Oxidative DNA Damage and Proteostasis in Age-Related...

P Tokarz et al Journal of Biochemical and Pharmacological Research Vol 1 (2) 106-113 June 2013

ISSN 2168-8761 printISSN 2168-877X online ~ 106 ~ httpwwwresearchpuborgjournaljbprjbprhtml

Abstract Age-related macular degeneration (AMD) is a severe eye disease the prevalence of which continues to rise along with the increase in living expectancies Both genetic and environmental factors contribute to the onset and progression of the disease in which the capacity of retinal pigment epithelium (RPE) cells to support the photoreceptors is diminished RPE cells are heavily exposed to oxidative stress which predisposes bodyrsquos metabolically most active cells to several threats Protein homeostasis or proteostasis stands on the mTOR interconnecting pathways that are involved in controlling the production folding transporting posttranslational modification and degradation of proteins We will provide here a view how oxidative stress and the subsequent DNA damage result in disturbances in the proteostasis of aged cells and thereby contribute to the development of aggregation diseases such as AMD Keywords DNA damage macular degeneration oxidative stress proteostasis retinal pigment epithelium 1 Introduction

ge-related macular degeneration (AMD) is a progressive eye disease of the central part of the retina leading to a

vision loss in the elderly AMD is a multifactorial disease with many genetic and environmental factors most of which are

__________________________________________ aDepartment of Molecular Genetics Faculty of Biology and Environmental Protection University of Lodz Pomorska 141143 90-236 Lodz Poland bDepartment of Ophthalmology Institute of Clinical Medicine University of Eastern Finland Kuopio Finland cDepartment of Ophthalmology Kuopio University Hospital Kuopio Finland Corresponding author Fax +358-17-172486 Email KaiKaarnirantakuhfi (Received June 7 2013 Revised June 18 2013 Accepted June 19 2013 Published online June 24 2013)

associated with the generation of oxidative stress and chronic inflammation (Fig1) [1] Decline in the vision quality is a result of the degeneration and atrophy of retinal pigment epithelial (RPE) cells and neural cells (rod and cones) Since it is the responsibility of RPE cells to maintain the functionality of photoreceptors the overlying rod and cone cells become deprived due to an irreversible damage on RPE cells AMD is usually categorized into two main classes dry (atrophic) form and wet (exudative) form that account for about 85 and 15 of AMD respectively (Fig 2) [2] Both AMD classes show RPE hyper- and hypo-pigmentation formation of lipofuscin the presence of drusen and cell loss whereas only for wet AMD rapid and sudden loss of vision due to subretinal neovascularization (between the retina and choroid) is observed (Fig 2) Currently there is no proven treatment for dry AMD whereas the activity of wet AMD may be inhibited with the intraocular injections of antiangiogenic agents [3] Lipofuscin and drusen accumulations reflect to severity level of AMD [4] They are indication of disturbed proteostasis in conjunction with chronic oxidative stress DNA damage mechanistic target of rapamycin (mTOR) signaling and inflammation [1 4] 2 Oxidative stress and AMD The highest consumption of oxygen per cell in humans is in the retina Oxygen is a potent source of reactive oxygen species (ROS) including both oxygen radicals (Obullminus2 OH) and nonradicals (O3 H2O2 1O2) that are converted into free radicals These compounds have different reactivity hydroxyl radical (OH) being the most reactive Due to the high reactivity of ROS their interaction with biomolecules may be deleterious to a cell RPE cells are especially prone to generate an excess of ROS because of their high consumption of oxygen their exposure to blue light and their phagocytic function which is accompanied with respiratory burst ndash an ejection of ROS An imbalance between production and elimination of ROS may have detrimental consequences to tissues Normally cells respond to oxidative stress-induced cellular damages by activating DNA repair systems by the expression of antioxidant enzymes and molecular chaperones and by

Review

Oxidative DNA Damage and Proteostasis in Age-Related Macular Degeneration

Paulina Tokarza Anu Kauppinenb Kai Kaarnirantabc Janusz Blasiaka

A



Fig 2 Schematic representation of the physiological macula and the pathological changes occurring in the dry and wet AMD Contributors and mechanisms of the conversion of physiological macula or dry AMD to wet form still remain to be elucidated However choroidal neovascularization and accumulation of oumldema fluid in retina are clinical hallmarks of wet AMD

Fig 1 Risk factors that contribute to the generation of oxidative stress and development of AMD accelerating protein clearance [4] Failures in these systems lead to a progressive decrease in the clearance of ROS and aggregated proteins in conjunction with chronic inflammation that are recognized as important factors in the etiology of numerous late-onset degenerative diseases including AMD [14]

3 ROS as a causative factor for AMD ROS are indispensable for cell survival as they participate in cell signaling gene expression and cellular differentiation via regulating the cellular redox state or the balance between oxidationreduction reactions However the level of oxidants exceeding the cellrsquos antioxidant buffering capacity promotes oxidative stress Generally oxidative stress is believed to increase with aging [5] It was reported that aging is predictive of an increased risk of oxidative stress and that it is linked with a progressive and slow decline in antioxidant status in the European free-living healthy elderly [6] Interestingly the healthy elderly subjects were not exposed to an acute oxidative stress when compared with middle-aged subjects The oxidative stress theory of aging which is particularly enticing in the light of the damaging nature of oxidants in vivo explains the association between oxidative stress and age-related dysfunction at the level of cell and whole organism Such phenomena as the association between basal metabolic rate and life expectancy the accumulation of degenerative disorders in advanced age and the improvement of life-span with the use of caloric restriction may be easily clarified with this theory It is commonly postulated that the cellular antioxidant defense declines and the amount of ROS increases with aging [5 7] The rate of aging is established via the amount of cellular structural damage Also the retina ROS level elevates and the cellular oxidative damage increases with an age-related tendency In age-related neurodegenerative diseases which are associated with the oxidative stress including Alzheimerrsquos disease Parkinsonrsquos disease and AMD protein and DNA are damaged either directly by ROS or reactive nitrogen species (RNS) or indirectly by the products of lipid peroxidation [8] Thus the accumulation of oxidative damage during lifetime may lead to a dysfunction of RPE cells and increase their susceptibility to exogenous and endogenous insults eventually culminating in neural cell death and loss of visual function However it is difficult to assess whether the augmentation of oxidative damage in AMD is primarily due to elevated level of



ROS or decline in antioxidant defense or a combination of both or alternatively AMD is a disease related to separate aging-independent pathology In vitro studies showed that oxidative stress was generated when cells were exposed to irradiation and that the pre-treatment of cells with ROS scavengers such as vitamins A C and E protected against this injury [9] However the analysis of the level of these vitamins and the antioxidant status of subjects withwithout AMD are not evident since population-based studies of the dietary or plasma levels of antioxidants lack consistency due to the subjectivity of antioxidants nutritional intake estimation or the reflection to recent antioxidants nutritional intake only [10-13] Although the concentration of another ROS scavenger α-tocopherol within the retina is sensitive to its dietary intake a number of studies manifesting its protective effect seem to be convincing [14-16] Also high plasma levels of lutein and zeaxanthin antioxidants were associated with a reduced risk of neovascular AMD [17 10] The excessive amount of iron in the retina may contribute to the pathogenesis of AMD since it may generate ROS through the Fenton reaction The most convincing study in support of this hypothesis comes from the studies conducted on the post-mortem human retina showing that the concentrations of iron and iron-transporting enzyme transferrin were higher in the AMD patients than in sex- and age-matched individuals without visual disturbances [18 19] We showed that genetic polymorphism in a number of genes encoding proteins of iron metabolism NFE2L2 (rs6726395) NOS3 (rs1799983) TF (rs4481157) IRP1 (g32373708) and IRP2 (g49520870) may modulate the risk of AMD [20-23] However it is still a matter of debate whether iron is the cause of AMD or a byproduct of AMD pathogenesis A number of above examples are supportive for the hypothesis that AMD is ascribed to the cumulative oxidative stress [10 13 15] 4 DNA damage and repair in AMD 41 DNA repair decreases with age

There is a growing body of evidence that DNA repair decreases in age-dependent manner The 30-50 age-related decline in the DNA repair capacity was shown in C elegans at the whole organism level suggesting that it may contribute to the age-associated accumulation of DNA damage [24] With age the efficacy of base excision repair (BER) and non-homologous end joining (NHEJ) decreased in aging rat neurons [25] The lowered efficacy of BER was attributed to the deficiency of DNA polymerase β and DNA ligase in aging neurons The slower rate of the removal of UV-induced DNA lesions and the decreasing levels of proteins that participate in the repair process in aged humans in comparison to younger adults may suggest the decreasing NER function with aging [26-28] Apart from the observation of age-related diminishing of DNA repair efficacy the group of disorders characterized by accelerated aging (progeroid syndromes) is related to defects in DNA-processing proteins This suggests that maintaining the stability of the human genome seems to be of importance in delaying aging In the premature aging patients eg with

Werner and Cockayne syndromes NER-related disorders DNA damage repair systems were altered suggesting that an increased accumulation of DNA lesions resulting in premature aging play a causative role in these diseases [29-32] BER-related human progeroid syndromes are fewer than impaired NER disorders which may be explained by the lethality of embryos with defects in essential BER components or by the multitude of back-up systems which may reflect the critical role of BER in maintaining genome integrity [33-35] 42 DNA repair and AMD It has been demonstrated that endogenous DNA damage including DNA strand breaks and alkali-labile sites (ALS) in lymphocytes increases in AMD patients [36] In addition the efficacy of DNA repair in AMD patients decreases but in the study of Wozniak et al there was no difference in DNA repair efficiency between the patients with dry and wet form of AMD Given that DNA repair may be irregular in AMD it seems reasonable to consider the efficacy of DNA repair proteins as important factor influencing individual susceptibility to AMD However only few studies have been dedicated to this issue [37] Among DNA repair pathways BER is the most important for cellular survival in response to oxidative DNA damage since it mainly takes the form of DNA base modifications The key enzymes participating in BER are DNA glycosylases which recognize and remove damaged bases The 8-oxoG glycosylase (human OGG) is responsible for the recognition of 8-oxoG one of the most stable toxic and pre-mutagenic DNA damage of the oxidative origin The hOGG1 gene encodes 8-oxoguanine DNA glycosylase 1 This enzyme recognizes oxidized bases removes them and possesses AP (apurinic or apyrimidinic) lyase activity which allows hOGG1 to nick the DNA phosphodiester bond It was shown that OGG1 was decreased both at mRNA and protein level in aged rodent RPE and choroid [38] The expression level of hOGG1 decreased almost by half in the macular RPE cells of AMD subjects when compared to that of aged macular RPE cells of healthy controls suggesting that the protein level of hOGG1 may be reduced in AMD [39] Reports on the association of the pS326C polymorphism of the hOGG1 gene with the occurrence of AMD are dubious One study does not show any relationship between them [40] In contrast we demonstrated that the SC genotype and the C allele significantly increased the risk of AMD in both dry and wet forms and additionally the SS genotype and the S allele decreased this risk [41] Moreover we showed that the polymorphisms of the SMUG1 (rs3087404) and UNG (rs2337395) genes encoding single-strand-selective monofunctional uracil-DNA glycosylase 1 and UNG uracil-DNA glycosylase respectively were associated with the risk of AMD [37] The cminus32AgtG polymorphism (rs3087404) of the SMUG1 gene is located in the non-coding regulatory region and thus may influence its gene expression through modifying the mRNA stability and degradation The altered gene expression may in consequence disturb the activity of SMUG1 and thus decrease the DNA protection against oxidative damage The g4235TgtC (rs2337395) polymorphism of the UNG genes is located in the regulatory region and the



Fig 3 A perspective for the regulation of cellular stress response in young versus aged cells The major signaling controllers have been circled In young and healthy RPE cells antioxidant defence quality control of protein folding and regulation of energy metabolism are in balance while in the aged cells increased oxidative stress DNA damage and disturbed proteostasis are prominent factors

presence of the CC genotype and C allele increased the risk of dry AMD but not that of wet form Interestingly the CC genotype decreased the risk of AMD progression from its dry to wet form and the T allele was associated with a deleterious effect Despite that nucleotide excision repair (NER) is generally considered as a repair system for bulky adducts it has been demonstrated that NER repairs also non-bulky DNA lesions such as DNA oxidized bases with moderate efficacy [42 43] Thus NER cannot be taken into account when considering the repair of DNA oxidative-stress-induced damage but rather should be regarded as having a backup role for BER in the removal of such DNA adducts The XPD (Xeroderma pigmentosum group D) gene encodes a DNA helicase which is a component of the core-TFIIH basal transcription factor It is involved in NER by opening DNA at the site of damage and in RNA transcription by RNA polymerase II A relationship between the genetic variants of XPD gene and the AMD occurrence was manifested for two polymorphic sites pD312N and pK751Q where the 751QQ genotype and the 312D-751Q haplotype seemed to have a

protective effect against the development of AMD [44] The ERCC6CSB (excision repair cross-complementing rodent repair deficiency complementation group 6) encodes a DNA-binding protein important in the transcription-coupled nucleotide excision repair (TC-NER) which allows removing of RNA polymerase II-blocking lesions from the transcribed strand of active genes ERCC6 participates in the aging process and DNA repair [45] Disruption of this gene may be manifested in the ocular degeneration indicating a possible role of this gene in AMD The cminus6530CgtG polymorphism (rs3793784) is located in the 5 flanking region of this gene and influences different regulation of gene expression in vitro and in vivo An in silico study demonstrated that its presence might alter the putative transcriptional factor binding patterns around flanking sequences The C allele corresponds to a possible Sp1 binding element whereas the G allele corresponds to a possible binding element for Sp1 as well as Oct-1 and GATA-1 The SNP in ERCC6 demonstrated statistical epistasis with the SNP in CFH (rs380390) yielding a combined disease risk OR of 2305 for individuals homozygous for risk alleles at both the



CFH and ERCC6 polymorphisms [46] This biological epistasis may be related to the function of ERCC6 which participates in transcription as a component of RNA pol I transcription complex [45] Mitochondrial DNA (mtDNA) is more susceptible to oxidative stress-associated damage than nuclear DNA and thus mitochondrial dysfunction may play a pivotal role in AMD pathogenesis [47 38] Indeed the macula-specific increase in mtDNA damage and diminished repair were associated with aging and the severity of AMD [39] Mitochondrial DNA damage repair in the RPE was relatively slower and less efficient than the repair of nuclear DNA [48] Taking into account the increased susceptibility of mtDNA to oxidative damage and its weak repair it may be concluded that lowered mtDNA defenses against oxidative damage in RPE cells are a crucial factor in the pathogenesis of AMD [49] Moreover since the mtDNA damage repair is conducted via nucleus-encoded proteins the changes in nuclear DNA may also affect the maintenance of mtDNA stability Nuclear and mitochondrial DNA damages and decreased repair capacity is estimated to disturb proteostasis that coincide with elevated protein damages misfolding protein aggregation and impaired clearance in RPE cells [4 50-52] 5 mTOR and autophage in the maintenance of RPE cell proteostasis Autophagy plays multifunctional role in cellular adaptation to stress including oxidative insults by maintaining mitochondrial integrity and removing damaged protein [53] The autophagy process is initiated with the formation of isolation membranes called omegasomes that enlarge via phagophore stage to double membrane autophagosomes that engulfs degrading material [54] Autophagy flux is finalized when autophagosomes fuse with lysosomes and their contents are then degraded by lysosomal enzymes However autophagy flux may be impaired in aged postmitotic cells such as RPE cells [55] Pharmacological induction of autophagy can enhance the clearance of intracytoplasmic aggregate-prone proteins and ameliorate cellular and tissue pathology [56] The classical pathway that regulates autophagy acts through the mTOR a protein kinase that plays a key role as a sensor for energy nutrients growth factors stress and redox changes [57] mTOR is a ubiquitously expressed serinethreonine kinase belonging to the phosphoinositide 3-kinase (PI3K)-related kinase family mTOR inhibition evokes autophagy activation mTOR consists of a central regulatory catalytic core with two functionally distinct multiprotein complexes mTOR complex 1 (mTORC1) and complex 2 (mTORC2) Rheb Raptor PRAS40-P mLST8 and Deptor are regulatory units for mTORC1 while Sin1 Rictor mLST8 and Protor are the corresponding units for mTORC2 [58] Previous observations show that the rapamycin-induced mTORC1 inhibition and the activation of autophagy can slow down the aging process and preserve retinal cell function [59-62] At present there is convincing evidence that the modulation of mTOR may be a potential target for the development of new therapeutic

stategies for neurodegenerative diseases including AMD [1 56] In addition to mTOR the insulininsulin-like growth factor 1 (IGF-1) and AMP-activated protein kinase (AMPK) pathways as well as sirtuins are included in the signaling mechanisms that control the stress response and DNA repair systems in cells [52] (Fig 3) Despite of its important role in enhancing growth during development insulinIGF-1 signaling can potentiate aging by inhibiting autophagy through the activation of mTOR via PI3K and Akt [63] Moreover the insulin pathway can inhibit Forkhead box O (FoxO) transcription factors which could otherwise promote autophagy [64-67] FoxO proteins are evolutionarily conserved regulators downstream from insulinIGF-1 receptors that control central cellular functions such as cell cycle cellular metabolism and cell death [68] They can be mutually activated by SIRT1 and AMPK [6669-71] SIRT1 is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase which function has been associated with increased longevity [72] SIRT1 also supports autophagy through AMPK which further activates SIRT1 by a positive feedback mechanism [73-74] Peroxisome proliferator-activated receptor-γ coactivator (PGC-1 activated by AMPK in turn contributes to mitochondrial biogenesis and thereby inhibits the oxidative stress This defence response may simultaneously be supported with a crosstalk of endoplasmic reticulum (ER) and mTOR signaling that reduce ER stress and prevent AMD development [75-77]

6 Discussion and perspectives The correlative relationship between oxidative stress and AMD is strong and the causative role of oxidative stress in the onset and progression of AMD is convincing The excess of ROS pose a threat to both DNA and proteostasis Future work should be aimed at the research on the significance of the genetic variation in the proteins responsible for recognizing and removing oxidative damages DNA repair-oriented therapy could support currently applied antioxidant therapeutic strategies and could become a part of a multifaceted and personalized approach in the treatment of AMD Since AMD is also a protein aggregation disease it should be appreciated that autophagy may represent an important therapeutic target in AMD In particular the autophagy-regulating kinases AMPK and mTOR can be potential therapeutic targets for preventing RPE cell degeneration and AMD progression Acknowledgements This work was supported by the EVO (grants of Kuopio University Hospital the Finnish Cultural Foundation and its North Savo Fund (KK) the Finnish Eye Foundation (KK) the Finnish Funding Agency for Technology and Innovation (KK) Health Research Council of the Academy of Finland (KK AK) and the Paumlivikki and Sakari Sohlberg Foundation (AK)



Conflict of interest None declared References [1] Kaarniranta K Sinha D Blasiak J Kauppinen A Vereacuteb Z

Salminen A Boulton ME Petrovski G Autophagy and heterophagy dysregulation leads to retinal pigment epithelium dysfunction and development of age-related macular degeneration Autophagy 2013 91-12

[2] National Eye Institute National Institutes of Health (2010) Facts about age-related macular degeneration Retrieved from httpwwwneinihgovhealthmaculardegenarmd_factsasp

[3] Miller JW Treatment of age-related macular degeneration beyond VEGF Jpn J Ophthalmol 2010 54523-528

[4] Kaarniranta K Salminen A Eskelinen EL Kopitz J Heat shock proteins as gatekeepers of proteolytic pathways-Implications for age-related macular degeneration (AMD) Ageing Res Rev 2009 8128-139

[5] Sohal RS Weindruch R Oxidative stress caloric restriction and aging Science 1996 27359-63

[6] Andriollo-Sanchez M Hininger-Favier I Meunier N Venneria E OConnor JM Maiani G Coudray C Roussel AM Age-related oxidative stress and antioxidant parameters in middle-aged and older European subjects the ZENITH study Eur J Clin Nutr 2005 59 Suppl 2S58-862

[7] Kregel KC Zhang HJ An integrated view of oxidative stress in aging basic mechanisms functional effects and pathological considerations Am J Physiol Regul Integr Comp Physiol 2007 292R18-R36

[8] Jomova K Vondrakova D Lawson M Valko M Metals oxidative stress and neurodegenerative disorders Mol Cell Biochem 2010 34591-104

[9] Beatty S Koh H Phil M Henson D Boulton M The role of oxidative stress in the pathogenesis of age-related macular degeneration Surv Ophthalmol 2000 45115-134

[10] Seddon JM Ajani UA SperdutoRD et al Dietary carotenoids vitamins A C and E and advanced age-relatedmacular degeneration Eye Disease Case-Control Study Group JAMA 1994 2721413-1420

[11] VandenLangenberg GM Mares-Perlman JA Klein R Klein BE Brady WE Palta M Associations between antioxidant and zinc intake and the 5-year incidence of early age-related maculopathy in the Beaver Dam Eye Study Am J Epidemiol 1998 148204-214

[12] Smith W Mitchell P Webb K Leeder SR Dietary antioxidants and age-related maculopathy the Blue Mountains Eye Study Ophthalmology 1999 106761-767

[13] Delcourt C Cristol JP Tessier F Leacuteger CL Descomps B Papoz L Age-related macular degeneration and antioxidant status in the POLA study POLA Study Group Pathologies OculairesLieesalrsquoAge Arch Ophthalmol 1999 1171384-1390

[14] Vingerling JR Dielemans I Bots ML Hofman A Grobbee DE de Jong PT Age-related macular degeneration is associated with atherosclerosis The Rotterdam Study Am J Epidemiol 1995 142404-409

[15] Mares-Perlman JA Brady WE Klein R Klein BE Bowen P Stacewicz-Sapuntzakis M Palta M Serum antioxidants and age-related macular degeneration in a population-based case-control study Arch Ophthalmol 1995 1131518-1523

[16] West S Vitale S Hallfrisch J Muntildeoz B Muller D Bressler S Bressler NM Are antioxidants or supplements protective for

age-related macular degeneration Arch Ophthalmol 1994 112222-227

[17] Hammond BR Jr Curran-Celentano J Judd S Fuld K Krinsky NI Wooten BR Snodderly DM Sex differences in macular pigment optical density relation to plasma carotenoid concentrations and dietary patterns Vision Res 1996 362001-2012

[18] Chowers I Wong R Dentchev T Farkas RH Iacovelli J Gunatilaka TL Medeiros NE Presley JB Campochiaro PA Curcio CA Dunaief JL Zack DJ The iron carrier transferrin is upregulated in retinas from patients with age-related macular degeneration Invest Ophthalmol Vis Sci 2006 472135-2140

[19] Hahn P Milam AH Dunaief JL Maculas affected by age-related macular degeneration contain increased chelatable iron in the retinal pigment epithelium and Bruchs membrane Arch Ophthalmol 2003 1211099-1105

[20] Synowiec E Sliwinski T Danisz K Blasiak J Sklodowska A Romaniuk D Watala C Szaflik J Szaflik JP Association between polymorphism of the NQO1 NOS3 and NFE2L2 genes and AMD Front Biosci 2013 1880-90

[21] Wysokinski D Danisz K Blasiak J Dorecka M Romaniuk D Szaflik J Szaflik JP An association of transferrin gene polymorphism and serum transferrin levels with age-related macular degeneration Exp Eye Res 2013 10614-23

[22] Synowiec E Pogorzelska M Blasiak J Szaflik J Szaflik JP Genetic polymorphism of the iron-regulatory protein-1 and -2 genes in age-related macular degeneration Mol Biol Rep 2012 397077-7087

[23] Wysokinski D Szaflik J Sklodowska A Kolodziejska U Dorecka M Romaniuk D Wozniak K Blasiak J Szaflik JP The A Allele of the -576GgtA polymorphism of the transferrin gene is associated with the increased risk of age-related macular degeneration in smokers Tohoku J Exp Med 2011 223253-261

[24] Meyer JN Boyd WA Azzam GA Haugen AC Freedman JH Van Houten B Decline of nucleotide excision repair capacity in aging Caenorhabditiselegans Genome Biol 2007 8R70

[25] Rao KS DNA repair in aging rat neurons Neuroscience 2007 1451330-1340

[26] Moriwaki S Ray S Tarone RE Kraemer KH Grossman L The effect of donor age on the processing of UV-damaged DNA by cultured human cells reduced DNA repair capacity and increased DNA mutability Mutat Res 1996 364117-123

[27] Goukassian D Gad F Yaar M Eller MS Nehal US Gilchrest BA Mechanisms and implications of the age-associated decrease in DNA repair capacity FASEB J 2000 141325-1334

[28] Yamada M Udono MU Hori M Hirose R Sato S Mori T Nikaido O Aged human skin removes UVB-induced pyrimidine dimers from the epidermis more slowly than younger adult skin in vivo Arch Dermatol Res 2006 297294-302

[29] Davis T Wyllie FS Rokicki MJ Bagley MC Kipling D The role of cellular senescence in Werner syndrome toward therapeutic intervention in human premature aging Ann NY Acad Sci 2007 1100455-469

[30] Kipling D Davis T Ostler EL Faragher RG What can progeroid syndromes tell us about human aging Science 2004 3051426-1431

[31] Andressoo JO Hoeijmakers JH Transcription-coupled repair and premature ageing Mutat Res 2005 577179-194

[32] Kyng KJ May A Stevnsner T Becker KG Kolvra S Bohr VA Gene expression responses to DNA damage are altered in



human aging and in Werner Syndrome Oncogene 2005 245026-5042

[33] Larsen E Meza TJ Kleppa L Klungland A Organ and cell specificity of base excision repair mutants in mice Mutat Res 2007 61456-68

[34] Wilson DM 3rd Bohr VA The mechanics of base excision repair and its relationship to aging and disease DNA Repair (Amst) 2007 6544-559

[35] Hazra TK Das A Das S Choudhury S Kow YW Roy R Oxidative DNA damage repair in mammalian cells a new perspective DNA Repair (Amst) 2007 6470-480

[36] Wozniak K Szaflik JP Zaras M Sklodowska A Janik-Papis K Poplawski TR Blasiak J Szaflik J DNA DamageRepair and Polymorphism of the hOGG1 Gene in Lymphocytes of AMD Patients J Biomed Biotechnol 2009 827562

[37] Blasiak J Synowiec E Salminen A Kaarniranta K Genetic Variability in DNA Repair Proteins in Age-Related Macular Degeneration Int J Mol Sci 2012 1313378-13397

[38] Wang AL Lukas TJ Yuan M Neufeld AH Increased mitochondrial DNA damage and down-regulation of DNA repair enzymes in aged rodent retinal pigment epithelium and choroid Mol Vis 2008 14644-651

[39] Lin H Xu H Liang FQ Liang H Gupta P Havey AN Boulton ME Godley BF Mitochondrial DNA Damage and Repair in RPE Associated with Aging and Age-Related Macular Degeneration Invest Ophthalmol Vis Sci 2011 523521-3529

[40] Bojanowski CM Tuo J Vhew EY Csaky KG Chan CC Analysis of hemicentin-1 hOgg1 and E-selectin single nucleotide polymorphisms in age-related macular degenerationTrans Am Ophthalmol Soc 2005 10337-44

[41] Synowiec E Blasiak J Zaras M Szaflik J Szaflik JP Association between polymorphismsof the DNA base excision repair genes MUTYH and hOGG1 and age-related macular degeneration Exp Eye Res 2012 9858-66

[42] Branum ME Reardon JT Sancar A DNA repair excision nuclease attacks undamaged DNA A potential source of spontaneous mutations J BiolChem 2001 625421-25426

[43] Huang JC Hsu DS Kazantsev A Sancar A Substrate spectrum of human excinuclease repair of abasic sites methylated bases mismatches and bulky adducts Proc Natl Acad Sci USA 1994 9112213-12217

[44] Goumlrguumln E Guumlven M Unal M Batar B Guumlven GS Yenerel M Tatlipinar S Seven M Yuumlksel A Polymorphisms of the DNA repair genes XPD and XRCC1 and the risk of age-related macular degeneration Invest Ophthalmol Vis Sci 2010 514732-4737

[45] Tuo J Ning B Bojanowski CM Lin ZN Ross RJ Reed GF Shen D Jiao X Zhou M Chew EY Kadlubar FF Chan CC Synergic effect of polymorphisms in ERCC6 5 flanking region and complement factor H on age-related macular degeneration predisposition Proc Natl Acad Sci USA 2006 1039256-9261

[46] Ross JR Verma V Rosenberg KI Chan CC Tuo J Genetic markers and biomarkers for age-related macular degeneration Expert Rev Ophthalmol 2007 2443-457

[47] Karunadharma PP Nordgaard CL Olsen TW Ferrington DA Mitochondrial DNA Damage as a Potential Mechanism for Age-Related Macular Degeneration Invest Ophthalmol Vis Sci 2010 515470-5479

[48] Liang FQ Godley BF Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells a possible mechanism for RPE aging and age-related macular degeneration Exp Eye Res 2003 76397-403

[49] Godley BF Shamsi FA Liang FQ Jarrett SG Davies S Boulton M Blue light induces mitochondrial DNA damage

and free radical production in epithelial cells J Biol Chem 2005 28021061-21066

[50] Blasiak J Glowacki S Kauppinen A Kaarniranta K Mitochondrial and Nuclear DNA Damage and Repair in Age-Related Macular Degeneration Int J Mol Sci 2013 142996-3010

[51] Ryhaumlnen T Hyttinen JM Kopitz J Rilla K Kuusisto E Mannermaa E Viiri J Holmberg CI Immonen I Meri S Parkkinen J Eskelinen EL Uusitalo H Salminen A Kaarniranta K Crosstalk between Hsp70 molecular chaperone lysosomes and proteasomes in autophagy-mediated proteolysis in human retinal pigment epithelial cells J Cell Mol Med 2009 133616-3631

[52] Haigis MC Yankner BA The aging stress response Mol Cell 2010 40333-344

[53] Klettner A Kauppinen A Blasiak J Roider J Salminen A Kaarniranta K Cellular and molecular mechanisms of age-related macular degeneration From impaired autophagy to neovascularization Int J Biochem Cell Biol 2013 451457-1467

[54] Klionsky DJ et al Guidelines for the use and interpretation of assays for monitoring autophagy Autophagy 2012 8445-544

[55] Viiri J Hyttinen JM Ryhaumlnen T Rilla K Paimela T Kuusisto E Siitonen A Urtti A Salminen A Kaarniranta K p62sequestosome 1 as a regulator of proteasome inhibitor-induced autophagy in human retinal pigment epithelial cells Mol Vis 2010 161399-1414

[56] Kaarniranta K Kauppinen A Blasiak J Salminen A Autophagy regulating kinases as potential therapeutic targets for age-related macular degeneration Future Med Chem 2012 42153-2161

[57] Cai Z Yan L-J Rapamycin Autophagy and Alzheimeracutes disease J Biochem Pharmacol Res 2013 184-90

[58] Hyttinen JM Petrovski G Salminen A Kaarniranta K 5-Adenosine monophosphate-activated protein kinase--mammalian target of rapamycin axis as therapeutic target for age-related macular degeneration Rejuvenation Res 2011 14651-660

[59] Dejneka NS Kuroki AM Fosnot J Tang W Tolentino MJ Bennett J Systemic rapamycin inhibits retinal and choroidal neovascularizaion in mice Mol Vis 2004 10964ndash972

[60] Zhao C Yasumura D Li X Matthes M Lloyd M Nielsen G Ahern K Snyder M Bok D Dunaief JL LaVail MM Vollrath D mTORmediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice J Clin Invest 2011 121369-383

[61] Wilkinson JE Burmeister L Brooks SV Chan CC Friedline S Harrison DE Hejtmancik JF Nadon N Strong R Wood LK Woodward MA Miller RA Rapamycin slows aging in mice Aging Cell 2012 11675-682

[62] Rodriacuteguez-Muela N Koga H Garciacutea-Ledo L de la Villa P de la Rosa EJ Cuervo AM Boya P Aging Cell 2013 12478-88

[63] Jung Ch Ro SH Cao J Otto NM Kim DH mTOR regulation of autophagy FEBS Lett 2010 5841287-1295

[64] Kenyon C Chang J Gensch E Rudner A Tabtiang R A C elegans mutant that lives twice as long as wild type Nature 1993 366461-464

[65] Lin K Dorman JB Rodan A Kenyon C daf-16 An HNF-3forkhead family member that can function to double the life-span of Caenorhabditis elegans Science 1997 2781319-1322

[66] Brunet A Sweeney LB Sturgill JF Chua KF Greer PL Lin Y Tran H Ross SE Mostoslavsky R Cohen HY Hu LS Cheng HL Jedrychowski MP Gyji SP Sinclair DA Alt FW



Greenberg ME Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase Science 2004 3032011-2015

[67] Sengupta A Molkentin Paik JH DePinho RA Yutzey KE FoxO transcription factors promote cardiomyocyte survival upon induction of oxidative stress J Biol Chem 2011 2867468-7478

[68] Tzivion G Dobson M Ramakrisnan G FoxO transcription factors Regulation by AKT and 14-3-3 proteins Biochim Biophys Acta 2011 18131938-1945

[69] Xiong S Salazar G Patrushev N Alexander RW FoxO1 mediates an autofeedback loop regulating SIRT1 expression Biol Chem 2011 2865289-5299

[70] Sanchez AM Csibi A Raibon A Cornille K Gay S Bernardi H Candau R AMPK promotes skeletal muscle autophagy through activation of forkhead FoxO3a and interaction with Ulk1 J Cell Biochem 2012 113695-710

[71] Lee JH Budanov AV Park EJ Birse R Kim TE Perkins GA Ocorr K Ellisman MH Bodmer R Bier E Karin M Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies Science 2010 3271223-1228

[72] Bordone L Guarente L Calorie restriction SIRT1 and metabolism understanding longevity Nat Rev Mol Cell Biol 2005 6298-305

[73] Brenmoehl J Hoeflich A Dual control of mitochondrial biogenesis by sirtuin 1 and sirtuin Mitochondrion 2013 Apr 11 [Epub ahead of print]

[74] Salminen A Kaarniranta K AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network Ageing Res Rev 2012 11230-241

[75] Dou G Sreekumar PG Spee C He S Ryan SJ Kannan R Hinton DR Deficiency of αB crystallin augments ER stress-induced apoptosis by enhancing mitochondrial dysfunction Free Radic Biol Med 2012 531111-1122

[76] Salminen A Kauppinen A Hyttinen JM Toropainen E Kaarniranta K Endoplasmic reticulum stress in age-related macular degeneration trigger for neovascularization Mol Med 2010 16535-542

[77] Appenzeller-Herzog C Hall MN Bidirectional crosstalk between endoplasmic reticulum stress and mTOR signaling Trends Cell Biol 2012 22274-282



Fig 2 Schematic representation of the physiological macula and the pathological changes occurring in the dry and wet AMD Contributors and mechanisms of the conversion of physiological macula or dry AMD to wet form still remain to be elucidated However choroidal neovascularization and accumulation of oumldema fluid in retina are clinical hallmarks of wet AMD

Fig 1 Risk factors that contribute to the generation of oxidative stress and development of AMD accelerating protein clearance [4] Failures in these systems lead to a progressive decrease in the clearance of ROS and aggregated proteins in conjunction with chronic inflammation that are recognized as important factors in the etiology of numerous late-onset degenerative diseases including AMD [14]

3 ROS as a causative factor for AMD ROS are indispensable for cell survival as they participate in cell signaling gene expression and cellular differentiation via regulating the cellular redox state or the balance between oxidationreduction reactions However the level of oxidants exceeding the cellrsquos antioxidant buffering capacity promotes oxidative stress Generally oxidative stress is believed to increase with aging [5] It was reported that aging is predictive of an increased risk of oxidative stress and that it is linked with a progressive and slow decline in antioxidant status in the European free-living healthy elderly [6] Interestingly the healthy elderly subjects were not exposed to an acute oxidative stress when compared with middle-aged subjects The oxidative stress theory of aging which is particularly enticing in the light of the damaging nature of oxidants in vivo explains the association between oxidative stress and age-related dysfunction at the level of cell and whole organism Such phenomena as the association between basal metabolic rate and life expectancy the accumulation of degenerative disorders in advanced age and the improvement of life-span with the use of caloric restriction may be easily clarified with this theory It is commonly postulated that the cellular antioxidant defense declines and the amount of ROS increases with aging [5 7] The rate of aging is established via the amount of cellular structural damage Also the retina ROS level elevates and the cellular oxidative damage increases with an age-related tendency In age-related neurodegenerative diseases which are associated with the oxidative stress including Alzheimerrsquos disease Parkinsonrsquos disease and AMD protein and DNA are damaged either directly by ROS or reactive nitrogen species (RNS) or indirectly by the products of lipid peroxidation [8] Thus the accumulation of oxidative damage during lifetime may lead to a dysfunction of RPE cells and increase their susceptibility to exogenous and endogenous insults eventually culminating in neural cell death and loss of visual function However it is difficult to assess whether the augmentation of oxidative damage in AMD is primarily due to elevated level of








































































































































































































































































































































































































































































































































































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Oxidative DNA Damage and Proteostasis in Age-Related...

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