Age-Related Neuronal Degeneration: Complementary Roles of Nucleotide Excision Repair and Transcription-Coupled Repair in Preventing Neuropathology
Neuronal degeneration is a hallmark of many DNA repair syndromes. Yet, how DNA damage causes neuronal degeneration and whether defects in different repair systems affect the brain differently is largely unknown. Here, we performed a systematic detailed analysis of neurodegenerative changes in mouse models deficient in nucleotide excision repair (NER) and transcription-coupled repair (TCR), two partially overlapping DNA repair systems that remove helix-distorting and transcription-blocking lesions, respectively, and that are associated with the UV-sensitive syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS). TCR–deficient Csa−/− and Csb−/− CS mice showed activated microglia cells surrounding oligodendrocytes in regions with myelinated axons throughout the nervous system. This white matter microglia activation was not observed in NER–deficient Xpa−/− and Xpc−/− XP mice, but also occurred in XpdXPCS mice carrying a point mutation (G602D) in the Xpd gene that is associated with a combined XPCS disorder and causes a partial NER and TCR defect. The white matter abnormalities in TCR–deficient mice are compatible with focal dysmyelination in CS patients. Both TCR–deficient and NER–deficient mice showed no evidence for neuronal degeneration apart from p53 activation in sporadic (Csa−/−, Csb−/−) or highly sporadic (Xpa−/−, Xpc−/−) neurons and astrocytes. To examine to what extent overlap occurs between both repair systems, we generated TCR–deficient mice with selective inactivation of NER in postnatal neurons. These mice develop dramatic age-related cumulative neuronal loss indicating DNA damage substrate overlap and synergism between TCR and NER pathways in neurons, and they uncover the occurrence of spontaneous DNA injury that may trigger neuronal degeneration. We propose that, while Csa−/− and Csb−/− TCR–deficient mice represent powerful animal models to study the mechanisms underlying myelin abnormalities in CS, neuron-specific inactivation of NER in TCR–deficient mice represents a valuable model for the role of NER in neuronal maintenance and survival.
Vyšlo v časopise:
Age-Related Neuronal Degeneration: Complementary Roles of Nucleotide Excision Repair and Transcription-Coupled Repair in Preventing Neuropathology. PLoS Genet 7(12): e32767. doi:10.1371/journal.pgen.1002405
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002405
Souhrn
Neuronal degeneration is a hallmark of many DNA repair syndromes. Yet, how DNA damage causes neuronal degeneration and whether defects in different repair systems affect the brain differently is largely unknown. Here, we performed a systematic detailed analysis of neurodegenerative changes in mouse models deficient in nucleotide excision repair (NER) and transcription-coupled repair (TCR), two partially overlapping DNA repair systems that remove helix-distorting and transcription-blocking lesions, respectively, and that are associated with the UV-sensitive syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS). TCR–deficient Csa−/− and Csb−/− CS mice showed activated microglia cells surrounding oligodendrocytes in regions with myelinated axons throughout the nervous system. This white matter microglia activation was not observed in NER–deficient Xpa−/− and Xpc−/− XP mice, but also occurred in XpdXPCS mice carrying a point mutation (G602D) in the Xpd gene that is associated with a combined XPCS disorder and causes a partial NER and TCR defect. The white matter abnormalities in TCR–deficient mice are compatible with focal dysmyelination in CS patients. Both TCR–deficient and NER–deficient mice showed no evidence for neuronal degeneration apart from p53 activation in sporadic (Csa−/−, Csb−/−) or highly sporadic (Xpa−/−, Xpc−/−) neurons and astrocytes. To examine to what extent overlap occurs between both repair systems, we generated TCR–deficient mice with selective inactivation of NER in postnatal neurons. These mice develop dramatic age-related cumulative neuronal loss indicating DNA damage substrate overlap and synergism between TCR and NER pathways in neurons, and they uncover the occurrence of spontaneous DNA injury that may trigger neuronal degeneration. We propose that, while Csa−/− and Csb−/− TCR–deficient mice represent powerful animal models to study the mechanisms underlying myelin abnormalities in CS, neuron-specific inactivation of NER in TCR–deficient mice represents a valuable model for the role of NER in neuronal maintenance and survival.
Zdroje
1. HoeijmakersJH 2009 DNA damage, aging, and cancer. N Engl J Med 361 1475 1485
2. NouspikelT 2007 DNA repair in differentiated cells: some new answers to old questions. Neuroscience 145 1213 1221
3. RassUAhelIWestSC 2007 Defective DNA repair and neurodegenerative disease. Cell 130 991 1004
4. FriedbergECAguileraAGellertMHanawaltPCHaysJB 2006 DNA repair: from molecular mechanism to human disease. DNA Repair (Amst) 5 986 996
5. McKinnonPJ 2009 DNA repair deficiency and neurological disease. Nat Rev Neurosci 10 100 112
6. HoeijmakersJH 2001 Genome maintenance mechanisms for preventing cancer. Nature 411 366 374
7. HanawaltPCSpivakG 2008 Transcription-coupled DNA repair: two decades of progress and surprises. Nat Rev Mol Cell Biol 9 958 970
8. CleaverJELamETRevetI 2009 Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity. Nat Rev Genet 10 756 768
9. StevnsnerTMuftuogluMAamannMDBohrVA 2008 The role of Cockayne Syndrome group B (CSB) protein in base excision repair and aging. Mech Ageing Dev 129 441 448
10. MuftuogluMde Souza-PintoNCDoganAAamannMStevnsnerT 2009 Cockayne Syndrome Group B Protein Stimulates Repair of Formamidopyrimidines by NEIL1 DNA Glycosylase. J Biol Chem 284 9270 9279
11. SoufirNGedCBourillonAAusterlitzFCheminC 2010 A prevalent mutation with founder effect in xeroderma pigmentosum group C from north Africa. J Invest Dermatol 130 1537 1542
12. KhanSGOhKSEmmertSImotoKTamuraD 2009 XPC initiation codon mutation in xeroderma pigmentosum patients with and without neurological symptoms. DNA Repair (Amst) 8 114 125
13. FousteriMVermeulenWvan ZeelandAAMullendersLH 2006 Cockayne syndrome A and B proteins differentially regulate recruitment of chromatin remodeling and repair factors to stalled RNA polymerase II in vivo. Mol Cell 23 471 482
14. KraemerKHPatronasNJSchiffmannRBrooksBPTamuraD 2007 Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship. Neuroscience 145 1388 1396
15. NanceMABerrySA 1992 Cockayne syndrome: review of 140 cases. Am J Med Genet 42 68 84
16. LaugelVDallozCDurandMSauvanaudFKristensenU 2010 Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome. Hum Mutat 31 113 126
17. MimakiTItohNAbeJTagawaTSatoK 1986 Neurological manifestations in xeroderma pigmentosum. Ann Neurol 20 70 75
18. KraemerKHLeeMMScottoJ 1987 Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 123 241 250
19. AnttinenAKouluLNikoskelainenEPortinRKurkiT 2008 Neurological symptoms and natural course of xeroderma pigmentosum. Brain 131 1979 1989
20. de WaardHde WitJAndressooJOvan OostromCTRiisB 2004 Different effects of CSA and CSB deficiency on sensitivity to oxidative DNA damage. Mol Cell Biol 24 7941 7948
21. NardoTOnedaRSpivakGVazBMortierL 2009 A UV-sensitive syndrome patient with a specific CSA mutation reveals separable roles for CSA in response to UV and oxidative DNA damage. Proc Natl Acad Sci U S A
22. BrooksPJChengTFCooperL 2008 Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage? DNA Repair (Amst) 7 834 848
23. LakeRJGeykoAHemashettarGZhaoYFanHY 2010 UV-induced association of the CSB remodeling protein with chromatin requires ATP-dependent relief of N-terminal autorepression. Mol Cell 37 235 246
24. ScharerOD 2008 Hot topics in DNA repair: the molecular basis for different disease states caused by mutations in TFIIH and XPG. DNA Repair (Amst) 7 339 344
25. ItoSKuraokaIChymkowitchPCompeETakedachiA 2007 XPG stabilizes TFIIH, allowing transactivation of nuclear receptors: implications for Cockayne syndrome in XP-G/CS patients. Mol Cell 26 231 243
26. ShiomiNMoriMKitoSHaradaYNTanakaK 2005 Severe growth retardation and short life span of double-mutant mice lacking Xpa and exon 15 of Xpg. DNA Repair (Amst) 4 351 357
27. LehmannAR 2008 XPD structure reveals its secrets. DNA Repair (Amst) 7 1912 1915
28. AndressooJOJansJde WitJCoinFHoogstratenD 2006 Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles. PLoS Biol 4 e322 doi:10.1371/journal.pbio.0040322
29. AndressooJOWeedaGde WitJMitchellJRBeemsRB 2009 An Xpb mouse model for combined xeroderma pigmentosum and cockayne syndrome reveals progeroid features upon further attenuation of DNA repair. Mol Cell Biol 29 1276 1290
30. CoinFOksenychVEglyJM 2007 Distinct roles for the XPB/p52 and XPD/p44 subcomplexes of TFIIH in damaged DNA opening during nucleotide excision repair. Mol Cell 26 245 256
31. StefaniniMBottaELanzafameMOrioliD 2010 Trichothiodystrophy: from basic mechanisms to clinical implications. DNA Repair (Amst) 9 2 10
32. ScharerOD 2008 XPG: its products and biological roles. Adv Exp Med Biol 637 83 92
33. AndrewsADBarrettSFRobbinsJH 1976 Relation of D.N.A. repair processes to pathological ageing of the nervous system in xeroderma pigmentosum. Lancet 1 1318 1320
34. MaedaTSatoKMinamiHTaguchiHYoshikawaK 1995 Chronological difference in walking impairment among Japanese group A xeroderma pigmentosum (XP-A) patients with various combinations of mutation sites. Clin Genet 48 225 231
35. ItohMHayashiMShiodaKMinagawaMIsaF 1999 Neurodegeneration in hereditary nucleotide repair disorders. Brain Dev 21 326 333
36. MimakiTNittaMSaijoMTachiNMinamiR 1996 Truncated XPA protein detected in atypical group A xeroderma pigmentosum. Acta Paediatr 85 511 513
37. HashimotoSSugaTKudoEIhnHUchinoM 2008 Adult-onset neurological degeneration in a patient with Cockayne syndrome and a null mutation in the CSB gene. J Invest Dermatol 128 1597 1599
38. RapinIWeidenheimKLindenbaumYRosenbaumPMerchantSN 2006 Cockayne syndrome in adults: review with clinical and pathologic study of a new case. J Child Neurol 21 991 1006
39. SpivakGHanawaltPC 2006 Host cell reactivation of plasmids containing oxidative DNA lesions is defective in Cockayne syndrome but normal in UV-sensitive syndrome fibroblasts. DNA Repair (Amst) 5 13 22
40. NiedernhoferLJ 2008 Nucleotide excision repair deficient mouse models and neurological disease. DNA Repair (Amst) 7 1180 1189
41. de VriesAvan OostromCTHofhuisFMDortantPMBergRJ 1995 Increased susceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excision repair gene XPA. Nature 377 169 173
42. NakaneHTakeuchiSYubaSSaijoMNakatsuY 1995 High incidence of ultraviolet-B-or chemical-carcinogen-induced skin tumours in mice lacking the xeroderma pigmentosum group A gene. Nature 377 165 168
43. MelisJPWijnhovenSWBeemsRBRoodbergenMvan den BergJ 2008 Mouse models for xeroderma pigmentosum group A and group C show divergent cancer phenotypes. Cancer Res 68 1347 1353
44. NakaneHHirotaSBrooksPJNakabeppuYNakatsuY 2008 Impaired spermatogenesis and elevated spontaneous tumorigenesis in xeroderma pigmentosum group A gene (Xpa)-deficient mice. DNA Repair (Amst) 7 1938 1950
45. van der HorstGTvan SteegHBergRJvan GoolAJde WitJ 1997 Defective transcription-coupled repair in Cockayne syndrome B mice is associated with skin cancer predisposition. Cell 89 425 435
46. van der HorstGTMeiraLGorgelsTGde WitJVelasco-MiguelS 2002 UVB radiation-induced cancer predisposition in Cockayne syndrome group A (Csa) mutant mice. DNA Repair (Amst) 1 143 157
47. CheoDLRuvenHJMeiraLBHammerREBurnsDK 1997 Characterization of defective nucleotide excision repair in XPC mutant mice. Mutat Res 374 1 9
48. GorgelsTGvan der PluijmIBrandtRMGarinisGAvan SteegH 2007 Retinal degeneration and ionizing radiation hypersensitivity in a mouse model for Cockayne syndrome. Mol Cell Biol 27 1433 1441
49. AndressooJOMitchellJRde WitJHoogstratenDVolkerM 2006 An Xpd mouse model for the combined xeroderma pigmentosum/Cockayne syndrome exhibiting both cancer predisposition and segmental progeria. Cancer Cell 10 121 132
50. de BoerJde WitJvan SteegHBergRJMorreauH 1998 A mouse model for the basal transcription/DNA repair syndrome trichothiodystrophy. Mol Cell 1 981 990
51. de BoerJvan SteegHBergRJGarssenJde WitJ 1999 Mouse model for the DNA repair/basal transcription disorder trichothiodystrophy reveals cancer predisposition. Cancer Res 59 3489 3494
52. WijnhovenSWBeemsRBRoodbergenMvan den BergJLohmanPH 2005 Accelerated aging pathology in ad libitum fed Xpd(TTD) mice is accompanied by features suggestive of caloric restriction. DNA Repair (Amst) 4 1314 1324
53. DolleMEBusuttilRAGarciaAMWijnhovenSvan DrunenE 2006 Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice. Mutat Res 596 22 35
54. de WaardHde WitJGorgelsTGvan den AardwegGAndressooJO 2003 Cell type-specific hypersensitivity to oxidative damage in CSB and XPA mice. DNA Repair (Amst) 2 13 25
55. de WaardHSonneveldEde WitJEsveldt-van LangeRHoeijmakersJH 2008 Cell-type-specific consequences of nucleotide excision repair deficiencies: Embryonic stem cells versus fibroblasts. DNA Repair (Amst) 7 1659 1669
56. WijnhovenSWHoogervorstEMde WaardHvan der HorstGTvan SteegH 2007 Tissue specific mutagenic and carcinogenic responses in NER defective mouse models. Mutat Res 614 77 94
57. LevineAJHuWFengZ 2006 The P53 pathway: what questions remain to be explored? Cell Death Differ 13 1027 1036
58. RotshenkerSReichertFGitikMHaklaiRElad-SfadiaG 2008 Galectin-3/MAC-2, Ras and PI3K activate complement receptor-3 and scavenger receptor-AI/II mediated myelin phagocytosis in microglia. Glia 56 1607 1613
59. StreitWJWalterSAPennellNA 1999 Reactive microgliosis. Prog Neurobiol 57 563 581
60. IwakiTIwakiATateishiJSakakiYGoldmanJE 1993 Alpha B-crystallin and 27-kd heat shock protein are regulated by stress conditions in the central nervous system and accumulate in Rosenthal fibers. Am J Pathol 143 487 495
61. LiHYuanJ 1999 Deciphering the pathways of life and death. Curr Opin Cell Biol 11 261 266
62. MuraiMEnokidoYInamuraNYoshinoMNakatsuY 2001 Early postnatal ataxia and abnormal cerebellar development in mice lacking Xeroderma pigmentosum Group A and Cockayne syndrome Group B DNA repair genes. Proc Natl Acad Sci U S A 98 13379 13384
63. van der PluijmIGarinisGABrandtRMGorgelsTGWijnhovenSW 2007 Impaired genome maintenance suppresses the growth hormone–insulin-like growth factor 1 axis in mice with Cockayne syndrome. PLoS Biol 5 e2 doi:10.1371/journal.pbio.0050002
64. LaposaRRHuangEJCleaverJE 2007 Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-deficient Cockayne syndrome mice. Proc Natl Acad Sci U S A 104 1389 1394
65. SakaiKMiyazakiJ 1997 A transgenic mouse line that retains Cre recombinase activity in mature oocytes irrespective of the cre transgene transmission. Biochem Biophys Res Commun 237 318 324
66. DragatsisIZeitlinS 2000 CaMKIIalpha-Cre transgene expression and recombination patterns in the mouse brain. Genesis 26 133 135
67. FukuiHDiazFGarciaSMoraesCT 2007 Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 104 14163 14168
68. HolmesAYangRJCrawleyJN 2002 Evaluation of an anxiety-related phenotype in galanin overexpressing transgenic mice. J Mol Neurosci 18 151 165
69. FanFJinSAmundsonSATongTFanW 2002 ATF3 induction following DNA damage is regulated by distinct signaling pathways and over-expression of ATF3 protein suppresses cells growth. Oncogene 21 7488 7496
70. TurchiLFarehMAberdamEKitajimaSSimpsonF 2009 ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress. Cell Death Differ 16 728 737
71. BarskiJJDethleffsenKMeyerM 2000 Cre recombinase expression in cerebellar Purkinje cells. Genesis 28 93 98
72. SofferDGrotskyHWRapinISuzukiK 1979 Cockayne syndrome: unusual neuropathological findings and review of the literature. Ann Neurol 6 340 348
73. LeechRWBrumbackRAMillerRHOtsukaFTaroneRE 1985 Cockayne syndrome: clinicopathologic and tissue culture studies of affected siblings. J Neuropathol Exp Neurol 44 507 519
74. RothKA 2001 Caspases, apoptosis, and Alzheimer disease: causation, correlation, and confusion. J Neuropathol Exp Neurol 60 829 838
75. GueganCPrzedborskiS 2003 Programmed cell death in amyotrophic lateral sclerosis. J Clin Invest 111 153 161
76. KohjiTHayashiMShiodaKMinagawaMMorimatsuY 1998 Cerebellar neurodegeneration in human hereditary DNA repair disorders. Neurosci Lett 243 133 136
77. EnokidoYInamuraNArakiTSatohTNakaneH 1997 Loss of the xeroderma pigmentosum group A gene (XPA) enhances apoptosis of cultured cerebellar neurons induced by UV but not by low-K+ medium. J Neurochem 69 246 251
78. DzagnidzeAKatsaravaZMakhalovaJLiedertBYoonMS 2007 Repair capacity for platinum-DNA adducts determines the severity of cisplatin-induced peripheral neuropathy. J Neurosci 27 9451 9457
79. BrooksPJ 2008 The 8,5′-cyclopurine-2′-deoxynucleosides: candidate neurodegenerative DNA lesions in xeroderma pigmentosum, and unique probes of transcription and nucleotide excision repair. DNA Repair (Amst) 7 1168 1179
80. NouspikelT 2008 Nucleotide excision repair and neurological diseases. DNA Repair (Amst) 7 1155 1167
81. de WaardMCvan der PluijmIZuiderveen BorgesiusNComleyLHHaasdijkED 2010 Age-related motor neuron degeneration in DNA repair-deficient Ercc1 mice. Acta Neuropathol 120 461 475
82. Pastoriza-GallegoMArmierJSarasinA 2007 Transcription through 8-oxoguanine in DNA repair-proficient and Csb(−)/Ogg1(−) DNA repair-deficient mouse embryonic fibroblasts is dependent upon promoter strength and sequence context. Mutagenesis 22 343 351
83. NgJMVrielingHSugasawaKOomsMPGrootegoedJA 2002 Developmental defects and male sterility in mice lacking the ubiquitin-like DNA repair gene mHR23B. Mol Cell Biol 22 1233 1245
84. KadotaniHHiranoTMasugiMNakamuraKNakaoK 1996 Motor discoordination results from combined gene disruption of the NMDA receptor NR2A and NR2C subunits, but not from single disruption of the NR2A or NR2C subunit. J Neurosci 16 7859 7867
85. PaxinosGFranklinKBJ 2001 The mouse brain in stereotaxic coordinates London Academic Press
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 12
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Targeted Proteolysis of Plectin Isoform 1a Accounts for Hemidesmosome Dysfunction in Mice Mimicking the Dominant Skin Blistering Disease EBS-Ogna
- The RNA Silencing Enzyme RNA Polymerase V Is Required for Plant Immunity
- The FGFR4-G388R Polymorphism Promotes Mitochondrial STAT3 Serine Phosphorylation to Facilitate Pituitary Growth Hormone Cell Tumorigenesis
- Hierarchical Generalized Linear Models for Multiple Groups of Rare and Common Variants: Jointly Estimating Group and Individual-Variant Effects