Molecular Pathways of Frontotemporal Lobar Degeneration Kristel Sleegers, 1,2,3 Marc Cruts, 1,2,3 and Christine Van Broeckhoven 1,2,3 1 Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, 2 Laboratory of Neurogenetics, Institute Born-Bunge, and 3 University of Antwerp, Universiteitsplein 1, B-2610, Antwerpen, Belgium; email: [email protected], [email protected], [email protected]Annu. Rev. Neurosci. 2010. 33:71–88 First published online as a Review in Advance on March 22, 2010 The Annual Review of Neuroscience is online at neuro.annualreviews.org This article’s doi: 10.1146/annurev-neuro-060909-153144 Copyright c 2010 by Annual Reviews. All rights reserved 0147-006X/10/0721-0071$20.00 Key Words progranulin, TDP-43, neurodegeneration, etiological heterogeneity Abstract Frontotemporal lobar degeneration (FTLD) is a neurodegenerative condition that predominantly affects behavior, social awareness, and language. It is characterized by extensive heterogeneity at the clinical, pathological, and genetic levels. Recognition of these levels of hetero- geneity is important for proper disease management. The identification of progranulin and TDP-43 as key proteins in a significant proportion of FTLD patients has provided the impetus for a wealth of studies prob- ing their role in neurodegeneration. This review highlights the most recent developments and future directions in this field and puts them in perspective of the novel insights into the neurodegenerative process, which have been gained from related disorders, e.g., the role of FUS in amyotrophic lateral sclerosis. 71 Annu. Rev. Neurosci. 2010.33:71-88. Downloaded from www.annualreviews.org by University of Connecticut on 10/29/12. For personal use only.
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NE33CH04-VanBroeckhoven ARI 14 May 2010 16:24
Molecular Pathwaysof FrontotemporalLobar DegenerationKristel Sleegers,1,2,3 Marc Cruts,1,2,3
and Christine Van Broeckhoven1,2,3
1Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB,2Laboratory of Neurogenetics, Institute Born-Bunge, and 3University of Antwerp,Universiteitsplein 1, B-2610, Antwerpen, Belgium; email: [email protected],[email protected], [email protected]
Annu. Rev. Neurosci. 2010. 33:71–88
First published online as a Review in Advance onMarch 22, 2010
The Annual Review of Neuroscience is online atneuro.annualreviews.org
This article’s doi:10.1146/annurev-neuro-060909-153144
Frontotemporal lobar degeneration (FTLD) is a neurodegenerativecondition that predominantly affects behavior, social awareness, andlanguage. It is characterized by extensive heterogeneity at the clinical,pathological, and genetic levels. Recognition of these levels of hetero-geneity is important for proper disease management. The identificationof progranulin and TDP-43 as key proteins in a significant proportion ofFTLD patients has provided the impetus for a wealth of studies prob-ing their role in neurodegeneration. This review highlights the mostrecent developments and future directions in this field and puts themin perspective of the novel insights into the neurodegenerative process,which have been gained from related disorders, e.g., the role of FUS inamyotrophic lateral sclerosis.
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FTD: frontotemporaldementia
SD: semanticdementia
PNFA: progressivenonfluent aphasia
MND: motor neurondisease
FTLD-tau:frontotemporal lobardegeneration with taupathology
PGRN AND TDP-43 . . . . . . . . . . . . . . . . 79TDP-43 AND FUS SUGGEST A
ROLE FOR ABERRANT RNAPROCESSING INNEURODEGENERATION . . . . . . 80
CONCLUDING REMARKS . . . . . . . . . 81
INTRODUCTION
Frontotemporal dementia (FTD), semantic de-mentia (SD), and progressive nonfluent aphasia(PNFA) are gravely disabling and irreversibleclinical conditions that are characterized byprogressive neuronal loss in the frontal and/ortemporal cortices, collectively referred to asfrontotemporal lobar degeneration (FTLD).Different patterns of neurodegeneration can bedistinguished, with predominant prefrontal andanterotemporal atrophy in FTD, atrophy of themiddle and inferotemporal cortex in SD, andasymmetric atrophy of the left frontal and tem-poral cortices in PNFA (Neary et al. 2005).These topological differences are reflected inthe clinical presentation. FTD, often referredto as behavioral variant FTLD, presents clini-cally with changes in behavior and social con-duct, including loss of social awareness, poorimpulse control, and stereotypic, ritualized be-havior. Patients with SD develop a loss of se-mantic (long-established) knowledge of faces,emotions, objects, and language, resulting inimpaired word comprehension with otherwise
fluent and grammatically faultless speech. Incontrast, patients with PNFA progressively losefluency of speech with intact word comprehen-sion. In later stages of FTLD, the distinct clin-ical phenotypes usually start to show overlap,possibly reflecting the progressive involvementof other brain regions. Moreover, motor neu-ron disease (MND) and parkinsonism compli-cate the disease in up to 15% of patients, andoverlap with symptoms of Alzheimer disease(AD), corticobasal syndrome (CBS), and pro-gressive supranuclear palsy (PSP) is not un-common (Boeve 2007). Onset age of FTLDranges on average from 45 to 65 years (Nearyet al. 2005), often affecting people who are mid-career and still raising a family. Because of in-sidious onset, clinical heterogeneity, and thecurrent lack of rapid and conclusive diagnostictests, erroneous referrals tend to prolong thediagnostic trajectory, with an average diagnos-tic delay of three to four years (Hodges et al.2003). At present, no cure exists. In addition toclinical heterogeneity, FTLD is markedly het-erogeneous at the pathological as well as geneticlevel. As long as this etiological heterogeneityis not fully characterized and recognized, it willseriously impede the development of diagnosticmarkers and of drugs and/or treatments. Break-throughs in recent years, however, have signifi-cantly advanced our understanding of the com-plexity and heterogeneity of FTLD, opening upavenues for further research, several of whichare highlighted in this review.
ETIOLOGICALHETEROGENEITY
The intraneuronal accumulation of filamen-tous, hyperphosphorylated microtubule associ-ated protein tau is the most thoroughly inves-tigated molecular signature of FTLD (FTLD-tau), driven by A. Pick’s (1892) report of charac-teristic lesions in the brain of an FTD patient,hence the eponym Pick’s disease (Pick 1892),and the affirmative observation more than 100years later that mutations in the gene encod-ing microtubule associated protein tau (MAPT)cause FTLD-tau (Hutton et al. 1998). Tau is
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TDP-43: 43 kDatransactivatingresponsive sequenceDNA-binding protein
FTLD-UPS:frontotemporal lobardegeneration with tau-and TDP-43-negativeinclusions, which areimmunoreactive toproteins of theubiquitin-proteasomesystem
abundantly expressed in the central nervous sys-tem, where it interacts with microtubules to sta-bilize the microtubule network and regulatesaxonal transport, mediated by three or four mi-crotubule binding repeat regions (3R or 4R) intau. Most MAPT mutations identified to dateare missense, deletion, or silent mutations orintronic mutations affecting splice sites, result-ing in decreased ability to bind microtubules,increased tendency to form filaments, or alteredratio of tau 4R and 3R isoforms by alterna-tive splicing of exon 10, which encodes the sec-ond of the four microtubule binding repeat re-gions (see the FTD mutation database, http://www.molgen.ua.ac.be/FTDmutations; forreview, see Rademakers et al. 2004). In addi-tion to FTLD-tau, tauopathy is a pathologicalhallmark of other neurodegenerative diseasesas well, including AD, CBS, PSP, and argy-rophilic grain disease (AGD). Although severalquestions remain to be resolved about the waysin which aberrant tau leads to neuronal death(Wolfe 2009), it indisputably plays a role in neu-rodegeneration.
In most FTLD patients who come to au-topsy, however, tau pathology cannot be de-tected. In most of these FTLD brains, neu-ronal cytoplasmic and intranuclear inclusionsare present that are immunoreactive to ubiqui-tin (Bergmann et al. 1996, Johnson et al. 2005,Josephs et al. 2004). Adding to this ambigu-ity was the observation that several multiplextau-negative FTLD families showed conclu-sive genetic linkage to the chromosomal region17q21 harboring MAPT, but they carried nomutations in MAPT (e.g., Rademakers et al.2002, van der Zee et al. 2006). The fog be-gan to clear with the 2006 discovery of mu-tations in progranulin (GRN), located 1.7 Mbcentromeric of MAPT, explaining disease inthese tau-negative, ubiquitin-positive FTLDfamilies linked to 17q21 (Baker et al. 2006,Cruts et al. 2006). Since then, the cause ofFTLD has rapidly been resolved in many pa-tients; with 68 GRN mutations in 210 familiescurrently known worldwide (Gijselinck et al.2008a), GRN mutations are as important a causeof FTLD as MAPT mutations (http://www.
molgen.ua.ac.be/FTDmutations) (Table 1).The story quickened further with the near-simultaneous discovery of pathological 43 kDaTAR DNA-binding protein (TDP-43) asthe principal component of the ubiquitin-immunoreactive inclusions in tau-negativeFTLD-brains (FTLD-TDP) (Arai et al. 2006,Neumann et al. 2006). Taken together, tauand TDP-43 pathology still does not fully ex-plain the occurrence of FTLD. Some FTLDbrains show inclusions that are immunoreactiveonly to proteins of the ubiquitin-proteasomesystem (FTLD-UPS), and some have no in-clusions (FTLD-ni) (Mackenzie et al. 2009).And other genes besides MAPT and GRNcause FTLD (http://www.molgen.ua.ac.be/FTDmutations): Valosin-containing proteingene (VCP) mutations cause FTLD-TDP inthe frame of a broader syndrome includingPaget’s disease of the bone and inclusion bodymyopathy (IBMPFD; Watts et al. 2004), raremutations in the charged multivesicular bodyprotein 2B gene (CHMP2B) are found inFTLD-UPS (Holm et al. 2007, Skibinski et al.2005, van der Zee et al. 2008), and numer-ous families with both FTLD-TDP and MNDshow linkage to a region on chromosome 9,which suggests that at least one other gene forFTLD exists (Gijselinck et al. 2010, Le Beret al. 2009, Morita et al. 2006, Valdmanis et al.2007, Vance et al. 2006) (Table 1). Neverthe-less, with the discovery of GRN and TDP-43,the knowledge of FTLD is rapidly crystalliz-ing, which has already led to a highly sensi-tive and specific biomarker for FTLD-TDPcaused by GRN mutations (Ghidoni et al. 2008,Finch et al. 2009, Sleegers et al. 2009) as a firststep toward personalized health care for FTLDpatients.
TDP-43
TDP-43 is a DNA-, RNA-, and protein-binding nucleoprotein implicated in theregulation of numerous processes, includingtranscription, splicing, cell cycle regula-tion, apoptosis, microRNA biogenesis, mRNAtransport to and local translation at the synapse,
aAbbreviations: CHMP2B, charged multivesicular body protein 2B; VCP, valosin-containing protein; MAPT, microtubule associated protein tau; GRN,progranulin; FTLD, frontotemporal lobar degeneration; IBMPFD, inclusion body myopathy associated with Paget’s disease of bone and frontotemporaldementia; MND, motor neuron disease; UPS, ubiquitine-proteasome system; TDP, TDP-43.bNomenclature according to Mackenzie et al. 2009.cFirst family published.
Proteinopathy:pathologycharacterized by theabnormal aggregationof proteins, e.g.,TDP-43 or tau; afrequentneuropathologicalobservation inneurodegenerativediseases
ALS: amyotrophiclateral sclerosis
and scaffolding for nuclear bodies (for review,see Buratti & Baralle 2008). Structurally, TDP-43 contains two RNA-recognition motifs anda carboxyl (C)-terminal glycine-rich regioninvolved in protein-binding (Wang et al.2004). Its exact role in neurodegeneration isstill a topic of intense investigation. Inclusion-bearing cells (neurons, but also glia) often showa change in subcellular distribution of TDP-43,with loss of nuclear TDP-43 and cytoplasmicsequestration (Arai et al. 2006, Neumann et al.2006). These inclusions contain both full-length TDP-43 and N-terminally truncatedfragments, which are hyperphosphorylatedand ubiquitinated. These posttranslationalmodifications are late events in the patholog-ical process (Dormann et al. 2009, Neumann2009), and N-terminal truncation is not re-quired for aggregation (Dormann et al. 2009).Like tauopathy, TDP-43 proteinopathy is notunique to FTLD but is also a pathologicalhallmark of other neurodegenerative disor-ders, e.g., amyotrophic lateral sclerosis (ALS)with or without dementia (Arai et al. 2006,Neumann et al. 2006) and Perry syndrome,an autosomal dominant form of parkinsonism(Wider et al. 2009). Furthermore, investigatorshave observed secondary TDP-43 pathologyin various other neurodegenerative disor-ders, including AD, hippocampal sclerosis,
α-synucleinopathies [Parkinson disease (PD),dementia with Lewy bodies (DLB)] andHuntington disease (for review, see Geser et al.2009). Inclusions in cortical brain regions arerich in C-terminal fragments, whereas inclu-sions in spinal cord contain more full-lengthTDP-43 (Igaz et al. 2008, Neumann et al.2009), suggesting different pathomechanismsin at least some TDP-43 proteinopathies, butphosphorylation at serine residues 409 and410 is a shared feature of all known TDP-43proteinopathies (Neumann et al. 2009). Never-theless, the inclusions contain TDP-43, leavingthe possibility that TDP-43 accumulation isnot a primary event in the pathogenesis, butrather a by-product of neurodegenerationsequestered by other aggregated components.Strongest evidence that aberrant TDP-43is sufficient to trigger neurodegeneration,however, comes from the detection of au-tosomal dominant mutations in the geneencoding TDP-43 (TARDBP) in familialALS (Kabashi et al. 2008, Sreedharan et al.2008, Van Deerlin et al. 2008). To date, mostmutations identified reside in the C-terminalglycine-rich region of the gene (http://www.molgen.ua.ac.be/FTDmutations), which isnecessary for binding of heterogeneous nuclearribonucleoproteins (hnRNP) in exon skippingand splicing activity (Buratti et al. 2005).
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Loss-of-functionmutation: anymutation that givesrise to a gene productwith a complete orpartial loss of itsfunction
PGRN (or GRN):progranulin(protein/gene)
Several mutations are predicted to affectphosphorylation by introducing new phospho-rylation sites or increasing phosphorylationat adjacent residues, suggesting a role for ab-normal phosphorylation in neurodegeneration(Neumann et al. 2009), although phosphory-lation was found to be a relatively late eventin the conversion of soluble to insolubleTDP-43 (Dormann et al. 2009). The obser-vation of pathological TDP-43 inclusions inthe cytoplasm suggests that a loss of normalfunction in the nucleus could result in neu-rodegeneration, e.g., through a dysfunctionalshuttling of TDP-43 to and from the nucleusand the cytoplasm (Winton et al. 2008a).Drosophila melanogaster depleted of TDP-43shows atrophic presynaptic terminals at theneuromuscular junction, impaired locomotion,and reduced life span, which can be rescued byexpressing human TDP-43; this observationis indicative of a pathogenic loss-of-functionmechanism (Feiguin et al. 2009). The patternof nuclear clearing of TDP-43 is in line witha loss-of-function mechanism, but it is notobvious how the intranuclear inclusions ofTDP-43, which are frequently observed inGRN and VCP mutation carriers (Mackenzieet al. 2006, Sampathu et al. 2006), for example,fit into this picture. Conversely, a toxic gainof function is also conceivable. In a yeastmodel, several TARDBP mutations acceleratedaggregation of TDP-43 and were more toxicthan wild-type TDP-43 expressed at equallyhigh levels, suggesting a toxic gain of function(Johnson et al. 2009). Other investigators(Igaz et al. 2009, Zhang et al. 2009) have alsoobserved cytotoxicity of C-terminal fragments.Overexpression of TDP-43 in rat substantianigra through an adeno-associated virus vectorbrought about a neurodegeneration patternthat resembles human TDP-43 proteinopa-thy as well as behavioral motor dysfunction(Tatom et al. 2009), an observation thatwas further strengthened by TDP-43 trans-genic mouse lines (whether overexpressingmutant or wild-type human TDP-43) thatdisplayed a neurodegenerative phenotype(Wegorzewska et al. 2009, Wils et al.
2010), with homozygous and hemizygouswild-type TDP-43 transgenic mice showingdose-dependent neurodegeneration (Wils et al.2010). On the other hand, both overexpressionof mutant human TDP-43 and knockdownof tardbp in Danio rerio embryos caused asimilar motor phenotype, which suggestedthat both gain- and loss-of-function of TDP-43 can induce neurodegeneration (Kabashiet al. 2010). Further proof could come fromthe observation of genetic variants affectinggene dosage, but so far, no copy-numbervariants have been detected in ALS or FTLD(Gijselinck et al. 2009). Of note, althoughTARDBP missense mutations appeared to beunique for ALS, missense mutations have beenreported in patients with a clinical diagnosisof FTLD with or without MND (Benajibaet al. 2009, Winton et al. 2008b), andKovacs et al. (2009) recently described a novelmissense mutation in a patient with pathologi-cally confirmed FTLD-TDP with concomitantsupranuclear palsy and choreatic movements,but without signs of MND. Although theevidence supporting a pathogenic nature ofsome of these variants is not yet conclusive(e.g., lack of family data for segregation analysisor functional assay), these data suggest that ge-netic screening for TARDBP mutations shouldbe considered in the broader spectrum ofneurodegeneration.
PROGRANULIN
Progranulin (PGRN) is a ubiquitously ex-pressed secreted precursor protein that containstandem repeats of a unique (10- or) 12-cysteine(Cys) motif, which are proteolytically cleavedto form seven granulin (grn) peptides (grn A-G) (He & Bateman 2003). Both full-lengthPGRN and the grn peptides are implicated ina wide variety of biological functions, startingat embryonic development, including cell cy-cle regulation, wound repair, tumor growth,and inflammation, sometimes with opposite ef-fects (e.g., Daniel et al. 2003, He et al. 2003,He & Bateman 2003, Plowman et al. 1992).The balance between PGRN and grn peptides
Null allele mutation:a mutation in an allelethat preventstranscription of thegene and/ortranslation into afunctional protein
Haploinsufficiency:condition in which lossof one functional alleleof a gene is sufficientto cause an abnormalphenotype
is regulated by secretory leukocyte proteaseinhibitor (SLPI), which binds to PGRN to pre-vent proteolysis by elastase (Zhu et al. 2002).PGRN is abundantly expressed in mitoticallyactive tissues or upon injury in tissues thatare less mitotically active (Daniel et al. 2000).Elevated PGRN is a frequent observation in tu-mors (He & Bateman 2003). PGRN is also ex-pressed in the central nervous system, alreadyat the embryonic stage, and significant expres-sion has been observed in the pyramidal andgranule cells of the hippocampus, the Purkinjecells, and cortical neurons (Daniel et al. 2000,Daniel et al. 2003), but its exact role in the post-mitotic neurons of the adult nervous system isless well-characterized.
All pathogenic GRN mutations identifiedin FTLD so far are dominant loss-of-functionmutations, including whole gene deletions(Gijselinck et al. 2008b) and nonsense andframeshift mutations leading to prematuretermination codons with subsequent non-sense mediated mRNA decay of the mutanttranscript, as well as mutations in the signalpeptide leading to protein mislocalization anddegradation and mutations in the initiationcodon preventing translation (i.e., GRN nullallele mutations) (for review, see Cruts & VanBroeckhoven 2008, Gijselinck et al. 2008a).These dominant null allele mutations in GRNinvariably result in PGRN haploinsufficiency(i.e., loss of 50% PGRN), implying that PGRNis critical for survival of neurons in the adultbrain. Several observations further support thishypothesis. Investigators have documentedsignificantly increased levels of PGRN indiseased tissue in ALS (Malaspina et al. 2001,Irwin, Lippa & Rosso 2009), Creutzfeldt-Jakobdisease (Baker & Manuelidis 2003), and AD(Baker et al. 2006; Pereson et al. 2009). Fur-thermore, full-length PGRN enhanced axonaloutgrowth, and grn E promoted neuronalsurvival of cultured neurons (Van Damme et al.2008). Last, GRN mutation carriers can show awide range of clinical presentations, includingAD, PD, and CBS (e.g., Benussi et al. 2009,Brouwers et al. 2007, Le Ber et al. 2008, Rade-makers et al. 2007), which could be interpreted
to reflect a loss of neuroprotection againstother looming neurodegenerative injuries.
GRN null allele mutations have not yet beenobserved in patients with ALS, despite the pres-ence of a similar TDP-43 proteinopathy, whichsuggests that motor neurons are less sensitiveto a 50% reduction in PGRN. Partial loss ofGRN is clearly not detrimental for all functionsof PGRN because patients carrying a GRNnull allele mutation have no other apparent ab-normalities, e.g., in development, growth, orwound repair. There could be many reasonswhy GRN is not always harmful, includingfunctional redundancy in these important bio-logical processes, regulation of expression of thefunctional allele of the gene, differences in sig-nal transduction (Zanocco-Marani et al. 1999),differences in receptors (which are currentlyunknown), and/or the presence of strong modi-fying factors. Homozygous Grn knockout miceshow only a mild male-type behavioral pheno-type (Kayasuga et al. 2007), underscoring thatPGRN is not indispensable for many of the bi-ological processes in which it is involved. Ofnote, even though some patients develop firstsymptoms of FTLD in their early forties, somemutation carriers live well beyond 70 yearswithout any cognitive complaints, even withinone family (e.g., Brouwers et al. 2007), whichstrongly indicates modifying factors. Furtherexploration of these aspects will likely be in-strumental in identifying targets for therapy.
CAN THE UNDERLYINGETIOLOGY BE ESTABLISHEDIN VIVO?
In postmortem tissue, distinct pathologicalprofiles of FTLD-TDP can be discernedthat appear to correlate well with the clinicaland genetic subtypes (Mackenzie et al. 2006,Sampathu et al. 2006). Small neurites, cytoplas-mic inclusions, and intranuclear inclusions arefrequent in GRN mutation carriers and in FTDor PNFA patients. Intranuclear inclusions areless frequent in families linked to chromosome9 and patients with FTD-MND or SD, andthe latter often have a predominance of long
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neurites. Patients with IBMPFD with a VCPmutation typically have more intranuclear thancytoplasmic inclusions (Mackenzie et al. 2006,Sampathu et al. 2006). Conversely, the abilityto distinguish between the different etiologicalpathways during life is less straightforward,even though this knowledge is crucial tomake the correct treatment decisions whendrugs targeting the pathological proteins aredeveloped. VCP mutations cause the raredisorder IBMPFD (Watts et al. 2004), butthis correlation is not perfect; even in carriersof an identical VCP mutation, investigatorshave observed marked heterogeneity in clinicalexpression, such as VCP p.Arg159His, whichpresented with FTD only in one family, withFTD and/or Paget’s disease of the bone in an-other family, and with predominant inclusionbody myopathy or Paget’s disease in a thirdfamily (van der Zee et al. 2009). Nevertheless,presence of Paget’s disease or inclusion bodymyopathy in a patient with FTD strongly sug-gests an underlying VCP mutation. Apart fromFTLD-TDP caused by rare mutations in VCP,however, no set of clinical symptoms is specificfor one genetic or pathological subtype ofFTLD (Boeve & Hutton 2008). Roughly halfof patients with FTD will have FTLD-tau, andthe other half will have FTLD-TDP (Formanet al. 2006, Johnson et al. 2005). The presenceof MND is thought to be more frequent inFTLD-TDP, but not in those patients carryinga GRN mutation (e.g., Pickering-Brown et al.2008). Several symptoms are present at anunusually high frequency in GRN mutationcarriers, including early ideomotor apraxia,early memory impairment, and hallucinations(Rademakers et al. 2007, Le Ber et al. 2008),the latter two sometimes leading to an initialclinical diagnosis of AD or DLB. Furthermore,onset age tends to be earlier in MAPT mutationcarriers than in GRN mutation carriers (Cruts& Van Broeckhoven 2008). However, none ofthese features allows perfect discrimination,and they might also be dependent on thepresence of modifying factors in families. Inaddition, GRN mutation carriers may have anatypical clinical presentation, such as CBS or
AD [15% in French series (Le Ber et al. 2008)],and go unnoticed when no relatives are affected.At neuroimaging of GRN mutation carriers,asymmetrical atrophy seems to be a frequentfeature (e.g., Beck et al. 2008, Le Ber et al. 2008,van der Zee et al. 2007). For positron emissiontomography, development of radioisotopes andtracers specific for tau or TDP-43 will likelybe an important step forward to allow in vivoimaging of the proteinopathies comparableto imaging of amyloid deposition in ADusing Pittsburgh compound B (Klunk et al.2004). The inconsistent results of biomarkerstudies in FTLD focusing on levels of tau incerebrospinal fluid (CSF) (Green et al. 1999,Grossman et al. 2005) may have been causedby unrecognized etiological heterogeneity inthe study population, with an expected 50%of tau-negative patients (Bian & Grossman2007). The recent advances, however, havestimulated the exploration of disease-specificbiomarkers. Foulds et al. (2008) reportedTDP-43 protein plasma levels to be elevated inapproximately half of the patients with clinicalFTD, compatible with what is expected basedon neuropathological studies. This biomarkerassay will most likely facilitate drug trials tar-geting TDP-43 pathology by allowing a morecareful trial design. Plasma TDP-43 levelswere also elevated in 20% of AD patients and8% of cognitively healthy individuals (Fouldset al. 2008). Similarly, TDP-43 levels in CSFwere elevated in patients with FTLD and ALSbut showed considerable overlap with controlindividuals (Kasai et al. 2009, Steinacker et al.2008). In contrast, reduced PGRN levels inserum and plasma proved to be up to 100%sensitive and specific for underlying GRNmutations (Finch et al. 2009, Ghidoni et al.2008, Sleegers et al. 2009) already in unaffectedmutation carriers. Because this biomarkeraccurately reflects the underlying disease entityand can already predict disease in a prodromalstage, it holds great promise for the futureof FTLD disease management. Furthermore,it may have an application in drug develop-ment aiming to restore PGRN levels becauseelevated levels are associated with various
cancers. A panel of rapid, noninvasive testscovering all distinct etiological entities shouldultimately facilitate the diagnostic process.
CAN GRN MUTATIONS OTHERTHAN NULL ALLELEMUTATIONS CAUSE DISEASE?
Large-scale sequencing projects of GRNhave uncovered other genetic variants thatoccur only, or more frequently, in pa-tients, but which are not manifestly null al-lele mutations (http://www.molgen.ua.ac.be/FTDmutations). The pathogenic potential ofsome of these genetic variants is still hotly de-bated. Patient-specific missense mutations havebeen detected, for example, in the evolution-arily highly conserved grn domains (Brouwerset al. 2008, van der Zee et al. 2007). Muta-tions that introduce or replace a Cys-residueare especially predicted to be pathogenic be-cause Cys-residues are required to stabilizethe fold of four stacked beta-hairpins charac-teristic for the grn domains through disulfidebridges between these residues (Hrabal et al.1996, Tolkatchev et al. 2000). These muta-tions could result in misfolding of the protein,which may lose its normal activity (Tolkatchevet al. 2008) or be destined for degradationin the endoplasmic reticulum (ER), resultingin reduced amounts of functional protein. Insupport of this hypothesis, pathogenic Cys-residue mutations in several other proteins con-taining disulfide bond-rich epidermal-growth-factor (EGF)-like domains [fibrillin-1 (FBN1),uromodulin (UMOD)] (Robinson et al. 2002,Scolari et al. 2004) indeed induce retentionof the mutant transcript in the ER becauseof abnormal protein folding (Bernascone et al.2006, Whiteman & Handford 2003). Alterna-tively, because gain or loss of a Cys-residueresults in an odd number of Cys-residues,the unpaired Cys-residue in turn could havean increased propensity to form multimersthrough aberrant disulfide bond formation, aswas recently reported for pathogenic muta-tions in NOTCH3, which caused cerebral auto-somal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL)(Opherk et al. 2009). Pathogenic mutations inNOTCH3 almost all lead to an odd number ofCys-residues in one of its EGF-like domains(Federico et al. 2005, Joutel et al. 1997). In ayeast-two hybrid assay, a grn dimeric repeatconsisting of grn B and A was shown to bindhuman immunodeficiency virus (HIV) Tat pro-teins, and mutation of grn Cys-residues weak-ened this binding ability (Trinh et al. 1999),further highlighting the pathogenic potentialof Cys-residue mutations.
Other GRN missense mutations haveaffected highly conserved Pro-residues occur-ring in a loop of the protein backbone of thegrn domain. Molecular modeling predictedamino acid substitutions at this position toaffect folding and stability of the grn domain(Brouwers et al. 2008, van der Zee et al. 2007).Arguing against a putative pathogenic natureof GRN missense mutations is the fact thatsome, albeit different, missense mutationsalso occur in healthy control individuals.FTLD-TDP has not been pathologicallyconfirmed, and segregation data are sparse.One mutation, p.Arg432Cys, was observed inthree (genetically distantly) related patientswith clinical FTLD (van der Zee et al. 2007);p.Cys521Tyr was observed in four affectedrelatives from a PNFA family but also inseveral unaffected siblings, although cognitivetests of carriers predicted a mild cognitiveimpairment (Cruchaga et al. 2009). However,in cultured cells, two predicted pathogenicmutations, p.Pro248Leu and p.Arg432Cys,showed less efficient transport through thesecretory pathway, which led to a significant(70% and 45%) reduction in PGRN secretion(Shankaran et al. 2008). This partial loss offunctional protein suggests that these raremutant alleles act as low penetrant risk factors,as opposed to the autosomal dominant natureof null allele mutations that create completehaploinsufficiency. This hypothesis is very wellcompatible with the presence of some of thesemutations in control individuals and with thelack of segregation data. Of note, the frequencyof these missense mutations in both patients
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and healthy individuals is usually rare, withminor allele frequencies less than 1%. In ad-dition, missense mutations are also detected inother neurodegenerative disorders, such as AD(Brouwers et al. 2008), PD (Nuytemans et al.2008), and ALS (Schymick et al. 2007, Sleegerset al. 2008), which again suggests that theserare mutant alleles might increase susceptibilityfor neurodegeneration by failing neurotrophicproperties. In line with this speculation, invivo data on circulating protein levels inplasma or serum show a partial reduction ofPGRN in some predicted pathogenic missensemutation carriers [e.g., unrelated carriers ofp.Cys139Arg had partially reduced PGRNlevels in two independent studies (Finch et al.2009, Sleegers et al. 2009)], with levels inter-mediate between noncarriers and null mutationcarriers, regardless of their clinical phenotype.Because of their low frequency and possibly lowpenetrance, definite proof of the pathogenicityof some of these mutations relies on continuedfunctional experiments, which could, amongothers, address the question of whether loss ofone grn peptide is sufficient to affect diseaserisk, and if so, which grn peptides are relevantfor neuroprotection, whether acting alone orin multimers. Of note, the ability to adopt agrn fold is necessary but not sufficient for bio-logical activity of the grn peptides (Tolkatchevet al. 2008), which suggests that not everygrn domain will be equally sensitive to aminoacid substitutions. Common GRN geneticvariants have also been implicated in diseaserisk, affecting onset age and survival in patientswith ALS (Sleegers et al. 2008) among others,and a common 3′ UTR variant affected riskof FTLD by influencing a microRNA bindingsite (Rademakers et al. 2008); however, otherinvestigators have been unable to replicatethese findings (Rollinson et al. 2010). Becauseof their potential therapeutic implications,however, these findings warrant follow-up.
PGRN AND TDP-43
One of the puzzles that remain to be resolved iswhether and how loss of PGRN is linked with
the pathological accumulation of TDP-43.Mutant TARDBP is clearly sufficient to induceTDP-43 pathology in ALS patients, but muta-tions in TARDBP are at best a rare occurrencein FTLD (Benajiba et al. 2009, Gijselinck et al.2009, Kovacs et al. 2009, Winton et al. 2008b),and conversely, despite similarities at thepathological level between FTLD-TDP andALS, GRN null allele mutations have not beenfound in ALS (Schymick et al. 2007, Sleegerset al. 2008). VCP mutations, which are asso-ciated with predominant neuronal intranuclearTDP-43 inclusions (Mackenzie et al. 2006,Sampathu et al. 2006), altered localization ofTDP-43 between nucleus and cytosol, and aminority of TDP-43-positive inclusions wasalso VCP-immunoreactive (Gitcho et al. 2009);for GRN mutations, however, no such evidenceexists at present. Knockdown of neuronal GRNexpression using small interfering RNA incell culture models led to abnormal caspase3-mediated cleavage of TDP-43 (Zhang et al.2007), but this finding has been challengedby others (Shankaran et al. 2008). Brains of7–8-month-old PGRN knockout mice showedno evidence for accumulation of C-terminalfragments of TDP-43 or of phosphorylatedTDP-43 (Dormann et al. 2009). In an axotomymodel in mice, TDP-43 showed increasedexpression and relocalization to the cytosolfollowing acute neuronal injury, while aneuronal decrease in PGRN was observed(Moisse et al. 2009). The increase in TDP-43upon injury indicates a physiological role inneuronal repair. The concomitant decrease inneuronal PGRN is less well interpretable butcould reflect secretion of PGRN, given theneurotrophic properties of secreted PGRN(Moisse et al. 2009). However, Matzilevichet al. (2002) also reported a delayed responseof PGRN expression to acute neuronal injury,which suggests that it has a more promi-nent role in long-term neuronal survival(Ahmed et al. 2007). In surrounding microglia,expression of PGRN was upregulated inresponse to axotomy, which is compatible witha role in inflammation and repair (Ahmed et al.2007). Nevertheless, this occurrence does not
imply a direct functional link between TDP-43and PGRN. Given the possible role of grn pep-tides in HIV Tat protein binding (Trinh et al.1999), and the ability of TDP-43 to bind to theHIV TAR DNA element to which Tat proteinsbind to activate gene expression (Ou et al.1995), Ahmed et al. (2007) have speculated thatPGRN and TDP-43 may be able to interact di-rectly; this awaits further exploration, however.
TDP-43 AND FUS SUGGEST AROLE FOR ABERRANT RNAPROCESSING INNEURODEGENERATION
Much may be learned from searching forunifying themes in related neurodegenerativedisorders. For FTLD-TDP, ALS seems tobe particularly relevant. Like FTLD, ALS isa mechanistically heterogeneous disorder, butone of the major ALS pathologies is TDP-43proteinopathy (Arai et al. 2006, Neumann et al.2006). Substantial overlap also exists at the clin-ical level. FTD is complicated by MND in a sig-nificant proportion of patients, and up to 50%of ALS patients develop symptoms of fron-totemporal dysfunction (Lomen-Hoerth et al.2003). Moreover, multiplex families in whichFTLD-TDP and ALS cosegregate have beenlinked to a region on chromosome 9p, whichimplies that mutations in one gene could in-duce both clinical phenotypes (Le Ber et al.2009, Morita et al. 2006, Valdmanis et al. 2007,Vance et al. 2006; Gijselinck et al. 2010). Thesedata support the notion that FTLD-TDP andALS are closely related conditions in a con-tinuum of neurodegeneration and that scien-tific breakthroughs in one area may have a rip-ple effect extending to other disorders alongthe continuum. Dominant familial ALS linkedto chromosome 16 was recently shown to re-sult from pathogenic mutations in FUS (fusionin sarcoma) (Kwiatkowski et al. 2009, Vanceet al. 2009). FUS is an RNA/DNA process-ing protein like TDP-43, and its implicationin ALS bears remarkable resemblance to TDP-43 (Sleegers & Van Broeckhoven 2009). LikeTDP-43, FUS is associated with hnRNP, and
its functions include DNA repair, transcrip-tion, RNA splicing, transport of mRNA to andrapid local RNA translation at the synapse, andmicroRNA processing (for review, see Lagier-Tourenne & Cleveland 2009). Most mutationsidentified in FUS to date reside in the C-terminus (Kwiatkowski et al. 2009, Vance et al.2009), resembling the C-terminal clustering ofpathogenic mutations in TARDBP. In spinalcord and brain tissue of FUS mutation carri-ers, cytoplasmic inclusions containing mutantFUS protein could be observed, and in vitroexperiments confirmed relocation of mutantFUS to the cytoplasm (Kwiatkowski et al. 2009,Vance et al. 2009). FUS mutation carriers didnot show TDP-43 pathology, which impliesthe involvement of different pathways that leadto neurodegeneration. Mutations could lead toa loss of normal function or a gain of toxicfunction of FUS in the nucleus, resulting in(potentially general) impaired RNA process-ing. Instead of RNA metabolism per se, a spe-cific RNA target of FUS could be crucial forneuron viability; identifying such RNA targetsmay provide a link between FUS and TDP-43 but also among other ALS-associated RNAprocessing proteins such as ELP3 (Simpsonet al. 2008). Mislocalization of mutant FUS tothe cytoplasm could create a loss of its func-tion in the nucleus, but cytoplasmic aggre-gates of FUS could also be toxic to the cellor lead to sequestration of other proteins inthe cytoplasm. Last, mutant FUS or TDP-43could perturb normal mRNA transport to thedendrites and/or impair rapid RNA transla-tion at the postsynaptic site (e.g., in responseto stimulation by neurotrophic factors). Fu-ture research will likely shed more light on themechanisms by which aberrant FUS as well asTDP-43 affect neuron viability (Figure 1). Theidentification of aberrant TDP-43 and FUS inmotor neuron degeneration provides furthersupport for the hypothesis that impaired RNAprocessing plays a crucial role in neurodegener-ation (Gallo et al. 2005). Examples of impairedRNA processing seem especially numerous inMND (for review, see Simpson et al. 2008).Overexpression of TDP-43 in vitro enhances
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the transcript inclusion of exon 7 of survival ofmotor neuron 2 (SMN2) (Bose et al. 2008), en-coding an RNA-binding protein implicated inthe neurodegenerative disorder spinal muscu-lar atrophy (Lefebvre et al. 1995). In FTLD,RNA processing is already indirectly implicatedthrough alternative splicing of MAPT exon 10.Thus it is also of interest that synthetic mul-timers of grn repeats have been implicated inRNA processing by modulating transcriptionelongation through an interaction with cyclinT1 (Hoque et al. 2003). Broader involvementof RNA processing in FTLD is likely becauseit is involved in numerous biological processesspecific for proper neuronal functioning, in-cluding synaptic plasticity (Steward & Schuman2001). This, and the overlap between ALS andFTLD-TDP, raises the question of whetherFUS could also be involved in FTLD (Sleegers& Van Broeckhoven 2009). Although the re-search is in its early days, Mackenzie (2009) re-cently reported that some FTLD brains thatwere previously classified as FTLD-UPS be-cause of the presence of tau- as well as TDP-43-negative inclusions harbor FUS-positive in-clusions; likewise, we have recently identified anFTLD patient carrying a FUS missense muta-tion (p.Met254Val) affecting an evolutionarilyconserved residue in the glycine-rich region ofFUS, which is predicted to affect protein func-tion (Van Langenhove et al. 2010).
CONCLUDING REMARKS
The identification of mutations in MAPT,GRN, VCP, and CHMP2B in FTLD patientsand the observation of pathological intraneu-ronal accumulation of tau, TDP-43, and FUSprotein in brains of FTLD patients demon-strate the diversity of molecular pathways in-volved in this condition. Rare variants inTARDBP and FUS in FTLD patients may fur-ther contribute to the genetic heterogeneity ofFTLD, and at least one other genetic causefor FTLD (on 9p) remains to be uncovered.These recent observations suggest that the fieldof FTLD research might be on the verge of anew wave of discoveries. Although the search
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Presynaptic
RNA-containinggranules
RNA
DNA
Aggregatedproteins
Normalprotein
Mutantproteins
Postsynaptic
Figure 1Schematic representation of possible mechanisms by which mutant TARDBPor FUS might affect neuronal viability. (1) Mutant TDP-43 or FUS could leadto a loss of normal function or a gain of toxic function in the nucleus, resultingin impaired RNA processing; (2) a specific RNA target (possibly shared by FUSand TDP-43) could be crucial for neuron viability; (3) mislocalization ofmutant FUS or TDP-43 to the cytoplasm could create a loss of its function inthe nucleus; (4) cytoplasmic aggregates of FUS or TDP-43 (full-length orC-terminal fragments, ubiquitinated and phosphorylated) could be toxic to thecell; (5) mutant FUS or TDP-43 could perturb normal mRNA transport or (6)impair local RNA translation at the synapse in response to synaptic stimulation.
for mechanistic links between these pathwaysmay provide novel insights into the neurode-generative process, recognition of the etiolo-gial diversity will be crucial to advance patientcare. It allows studies focusing on more homo-geneous etiological subclasses, which can fa-cilitate development of diagnostic proceduresand drugs, but it may also increase our un-derstanding of disease mechanisms. The firstgenome-wide association study on FTLD, e.g.,including only patients with FTLD-TDP, re-cently uncovered common genetic variation
in the gene TMEM106B as a putative riskfactor for FTLD-TDP (Van Deerlin et al.2010). Further characterization of this trans-membrane protein of unknown function may
provide one more piece of the puzzle of FTLD.Hopefully, in the not-too-distant future thevarious etiological entities underlying FTLDwill be fully characterized.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings thatmight be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
Research in the authors’ research group was funded in part by the Special Research Fund of theUniversity of Antwerp, the Fund for Scientific Research Flanders (FWO-V), the InteruniversityAttraction Poles program (IAP) P6/43 of the Belgian Science Policy Office, the Medical Founda-tion Queen Elisabeth, the Foundation for Alzheimer Research (SAO/FRMA), the Association forFrontotemporal Dementias (AFTD), and a Methusalem Excellence Grant of the Flemish Govern-ment, Flanders, Belgium, and a Zenith award from the Alzheimer’s Association USA to C.V.B., aMarie-Therese de Lava Fund of the King Baudouin Foundation Belgium to M.C., and a Santkinaward from the National Alzheimer League Belgium to M.C. and K.S. K.S. is a postdoctoralfellow of the FWO-V.
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Annual Review ofNeuroscience
Volume 33, 2010Contents
Attention, Intention, and Priority in the Parietal LobeJames W. Bisley and Michael E. Goldberg � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1
The Role of the Human Prefrontal Cortex in Social Cognitionand Moral JudgmentChad E. Forbes and Jordan Grafman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 299
Sodium Channels in Normal and Pathological PainSulayman D. Dib-Hajj, Theodore R. Cummins, Joel A. Black,and Stephen G. Waxman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 325
Mechanisms of Synapse and Dendrite Maintenance and TheirDisruption in Psychiatric and Neurodegenerative DisordersYu-Chih Lin and Anthony J. Koleske � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 349
Connecting Vascular and Nervous System Development: Angiogenesisand the Blood-Brain BarrierStephen J. Tam and Ryan J. Watts � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 379
Motor Neuron Diversity in Development and DiseaseKevin C. Kanning, Artem Kaplan, and Christopher E. Henderson � � � � � � � � � � � � � � � � � � � � � � 409
The Genomic, Biochemical, and Cellular Responses of the Retina inInherited Photoreceptor Degenerations and Prospects for theTreatment of These DisordersAlexa N. Bramall, Alan F. Wright, Samuel G. Jacobson, and Roderick R. McInnes � � � 441
