 38 no 3 pp 357ndash3661995
[122] F RWiedemann GManfredi CMawrinM Flint Beal and EA Schon ldquoMitochondrial DNA and respiratory chain functionin spinal cords of ALS patientsrdquo Journal of Neurochemistry vol80 no 4 pp 616ndash625 2002
[123] G M Borthwick M A Johnson P G Ince P J Shaw and DM Turnbull ldquoMitochondrial enzyme activity in amyotrophiclateral sclerosis implications for the role of mitochondria inneuronal cell deathrdquoAnnals of Neurology vol 46 no 5 pp 787ndash790 2001
[124] P M Keeney and J P Bennett ldquoALS spinal neurons show variedand reducedmtDNAgene copy numbers and increasedmtDNAgene deletionsrdquoMolecular Neurodegeneration vol 5 no 1 p 212010
[125] M B Graeber E Grasbon-Frodl U V Eitzen and S K KoselldquoNeurodegeneration and aging role of the second genomerdquoJournal of Neuroscience Research vol 52 no 1 pp 1ndash6 1998
[126] K C Zimmermann C Bonzon andD R Green ldquoThemachin-ery of programmed cell deathrdquo Pharmacology andTherapeuticsvol 92 no 1 pp 57ndash70 2001
[127] P Nagley G C Higgins J D Atkin and P M Beart ldquoMul-tifaceted deaths orchestrated by mitochondria in neuronesrdquoBiochimica et Biophysica Acta vol 1802 no 1 pp 167ndash185 2010
[128] C GueganM Vila G Rosoklija A P Hays and S PrzedborskildquoRecruitment of the mitochondria-dependent apoptotic path-way in amyotrophic lateral sclerosisrdquo Journal of Neurosciencevol 21 no 17 pp 6569ndash6576 2001
[129] L J Martin Z Liu K Chen et al ldquoMotor neuron degenerationin amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice mechanisms of mitochondriopathy and celldeathrdquo Journal of Comparative Neurology vol 500 no 1 pp 20ndash46 2007
[130] P C Wong C A Pardo D R Borchelt et al ldquoAn adverseproperty of a familial ALS-linked SOD1 mutation causes motorneuron disease characterized by vacuolar degeneration ofmito-chondriardquo Neuron vol 14 no 6 pp 1105ndash1116 1995
[131] F M Menzies M R Cookson R W Taylor et al ldquoMitochon-drial dysfunction in a cell culturemodel of familial amyotrophiclateral sclerosisrdquo Brain vol 125 no 7 pp 1522ndash1533 2002
[132] M T Carrı A Ferri A Battistoni et al ldquoExpression of aCuZn superoxide dismutase typical of familial amyotrophiclateral sclerosis induces mitochondrial alteration and increaseof cytosolic Ca2+ concentration in transfected neuroblastomaSH-SY5Y cellsrdquo FEBS Letters vol 414 no 2 pp 365ndash368 1997
[133] S Sasaki and M Iwata ldquoUltrastructural study of synapses inthe anterior horn neurons of patients with amyotrophic lateralsclerosisrdquoNeuroscience Letters vol 204 no 1-2 pp 53ndash56 1996
[134] L Siklos J Engelhardt Y Harati R G Smith F Joo andS H Appel ldquoUltrastructural evidence for altered calcium inmotor nerve terminals in amyotrophic lateral sclerosisrdquo Annalsof Neurology vol 39 no 2 pp 203ndash216 1996
[135] M Cozzolino and M T Carrı ldquoMitochondrial dysfunction inALSrdquo Progress in Neurobiology vol 97 no 2 pp 54ndash66 2012
Oxidative Medicine and Cellular Longevity 11
[136] K Y Soo J D Atkin M Farg A K Walker M K Horne andP Nagley ldquoBim links ER stress and apoptosis in cells expressingmutant SOD1 associated with amyotrophic lateral sclerosisrdquoPloS One vol 7 no 4 Article ID e35413 2012
[137] K Hong Y Li W Duan et al ldquoFull-length TDP-43 and itsC-terminal fragments activate mitophagy in NSC34 cell linerdquoNeuroscience Letters vol 530 no 2 pp 144ndash149 2012
[138] R J Braun and B Westermann ldquoMitochondrial dynamics inyeast cell death and agingrdquo Biochemical Society Transactionsvol 39 pp 1520ndash1526 2011
[139] W Duan X Li J Shi Y Guo Z Li and C Li ldquoMutant TARDNA-binding protein-43 induces oxidative injury in motorneuron-like cellrdquo Neuroscience vol 169 no 4 pp 1621ndash16292010
[140] C Jung C M J Higgins and Z Xu ldquoMitochondrial electrontransport chain complex dysfunction in a transgenic mousemodel for amyotrophic lateral sclerosisrdquo Journal of Neurochem-istry vol 83 no 3 pp 535ndash545 2002
[141] A Ferri M Cozzolino C Crosio et al ldquoFamilial ALS-superoxide dismutases associate with mitochondria and shifttheir redox potentialsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 37 pp13860ndash13865 2006
[142] K Aquilano P Vigilanza G Rotilio and M R CiriololdquoMitochondrial damage due to SOD1 deficiency in SH-SY5Yneuroblastoma cells a rationale for the redundancy of SOD1rdquoThe FASEB Journal vol 20 no 10 pp 1683ndash1685 2006
[143] E M OrsquoBrien R Dirmeier M Engle and R O PoytonldquoMitochondrial protein oxidation in yeast mutants lackingmanganese- (MnSOD) or copper- and zinc-containing super-oxide dismutase (CuZnSOD) evidence that mnsod and cuzn-sod have both unique and overlapping functions in protectingmitochondrial proteins from oxidative damagerdquo Journal ofBiological Chemistry vol 279 no 50 pp 51817ndash51827 2004
[144] S Pickles and C V Velde ldquoMisfolded SOD1 and ALS zeroingin on mitochondriardquo Amyotrophic Lateral Sclerosis vol 13 pp333ndash340 2012
[145] B Bandy and A J Davison ldquoMitochondrial mutations mayincrease oxidative stress implications for carcinogenesis andagingrdquo Free Radical Biology andMedicine vol 8 no 6 pp 523ndash539 1990
[146] F Zhang A L Strom K Fukada S Lee L J Hayward andH Zhu ldquoInteraction between familial Amyotrophic LateralSclerosis (ALS)-linked SOD1mutants and the dynein complexrdquoJournal of Biological Chemistry vol 282 no 22 pp 16691ndash166992007
[147] S Sasaki and S Maruyama ldquoUltrastructutal study of skein-like inclusions in anterior horn neurons of patients with motorneuron diseaserdquoNeuroscience Letters vol 147 no 2 pp 121ndash1241992
[148] D A Figlewicz A Krizus M G Martinoli et al ldquoVariantsof the heavy neurofilament subunit are associated with thedevelopment of amyotrophic lateral sclerosisrdquo Human Molec-ular Genetics vol 3 no 10 pp 1757ndash1761 1994
[149] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[150] S M Chou H S Wang and K Komai ldquoColocalization of NOSand SOD1 in neurofilament accumulation within motor neu-rons of amyotrophic lateral sclerosis an immunohistochemicalstudyrdquo Journal of Chemical Neuroanatomy vol 10 no 3-4 pp249ndash258 1996
[151] H Zhang X Kong J Kang et al ldquoOxidative stress inducesparallel autophagy and mitochondria dysfunction in humangliomaU251 cellsrdquoToxicological Sciences vol 110 no 2 pp 376ndash388 2009
[152] J Lee S Giordano and J Zhang ldquoAutophagymitochondria andoxidative stress cross-talk and redox signallingrdquo BiochemicalJournal vol 441 pp 523ndash540 2012
[153] A Li X Zhang and W Le ldquoAltered macroautophagy in thespinal cord of SOD1 mutant micerdquo Autophagy vol 4 no 3 pp290ndash293 2008
[154] Y Zhong Q J Wang X Li et al ldquoDistinct regulation ofautophagic activity by Atg14L and Rubicon associated withBeclin 1-phosphatidylinositol-3-kinase complexrdquo Nature CellBiology vol 11 no 4 pp 468ndash476 2009
[155] S Sasaki ldquoAutophagy in spinal cord motor neurons in sporadicamyotrophic lateral sclerosisrdquo Journal of Neuropathology andExperimental Neurology vol 70 no 5 pp 349ndash359 2011
[156] N Morimoto M Nagai Y Ohta et al ldquoIncreased autophagyin transgenic mice with a G93A mutant SOD1 generdquo BrainResearch vol 1167 no 1 pp 112ndash117 2007
[157] M Schroder ldquoEndoplasmic reticulum stress responsesrdquo Cellu-lar andMolecular Life Sciences vol 65 no 6 pp 862ndash894 2008
[158] J D Atkin M A Farg B J Turner et al ldquoInduction ofthe unfolded protein response in familial amyotrophic lateralsclerosis and association of protein-disulfide isomerase withsuperoxide dismutase 1rdquo Journal of Biological Chemistry vol281 no 40 pp 30152ndash30165 2006
[159] C M Haynes E A Titus and A A Cooper ldquoDegradation ofmisfolded proteins prevents ER-derived oxidative stress and celldeathrdquoMolecular Cell vol 15 no 5 pp 767ndash776 2004
[160] K Kanekura H Suzuki S Aiso and M Matsuoka ldquoER stressand unfolded protein response in amyotrophic lateral sclerosisrdquoMolecular Neurobiology vol 39 no 2 pp 81ndash89 2009
[161] M A Farg K Y Soo A K Walker et al ldquoMutant FUS inducesendoplasmic reticulum stress in amyotrophic lateral sclerosisand interacts with protein disulfide-isomeraserdquoNeurobiology ofAging vol 33 no 12 pp 2855ndash2868 2012
[162] E V Ilieva V Ayala M Jove et al ldquoOxidative and endoplas-mic reticulum stress interplay in sporadic amyotrophic lateralsclerosisrdquo Brain vol 130 no 12 pp 3111ndash3123 2007
[163] J D Malhotra and R J Kaufman ldquoEndoplasmic reticulumstress and oxidative stress a vicious cycle or a double-edgedswordrdquo Antioxidants and Redox Signaling vol 9 no 12 pp2277ndash2293 2007
[164] A K Walker and J D Atkin ldquoMechanisms of neuroprotectionby protein disulphide isomerase in amyotrophic lateral scle-rosisrdquo Neurology Research International vol 2011 Article ID317340 7 pages 2011
[165] R B Freedman T R Hirst andM F Tuite ldquoProtein disulphideisomerase building bridges in protein foldingrdquo Trends inBiochemical Sciences vol 19 no 8 pp 331ndash336 1994
[166] C I Andreu U Woehlbier M Torres and C Hetz ldquoProteindisulfide isomerases in neurodegeneration from disease mech-anisms to biomedical applicationsrdquo FEBS Letters vol 586 no18 pp 2826ndash2834 2012
[167] J J Galligan and D R Petersen ldquoThe human protein disulfideisomerase gene familyrdquoHuman Genomics vol 6 no 1 pp 1ndash152012
[168] L Ellgaard and L W Ruddock ldquoThe human protein disulphideisomerase family substrate interactions and functional proper-tiesrdquo EMBO Reports vol 6 no 1 pp 28ndash32 2005
12 Oxidative Medicine and Cellular Longevity
[169] B Wilkinson and H F Gilbert ldquoProtein disulfide isomeraserdquoBiochimica et Biophysica Acta vol 1699 no 1-2 pp 35ndash44 2004
[170] T Tanaka H Nakamura A Nishiyama et al ldquoRedox regulationby thioredoxin superfamily protection against oxidative stressand agingrdquo Free Radical Research vol 33 no 6 pp 851ndash8552000
[171] C Turano S Coppari F Altieri and A Ferraro ldquoProteins ofthe PDI family unpredicted non-ER locations and functionsrdquoJournal of Cellular Physiology vol 193 no 2 pp 154ndash163 2002
[172] D M Ferrari and H D Soling ldquoThe protein disulphide-isomerase family unravelling a string of foldsrdquo BiochemicalJournal vol 339 no 1 pp 1ndash10 1999
[173] G Tian S Xiang R Noiva W J Lennarz and H SchindelinldquoThe crystal structure of yeast protein disulfide isomerasesuggests cooperativity between its active sitesrdquo Cell vol 124 no1 pp 61ndash73 2006
[174] P Klappa LW Ruddock N J Darby and R B Freedman ldquoThebrsquo domain provides the principal peptide-binding site of proteindisulfide isomerase but all domains contribute to binding ofmisfolded proteinsrdquo EMBO Journal vol 17 no 4 pp 927ndash9351998
[175] A Pirneskoski P Klappa M Lobell et al ldquoMolecular char-acterization of the principal substrate binding site of theubiquitous folding catalyst protein disulfide isomeraserdquo Journalof Biological Chemistry vol 279 no 11 pp 10374ndash10381 2004
[176] G Kozlov P Maattanen D Y Thomas and K Gehring ldquoAstructural overview of the PDI family of proteinsrdquo FEBS Journalvol 277 no 19 pp 3924ndash3936 2010
[177] Y Dai and C C Wang ldquoA mutant truncated protein disulfideisomerase with no chaperone activityrdquo Journal of BiologicalChemistry vol 272 no 44 pp 27572ndash27576 1997
[178] C E Jessop R H Watkins J J Simmons M Tasab andN J Bulleid ldquoProtein disulphide isomerase family membersshow distinct substrate specificity P5 is targeted to BiP clientproteinsrdquo Journal of Cell Science vol 122 no 23 pp 4287ndash42952009
[179] C Appenzeller-Herzog J Riemer E Zito et al ldquoDisulphideproduction by Ero1120572-PDI relay is rapid and effectively regu-latedrdquo EMBO Journal vol 29 no 19 pp 3318ndash3329 2010
[180] F Hatahet and L W Ruddock ldquoProtein disulfide isomerase acritical evaluation of its function in disulfide bond formationrdquoAntioxidants and Redox Signaling vol 11 no 11 pp 2807ndash28502009
[181] N J Bulleid and L Ellgaard ldquoMultiple ways to make disulfidesrdquoTrends in Biochemical Sciences 2011
[182] S Chakravarthi C E Jessop and N J Bulleid ldquoThe role ofglutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stressrdquo EMBOReports vol 7 no3 pp 271ndash275 2006
[183] J Lundstrom and A Holmgren ldquoDetermination of thereduction-oxidation potential of the thioredoxin-like domainsof protein disulfide-isomerase from the equilibrium with glu-tathione and thioredoxinrdquo Biochemistry vol 32 no 26 pp6649ndash6655 1993
[184] E Gross C S Sevier N Heldman et al ldquoGenerating disulfidesenzymatically reaction products and electron acceptors of theendoplasmic reticulum thiol oxidase Ero1prdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 2 pp 299ndash304 2006
[185] P I Merksamer A Trusina and F R Papa ldquoReal-time redoxmeasurements during endoplasmic reticulum stress reveal
interlinked protein folding functionsrdquo Cell vol 135 no 5 pp933ndash947 2008
[186] J W Cuozzo and C A Kaiser ldquoCompetition between glu-tathione and protein thiols for disulphide-bond formationrdquoNature Cell Biology vol 1 no 3 pp 130ndash135 1999
[187] L A Rutkevich M F Cohen-Doyle U Brockmeier and DB Williams ldquoFunctional relationship between protein disulfideisomerase family members during the oxidative folding ofhuman secretory proteinsrdquoMolecular Biology of the Cell vol 21no 18 pp 3093ndash3105 2010
[188] Y Honjo S Kaneko H Ito et al ldquoProtein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateralsclerosisrdquo Amyotrophic Lateral Sclerosis vol 12 no 6 pp 444ndash450 2011
[189] H Tsuda S M Han Y Yang et al ldquoThe amyotrophic lateralsclerosis 8 proteinVAPB is cleaved secreted and acts as a ligandfor Eph receptorsrdquo Cell vol 133 no 6 pp 963ndash977 2008
[190] D M Townsend Y Manevich H Lin et al ldquoNitrosative stress-induced S-glutathionylation of protein disulfide isomerase leadsto activation of the unfolded protein responserdquoCancer Researchvol 69 no 19 pp 7626ndash7634 2009
[191] T Uehara T Nakamura D Yao et al ldquoS-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegen-erationrdquo Nature vol 441 no 7092 pp 513ndash517 2006
[192] X Chen C Li T Guan et al ldquoS-nitrosylated protein disul-phide isomerase contributes to mutant SOD1 aggregates inamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol124 no 1 pp 45ndash58 2012
[193] J D Rothstein ldquoTherapeutic horizons for amyotrophic lateralsclerosisrdquo Current Opinion in Neurobiology vol 6 no 5 pp679ndash687 1996
[194] D W Cleveland ldquoNeuronal growth and death order anddisorder in the axoplasmrdquoCell vol 84 no 5 pp 663ndash666 1996
[136] K Y Soo J D Atkin M Farg A K Walker M K Horne andP Nagley ldquoBim links ER stress and apoptosis in cells expressingmutant SOD1 associated with amyotrophic lateral sclerosisrdquoPloS One vol 7 no 4 Article ID e35413 2012
[137] K Hong Y Li W Duan et al ldquoFull-length TDP-43 and itsC-terminal fragments activate mitophagy in NSC34 cell linerdquoNeuroscience Letters vol 530 no 2 pp 144ndash149 2012
[138] R J Braun and B Westermann ldquoMitochondrial dynamics inyeast cell death and agingrdquo Biochemical Society Transactionsvol 39 pp 1520ndash1526 2011
[139] W Duan X Li J Shi Y Guo Z Li and C Li ldquoMutant TARDNA-binding protein-43 induces oxidative injury in motorneuron-like cellrdquo Neuroscience vol 169 no 4 pp 1621ndash16292010
[140] C Jung C M J Higgins and Z Xu ldquoMitochondrial electrontransport chain complex dysfunction in a transgenic mousemodel for amyotrophic lateral sclerosisrdquo Journal of Neurochem-istry vol 83 no 3 pp 535ndash545 2002
[141] A Ferri M Cozzolino C Crosio et al ldquoFamilial ALS-superoxide dismutases associate with mitochondria and shifttheir redox potentialsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 37 pp13860ndash13865 2006
[142] K Aquilano P Vigilanza G Rotilio and M R CiriololdquoMitochondrial damage due to SOD1 deficiency in SH-SY5Yneuroblastoma cells a rationale for the redundancy of SOD1rdquoThe FASEB Journal vol 20 no 10 pp 1683ndash1685 2006
[143] E M OrsquoBrien R Dirmeier M Engle and R O PoytonldquoMitochondrial protein oxidation in yeast mutants lackingmanganese- (MnSOD) or copper- and zinc-containing super-oxide dismutase (CuZnSOD) evidence that mnsod and cuzn-sod have both unique and overlapping functions in protectingmitochondrial proteins from oxidative damagerdquo Journal ofBiological Chemistry vol 279 no 50 pp 51817ndash51827 2004
[144] S Pickles and C V Velde ldquoMisfolded SOD1 and ALS zeroingin on mitochondriardquo Amyotrophic Lateral Sclerosis vol 13 pp333ndash340 2012
[145] B Bandy and A J Davison ldquoMitochondrial mutations mayincrease oxidative stress implications for carcinogenesis andagingrdquo Free Radical Biology andMedicine vol 8 no 6 pp 523ndash539 1990
[146] F Zhang A L Strom K Fukada S Lee L J Hayward andH Zhu ldquoInteraction between familial Amyotrophic LateralSclerosis (ALS)-linked SOD1mutants and the dynein complexrdquoJournal of Biological Chemistry vol 282 no 22 pp 16691ndash166992007
[147] S Sasaki and S Maruyama ldquoUltrastructutal study of skein-like inclusions in anterior horn neurons of patients with motorneuron diseaserdquoNeuroscience Letters vol 147 no 2 pp 121ndash1241992
[148] D A Figlewicz A Krizus M G Martinoli et al ldquoVariantsof the heavy neurofilament subunit are associated with thedevelopment of amyotrophic lateral sclerosisrdquo Human Molec-ular Genetics vol 3 no 10 pp 1757ndash1761 1994
[149] J F Collard F Cote and J P Julien ldquoDefective axonal transportin a transgenic mouse model of amyotrophic lateral sclerosisrdquoNature vol 375 no 6526 pp 61ndash64 1995
[150] S M Chou H S Wang and K Komai ldquoColocalization of NOSand SOD1 in neurofilament accumulation within motor neu-rons of amyotrophic lateral sclerosis an immunohistochemicalstudyrdquo Journal of Chemical Neuroanatomy vol 10 no 3-4 pp249ndash258 1996
[151] H Zhang X Kong J Kang et al ldquoOxidative stress inducesparallel autophagy and mitochondria dysfunction in humangliomaU251 cellsrdquoToxicological Sciences vol 110 no 2 pp 376ndash388 2009
[152] J Lee S Giordano and J Zhang ldquoAutophagymitochondria andoxidative stress cross-talk and redox signallingrdquo BiochemicalJournal vol 441 pp 523ndash540 2012
[153] A Li X Zhang and W Le ldquoAltered macroautophagy in thespinal cord of SOD1 mutant micerdquo Autophagy vol 4 no 3 pp290ndash293 2008
[154] Y Zhong Q J Wang X Li et al ldquoDistinct regulation ofautophagic activity by Atg14L and Rubicon associated withBeclin 1-phosphatidylinositol-3-kinase complexrdquo Nature CellBiology vol 11 no 4 pp 468ndash476 2009
[155] S Sasaki ldquoAutophagy in spinal cord motor neurons in sporadicamyotrophic lateral sclerosisrdquo Journal of Neuropathology andExperimental Neurology vol 70 no 5 pp 349ndash359 2011
[156] N Morimoto M Nagai Y Ohta et al ldquoIncreased autophagyin transgenic mice with a G93A mutant SOD1 generdquo BrainResearch vol 1167 no 1 pp 112ndash117 2007
[157] M Schroder ldquoEndoplasmic reticulum stress responsesrdquo Cellu-lar andMolecular Life Sciences vol 65 no 6 pp 862ndash894 2008
[158] J D Atkin M A Farg B J Turner et al ldquoInduction ofthe unfolded protein response in familial amyotrophic lateralsclerosis and association of protein-disulfide isomerase withsuperoxide dismutase 1rdquo Journal of Biological Chemistry vol281 no 40 pp 30152ndash30165 2006
[159] C M Haynes E A Titus and A A Cooper ldquoDegradation ofmisfolded proteins prevents ER-derived oxidative stress and celldeathrdquoMolecular Cell vol 15 no 5 pp 767ndash776 2004
[160] K Kanekura H Suzuki S Aiso and M Matsuoka ldquoER stressand unfolded protein response in amyotrophic lateral sclerosisrdquoMolecular Neurobiology vol 39 no 2 pp 81ndash89 2009
[161] M A Farg K Y Soo A K Walker et al ldquoMutant FUS inducesendoplasmic reticulum stress in amyotrophic lateral sclerosisand interacts with protein disulfide-isomeraserdquoNeurobiology ofAging vol 33 no 12 pp 2855ndash2868 2012
[162] E V Ilieva V Ayala M Jove et al ldquoOxidative and endoplas-mic reticulum stress interplay in sporadic amyotrophic lateralsclerosisrdquo Brain vol 130 no 12 pp 3111ndash3123 2007
[163] J D Malhotra and R J Kaufman ldquoEndoplasmic reticulumstress and oxidative stress a vicious cycle or a double-edgedswordrdquo Antioxidants and Redox Signaling vol 9 no 12 pp2277ndash2293 2007
[164] A K Walker and J D Atkin ldquoMechanisms of neuroprotectionby protein disulphide isomerase in amyotrophic lateral scle-rosisrdquo Neurology Research International vol 2011 Article ID317340 7 pages 2011
[165] R B Freedman T R Hirst andM F Tuite ldquoProtein disulphideisomerase building bridges in protein foldingrdquo Trends inBiochemical Sciences vol 19 no 8 pp 331ndash336 1994
[166] C I Andreu U Woehlbier M Torres and C Hetz ldquoProteindisulfide isomerases in neurodegeneration from disease mech-anisms to biomedical applicationsrdquo FEBS Letters vol 586 no18 pp 2826ndash2834 2012
[167] J J Galligan and D R Petersen ldquoThe human protein disulfideisomerase gene familyrdquoHuman Genomics vol 6 no 1 pp 1ndash152012
[168] L Ellgaard and L W Ruddock ldquoThe human protein disulphideisomerase family substrate interactions and functional proper-tiesrdquo EMBO Reports vol 6 no 1 pp 28ndash32 2005
12 Oxidative Medicine and Cellular Longevity
[169] B Wilkinson and H F Gilbert ldquoProtein disulfide isomeraserdquoBiochimica et Biophysica Acta vol 1699 no 1-2 pp 35ndash44 2004
[170] T Tanaka H Nakamura A Nishiyama et al ldquoRedox regulationby thioredoxin superfamily protection against oxidative stressand agingrdquo Free Radical Research vol 33 no 6 pp 851ndash8552000
[171] C Turano S Coppari F Altieri and A Ferraro ldquoProteins ofthe PDI family unpredicted non-ER locations and functionsrdquoJournal of Cellular Physiology vol 193 no 2 pp 154ndash163 2002
[172] D M Ferrari and H D Soling ldquoThe protein disulphide-isomerase family unravelling a string of foldsrdquo BiochemicalJournal vol 339 no 1 pp 1ndash10 1999
[173] G Tian S Xiang R Noiva W J Lennarz and H SchindelinldquoThe crystal structure of yeast protein disulfide isomerasesuggests cooperativity between its active sitesrdquo Cell vol 124 no1 pp 61ndash73 2006
[174] P Klappa LW Ruddock N J Darby and R B Freedman ldquoThebrsquo domain provides the principal peptide-binding site of proteindisulfide isomerase but all domains contribute to binding ofmisfolded proteinsrdquo EMBO Journal vol 17 no 4 pp 927ndash9351998
[175] A Pirneskoski P Klappa M Lobell et al ldquoMolecular char-acterization of the principal substrate binding site of theubiquitous folding catalyst protein disulfide isomeraserdquo Journalof Biological Chemistry vol 279 no 11 pp 10374ndash10381 2004
[176] G Kozlov P Maattanen D Y Thomas and K Gehring ldquoAstructural overview of the PDI family of proteinsrdquo FEBS Journalvol 277 no 19 pp 3924ndash3936 2010
[177] Y Dai and C C Wang ldquoA mutant truncated protein disulfideisomerase with no chaperone activityrdquo Journal of BiologicalChemistry vol 272 no 44 pp 27572ndash27576 1997
[178] C E Jessop R H Watkins J J Simmons M Tasab andN J Bulleid ldquoProtein disulphide isomerase family membersshow distinct substrate specificity P5 is targeted to BiP clientproteinsrdquo Journal of Cell Science vol 122 no 23 pp 4287ndash42952009
[179] C Appenzeller-Herzog J Riemer E Zito et al ldquoDisulphideproduction by Ero1120572-PDI relay is rapid and effectively regu-latedrdquo EMBO Journal vol 29 no 19 pp 3318ndash3329 2010
[180] F Hatahet and L W Ruddock ldquoProtein disulfide isomerase acritical evaluation of its function in disulfide bond formationrdquoAntioxidants and Redox Signaling vol 11 no 11 pp 2807ndash28502009
[181] N J Bulleid and L Ellgaard ldquoMultiple ways to make disulfidesrdquoTrends in Biochemical Sciences 2011
[182] S Chakravarthi C E Jessop and N J Bulleid ldquoThe role ofglutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stressrdquo EMBOReports vol 7 no3 pp 271ndash275 2006
[183] J Lundstrom and A Holmgren ldquoDetermination of thereduction-oxidation potential of the thioredoxin-like domainsof protein disulfide-isomerase from the equilibrium with glu-tathione and thioredoxinrdquo Biochemistry vol 32 no 26 pp6649ndash6655 1993
[184] E Gross C S Sevier N Heldman et al ldquoGenerating disulfidesenzymatically reaction products and electron acceptors of theendoplasmic reticulum thiol oxidase Ero1prdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 2 pp 299ndash304 2006
[185] P I Merksamer A Trusina and F R Papa ldquoReal-time redoxmeasurements during endoplasmic reticulum stress reveal
interlinked protein folding functionsrdquo Cell vol 135 no 5 pp933ndash947 2008
[186] J W Cuozzo and C A Kaiser ldquoCompetition between glu-tathione and protein thiols for disulphide-bond formationrdquoNature Cell Biology vol 1 no 3 pp 130ndash135 1999
[187] L A Rutkevich M F Cohen-Doyle U Brockmeier and DB Williams ldquoFunctional relationship between protein disulfideisomerase family members during the oxidative folding ofhuman secretory proteinsrdquoMolecular Biology of the Cell vol 21no 18 pp 3093ndash3105 2010
[188] Y Honjo S Kaneko H Ito et al ldquoProtein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateralsclerosisrdquo Amyotrophic Lateral Sclerosis vol 12 no 6 pp 444ndash450 2011
[189] H Tsuda S M Han Y Yang et al ldquoThe amyotrophic lateralsclerosis 8 proteinVAPB is cleaved secreted and acts as a ligandfor Eph receptorsrdquo Cell vol 133 no 6 pp 963ndash977 2008
[190] D M Townsend Y Manevich H Lin et al ldquoNitrosative stress-induced S-glutathionylation of protein disulfide isomerase leadsto activation of the unfolded protein responserdquoCancer Researchvol 69 no 19 pp 7626ndash7634 2009
[191] T Uehara T Nakamura D Yao et al ldquoS-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegen-erationrdquo Nature vol 441 no 7092 pp 513ndash517 2006
[192] X Chen C Li T Guan et al ldquoS-nitrosylated protein disul-phide isomerase contributes to mutant SOD1 aggregates inamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol124 no 1 pp 45ndash58 2012
[193] J D Rothstein ldquoTherapeutic horizons for amyotrophic lateralsclerosisrdquo Current Opinion in Neurobiology vol 6 no 5 pp679ndash687 1996
[194] D W Cleveland ldquoNeuronal growth and death order anddisorder in the axoplasmrdquoCell vol 84 no 5 pp 663ndash666 1996
[169] B Wilkinson and H F Gilbert ldquoProtein disulfide isomeraserdquoBiochimica et Biophysica Acta vol 1699 no 1-2 pp 35ndash44 2004
[170] T Tanaka H Nakamura A Nishiyama et al ldquoRedox regulationby thioredoxin superfamily protection against oxidative stressand agingrdquo Free Radical Research vol 33 no 6 pp 851ndash8552000
[171] C Turano S Coppari F Altieri and A Ferraro ldquoProteins ofthe PDI family unpredicted non-ER locations and functionsrdquoJournal of Cellular Physiology vol 193 no 2 pp 154ndash163 2002
[172] D M Ferrari and H D Soling ldquoThe protein disulphide-isomerase family unravelling a string of foldsrdquo BiochemicalJournal vol 339 no 1 pp 1ndash10 1999
[173] G Tian S Xiang R Noiva W J Lennarz and H SchindelinldquoThe crystal structure of yeast protein disulfide isomerasesuggests cooperativity between its active sitesrdquo Cell vol 124 no1 pp 61ndash73 2006
[174] P Klappa LW Ruddock N J Darby and R B Freedman ldquoThebrsquo domain provides the principal peptide-binding site of proteindisulfide isomerase but all domains contribute to binding ofmisfolded proteinsrdquo EMBO Journal vol 17 no 4 pp 927ndash9351998
[175] A Pirneskoski P Klappa M Lobell et al ldquoMolecular char-acterization of the principal substrate binding site of theubiquitous folding catalyst protein disulfide isomeraserdquo Journalof Biological Chemistry vol 279 no 11 pp 10374ndash10381 2004
[176] G Kozlov P Maattanen D Y Thomas and K Gehring ldquoAstructural overview of the PDI family of proteinsrdquo FEBS Journalvol 277 no 19 pp 3924ndash3936 2010
[177] Y Dai and C C Wang ldquoA mutant truncated protein disulfideisomerase with no chaperone activityrdquo Journal of BiologicalChemistry vol 272 no 44 pp 27572ndash27576 1997
[178] C E Jessop R H Watkins J J Simmons M Tasab andN J Bulleid ldquoProtein disulphide isomerase family membersshow distinct substrate specificity P5 is targeted to BiP clientproteinsrdquo Journal of Cell Science vol 122 no 23 pp 4287ndash42952009
[179] C Appenzeller-Herzog J Riemer E Zito et al ldquoDisulphideproduction by Ero1120572-PDI relay is rapid and effectively regu-latedrdquo EMBO Journal vol 29 no 19 pp 3318ndash3329 2010
[180] F Hatahet and L W Ruddock ldquoProtein disulfide isomerase acritical evaluation of its function in disulfide bond formationrdquoAntioxidants and Redox Signaling vol 11 no 11 pp 2807ndash28502009
[181] N J Bulleid and L Ellgaard ldquoMultiple ways to make disulfidesrdquoTrends in Biochemical Sciences 2011
[182] S Chakravarthi C E Jessop and N J Bulleid ldquoThe role ofglutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stressrdquo EMBOReports vol 7 no3 pp 271ndash275 2006
[183] J Lundstrom and A Holmgren ldquoDetermination of thereduction-oxidation potential of the thioredoxin-like domainsof protein disulfide-isomerase from the equilibrium with glu-tathione and thioredoxinrdquo Biochemistry vol 32 no 26 pp6649ndash6655 1993
[184] E Gross C S Sevier N Heldman et al ldquoGenerating disulfidesenzymatically reaction products and electron acceptors of theendoplasmic reticulum thiol oxidase Ero1prdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 2 pp 299ndash304 2006
[185] P I Merksamer A Trusina and F R Papa ldquoReal-time redoxmeasurements during endoplasmic reticulum stress reveal
interlinked protein folding functionsrdquo Cell vol 135 no 5 pp933ndash947 2008
[186] J W Cuozzo and C A Kaiser ldquoCompetition between glu-tathione and protein thiols for disulphide-bond formationrdquoNature Cell Biology vol 1 no 3 pp 130ndash135 1999
[187] L A Rutkevich M F Cohen-Doyle U Brockmeier and DB Williams ldquoFunctional relationship between protein disulfideisomerase family members during the oxidative folding ofhuman secretory proteinsrdquoMolecular Biology of the Cell vol 21no 18 pp 3093ndash3105 2010
[188] Y Honjo S Kaneko H Ito et al ldquoProtein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateralsclerosisrdquo Amyotrophic Lateral Sclerosis vol 12 no 6 pp 444ndash450 2011
[189] H Tsuda S M Han Y Yang et al ldquoThe amyotrophic lateralsclerosis 8 proteinVAPB is cleaved secreted and acts as a ligandfor Eph receptorsrdquo Cell vol 133 no 6 pp 963ndash977 2008
[190] D M Townsend Y Manevich H Lin et al ldquoNitrosative stress-induced S-glutathionylation of protein disulfide isomerase leadsto activation of the unfolded protein responserdquoCancer Researchvol 69 no 19 pp 7626ndash7634 2009
[191] T Uehara T Nakamura D Yao et al ldquoS-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegen-erationrdquo Nature vol 441 no 7092 pp 513ndash517 2006
[192] X Chen C Li T Guan et al ldquoS-nitrosylated protein disul-phide isomerase contributes to mutant SOD1 aggregates inamyotrophic lateral sclerosisrdquo Journal of Neurochemistry vol124 no 1 pp 45ndash58 2012
[193] J D Rothstein ldquoTherapeutic horizons for amyotrophic lateralsclerosisrdquo Current Opinion in Neurobiology vol 6 no 5 pp679ndash687 1996
[194] D W Cleveland ldquoNeuronal growth and death order anddisorder in the axoplasmrdquoCell vol 84 no 5 pp 663ndash666 1996
![Page 1: ReviewArticle Redox Regulation in Amyotrophic Lateral …...2 OxidativeMedicineandCellularLongevity disulphide isomerase (PDI), thioredoxin, and glutathione [16–20]. These proteins](https://reader035.documents.pub/reader035/viewer/2022071401/60ececd6fe9d3076ba4f58c4/html5/thumbnails/1.jpg)
![Page 2: ReviewArticle Redox Regulation in Amyotrophic Lateral …...2 OxidativeMedicineandCellularLongevity disulphide isomerase (PDI), thioredoxin, and glutathione [16–20]. These proteins](https://reader035.documents.pub/reader035/viewer/2022071401/60ececd6fe9d3076ba4f58c4/html5/thumbnails/2.jpg)
![Page 3: ReviewArticle Redox Regulation in Amyotrophic Lateral …...2 OxidativeMedicineandCellularLongevity disulphide isomerase (PDI), thioredoxin, and glutathione [16–20]. These proteins](https://reader035.documents.pub/reader035/viewer/2022071401/60ececd6fe9d3076ba4f58c4/html5/thumbnails/3.jpg)
![Page 4: ReviewArticle Redox Regulation in Amyotrophic Lateral …...2 OxidativeMedicineandCellularLongevity disulphide isomerase (PDI), thioredoxin, and glutathione [16–20]. These proteins](https://reader035.documents.pub/reader035/viewer/2022071401/60ececd6fe9d3076ba4f58c4/html5/thumbnails/4.jpg)
![Page 5: ReviewArticle Redox Regulation in Amyotrophic Lateral …...2 OxidativeMedicineandCellularLongevity disulphide isomerase (PDI), thioredoxin, and glutathione [16–20]. These proteins](https://reader035.documents.pub/reader035/viewer/2022071401/60ececd6fe9d3076ba4f58c4/html5/thumbnails/5.jpg)
![Page 6: ReviewArticle Redox Regulation in Amyotrophic Lateral …...2 OxidativeMedicineandCellularLongevity disulphide isomerase (PDI), thioredoxin, and glutathione [16–20]. These proteins](https://reader035.documents.pub/reader035/viewer/2022071401/60ececd6fe9d3076ba4f58c4/html5/thumbnails/6.jpg)
![Page 7: ReviewArticle Redox Regulation in Amyotrophic Lateral …...2 OxidativeMedicineandCellularLongevity disulphide isomerase (PDI), thioredoxin, and glutathione [16–20]. These proteins](https://reader035.documents.pub/reader035/viewer/2022071401/60ececd6fe9d3076ba4f58c4/html5/thumbnails/7.jpg)
![Page 8: ReviewArticle Redox Regulation in Amyotrophic Lateral …...2 OxidativeMedicineandCellularLongevity disulphide isomerase (PDI), thioredoxin, and glutathione [16–20]. These proteins](https://reader035.documents.pub/reader035/viewer/2022071401/60ececd6fe9d3076ba4f58c4/html5/thumbnails/8.jpg)
![Page 9: ReviewArticle Redox Regulation in Amyotrophic Lateral …...2 OxidativeMedicineandCellularLongevity disulphide isomerase (PDI), thioredoxin, and glutathione [16–20]. These proteins](https://reader035.documents.pub/reader035/viewer/2022071401/60ececd6fe9d3076ba4f58c4/html5/thumbnails/9.jpg)
![Page 10: ReviewArticle Redox Regulation in Amyotrophic Lateral …...2 OxidativeMedicineandCellularLongevity disulphide isomerase (PDI), thioredoxin, and glutathione [16–20]. These proteins](https://reader035.documents.pub/reader035/viewer/2022071401/60ececd6fe9d3076ba4f58c4/html5/thumbnails/10.jpg)
![Page 11: ReviewArticle Redox Regulation in Amyotrophic Lateral …...2 OxidativeMedicineandCellularLongevity disulphide isomerase (PDI), thioredoxin, and glutathione [16–20]. These proteins](https://reader035.documents.pub/reader035/viewer/2022071401/60ececd6fe9d3076ba4f58c4/html5/thumbnails/11.jpg)
![Page 12: ReviewArticle Redox Regulation in Amyotrophic Lateral …...2 OxidativeMedicineandCellularLongevity disulphide isomerase (PDI), thioredoxin, and glutathione [16–20]. These proteins](https://reader035.documents.pub/reader035/viewer/2022071401/60ececd6fe9d3076ba4f58c4/html5/thumbnails/12.jpg)
![Page 13: ReviewArticle Redox Regulation in Amyotrophic Lateral …...2 OxidativeMedicineandCellularLongevity disulphide isomerase (PDI), thioredoxin, and glutathione [16–20]. These proteins](https://reader035.documents.pub/reader035/viewer/2022071401/60ececd6fe9d3076ba4f58c4/html5/thumbnails/13.jpg)
