Ассоциации генов систем репарации ДНК с болезнью Паркинсона

Актуальность. Примерно 5–10 % случаев болезни Паркинсона (БП) являются моногенными, в остальных случаях патология имеет многофакторную природу. Одним из признанных патогенетических путей БП является митохондриальная дисфункция, в частности накопление повреждений в митохондриальной ДНК. Соответственно, гены белков систем репарации ДНК являются перспективными генами-кандидатами для многофакторных форм БП.
Цель исследования. Пилотное изучение вовлечённости генов белков систем репарации ДНК в развитие болезни Паркинсона.
Материалы и методы. Ассоциативный анализ проведён при сравнении группы пациентов с БП (n = 133) с популяционной выборкой г. Томска (n = 344). Методом SNaPshot-анализа изучены 8 SNP в генах белков систем репарации ДНК (rs560191 (TP53BP1); rs1805800 и rs709816 (NBN); rs473297 (MRE11A); rs1189037 и rs1801516 (ATM); rs1799977 (MLH1); rs1805321 (PMS2)).
Результаты. К развитию БП предрасполагают частые аллели и гомозиготные по ним генотипы rs1801516 в гене ATM (отношение шансов (OR, odds ratio) – 3,27 (p = 0,000004) и OR = 3,46 (p = 0,00008) для рисковых аллеля и генотипа соответственно) и rs1799977 в гене MLH1 (OR = 1,88 (p = 0,0004) и OR = 2,42 (p = 0,00007) соответственно); гетерозиготы обладают протективным эффектом (OR = 0,33 (p = 0,0007) и OR = 0,46 (p = 0,0007) для ATM и MLH1 соответственно). Также к БП предрасполагают редкий аллель rs1805800 в гене NBN (OR = 1,62 (p = 0,019)) и гомозиготный по нему генотип (OR = 2,28 (p = 0,016)). Ассоциации с БП генов ATM, MLH1, NBN выявлены впервые.
Заключение. Нарушение функционирования митохондрий является одним из ключевых в патогенезе БП; при этом по меньшей мере два из трёх белковых продукта ассоциированных генов вовлечены в развитие дисфункции митохондрий. Соответственно, можно предположить вовлеченность ассоциированных генов в патогенез БП именно через митохондриальную дисфункцию.

1. Elbaz A, Carcaillon L, Kab S, Moisan F. Epidemiology of Parkinson’s disease. Rev Neurol (Paris). 2016; 172(1): 14-26. doi: 10.1016/j.neurol.2015.09.012

2. Siitonen A, Nalls MA, Hernandez D, Gibbs JR, Ding J, Ylikotila P, et al. Genetics of early-onset Parkinson’s disease in Finland: Exome sequencing and genome-wide association study. Neurobiol Aging. 2017; 53: 195.e7-195.e10. doi: 10.1016/j.neurobiolaging.2017.01.019

3. Cherian A, Divya KP. Genetics of Parkinson’s disease. Acta Neurol Belg. 2020; 120(6): 1297-1305. doi: 10.1007/s13760-020-01473-5

4. Bloem BR, Okun MS, Klein C. Parkinson’s disease. Lancet. 2021; 397(10291): 2284-2303. doi: 10.1016/S0140-6736(21)00218-X

5. Schormair B, Kemlink D, Mollenhauer B, Fiala O, Machetanz G, Roth J, et al. Diagnostic exome sequencing in early-onset Parkinson’s disease confirms VPS13C as a rare cause of autosomal-recessive Parkinson’s disease. Clin Genet. 2018; 93(3): 603-612. doi: 10.1111/cge.13124

6. Puschmann A. New genes causing hereditary Parkinson’s disease or Parkinsonism. Curr Neurol Neurosci Rep. 2017; 17(9): 66. doi: 10.1007/s11910-017-0780-8

7. Lin CH, Chen PL, Tai CH, Lin HI, Chen CS, Chen ML, et al. A clinical and genetic study of early-onset and familial parkinsonism in Taiwan: An integrated approach combining gene dosage analysis and next-generation sequencing. Mov Disord. 2019; 34(4): 506-515. doi: 10.1002/mds.27633

8. Li N, Wang L, Zhang J, Tan EK, Li J, Peng J, et al. Wholeexome sequencing in early-onset Parkinson’s disease among ethnic Chinese. Neurobiol Aging. 2020; 90: 150.e5-150.e11. doi: 10.1016/j.neurobiolaging.2019.12.023

9. OMIM. URL: https://www.ncbi.nlm.nih.gov/omim [date of access: 16.05.2022].

10. Wu YY, Kuo HC. Functional roles and networks of noncoding RNAs in the pathogenesis of neurodegenerative diseases. J Biomed Sci. 2020; 27(1): 49. doi: 10.1186/s12929-020-00636-z

11. Angelova PR, Abramov AY. Role of mitochondrial ROS in the brain: From physiology to neurodegeneration. FEBS Lett. 2018; 592(5): 692-702. doi: 10.1002/1873-3468.12964

12. Vodickova A, Koren SA, Wojtovich AP. Site-specific mitochondrial dysfunction in neurodegeneration. Mitochondrion. 2022; 64: 1-18. doi: 10.1016/j.mito.2022.02.004

13. Celsi F, Pizzo P, Brini M, Leo S, Fotino C, Pinton P, et al. Mitochondria, calcium and cell death: A deadly triad in neurodegeneration. Biochim Biophys Acta. 2009; 1787(5): 335-344. doi: 10.1016/j.bbabio.2009.02.021

14. Subramaniam SR, Chesselet MF. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog Neurobiol. 2013; 106-107: 17-32. doi: 10.1016/j.pneurobio.2013.04.004

15. Paillusson S, Gomez-Suaga P, Stoica R, Little D, Gissen P, Devine MJ, et al. α-Synuclein binds to the ER-mitochondria tethering protein VAPB to disrupt Ca2+ homeostasis and mitochondrial ATP production. Acta Neuropathol. 2017; 134(1): 129-149. doi: 10.1007/s00401-017-1704-z

16. Chan DC. Mitochondrial dynamics and its involvement in disease. Annu Rev Pathol. 2020; 15: 235-259. doi: 10.1146/annurev-pathmechdis-012419-032711

17. Iwata R, Casimir P, Vanderhaeghen P. Mitochondrial dynamics in postmitotic cells regulate neurogenesis. Science. 2020; 369(6505): 858-862. doi: 10.1126/science.aba9760

18. Bose A, Beal MF. Mitochondrial dysfunction in Parkinson’s disease. J Neurochem. 2016; 139(Suppl 1): 216-231. doi: 10.1111/jnc.13731

19. Franco R, Rivas-Santisteban R, Navarro G, Pinna A, ReyesResina I. Genes implicated in familial Parkinson’s disease provide a dual picture of nigral dopaminergic neurodegeneration with mitochondria taking center stage. Int J Mol Sci. 2021; 22(9): 4643. doi: 10.3390/ijms22094643

20. Flones IH, Tzoulis C. Mitochondrial respiratory chain dysfunction – A hallmark pathology of idiopathic Parkinson’s disease? Front Cell Dev Biol. 2022; 10: 874596. doi: 10.3389/fcell.2022.874596

21. Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD. Mitochondrial complex I deficiency in Parkinson’s disease. Lancet. 1989; 1(8649): 1269. doi: 10.1016/s0140-6736(89)92366-0

22. Hoglinger GU, Lannuzel A, Khondiker ME, Michel PP, Duyckaerts C, Feger J, et al. The mitochondrial complex I inhibitor rotenone triggers a cerebral tauopathy. J Neurochem. 2005; 95(4): 930-939. doi: 10.1111/j.1471-4159.2005.03493.x

23. Rocha EM, De Miranda B, Sanders LH. Alpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease. Neurobiol Dis. 2018; 109(Pt B): 249-257. doi: 10.1016/j.nbd.2017.04.004

24. Zambon F, Cherubini M, Fernandes HJR, Lang C, Ryan BJ, Volpato V, et al. Cellular α-synuclein pathology is associated with bioenergetic dysfunction in Parkinson’s iPSC-derived dopamine neurons. Hum Mol Genet. 2019; 28(12): 2001-2013. doi: 10.1093/hmg/ddz038

25. Liu J, Liu W, Li R, Yang H. Mitophagy in Parkinson’s disease: From pathogenesis to treatment. Cells. 2019; 8(7): 712. doi: 10.3390/cells8070712

26. Van Laar VS, Berman SB. Mitochondrial dynamics in Parkinson’s disease. Exp Neurol. 2009; 218(2): 247-256. doi: 10.1016/j.expneurol.2009.03.019

27. Trimmer PA, Swerdlow RH, Parks JK, Keeney P, Bennett JP Jr, Miller SW, et al. Abnormal mitochondrial morphology in sporadic Parkinson’s and Alzheimer’s disease cybrid cell lines. Exp Neurol. 2000; 162(1): 37-50. doi: 10.1006/exnr.2000.7333

28. Malpartida AB, Williamson M, Narendra DP, Wade-Martins R, Ryan BJ. Mitochondrial dysfunction and mitophagy in Parkinson’s disease: From mechanism to therapy. Trends Biochem Sci. 2021; 46(4): 329-343. doi: 10.1016/j.tibs.2020.11.007

29. Ra D, Sa B, Sl B, Js M, Sj M, Da D, et al. Is exposure to BMAA a risk factor for neurodegenerative diseases? A response to a critical review of the BMAA hypothesis. Neurotox Res. 2021; 39(1): 81-106. doi: 10.1007/s12640-020-00302-0

30. Song S, Pursell ZF, Copeland WC, Longley MJ, Kunkel TA, Mathews CK. DNA precursor asymmetries in mammalian tissue mitochondria and possible contribution to mutagenesis through reduced replication fidelity. PNAS USA. 2005; 102: 4990-4995. doi: 10.1073/pnas.0500253102

31. Vasileiou PVS, Mourouzis I, Pantos C. Principal aspects regarding the maintenance of mammalian mitochondrial genome integrity. Int J Mol Sci. 2017; 18: 1821. doi: 10.3390/ijms18081821

32. Storr SJ, Woolston CM, Martin SG. Base excision repair, the redox environment and therapeutic implications. Curr Mol Pharmacol. 2012; 5: 88-101.

33. Zinovkina LA. Mechanisms of mitochondrial DNA repair in mammals. Biochemistry (Mosc). 2018; 83(3): 233-249. doi: 10.1134/S0006297918030045

34. Valentin-Vega YA, Maclean KH, Tait-Mulder J, Milasta S, Steeves M, Dorsey FC, et al. Mitochondrial dysfunction in ataxiatelangiectasia. Blood. 2012; 119: 1490-1500. doi: 10.1182/blood-2011-08-373639

35. Rashid S. Targeting the mitochondria for the treatment of MLH1-deficient disease: Thesis. 2017. URL: http://qmro.qmul.ac.uk/xmlui/handle/123456789/30924 [date of access: 16.05.2022].

36. Rashid S, Freitas MO, Cucchi D, Bridge G, Yao Z, Gay L, et al. MLH1 deficiency leads to deregulated mitochondrial metabolism. Cell Death Dis. 2019; 10(11): 795. doi: 10.1038/s41419-019-2018-y

37. Coene ED, Hollinshead MS, Waeytens AA, Schelfhout VR, Eechaute WP, Shaw MK, et al. Phosphorylated BRCA1 is predominantly located in the nucleus and mitochondria. Mol Biol Cell. 2005; 16: 997-1010. doi: 10.1091/mbc.e04-10-0895

38. Tadi SK, Sebastian R, Dahal S, Babu RK, Choudhary B, Raghavan SC. Microhomology-mediated end joining is the principal mediator of double-strand break repair during mitochondrial DNA lesions. Mol Biol Cell. 2016; 27: 223-235. doi: 10.1091/mbc.E15-05-0260

39. Seol JH, Shim EY, Lee SE. Microhomology-mediated end joining: Good, bad and ugly. Mutat Res. 2018; 809: 81-87. doi: 10.1016/j.mrfmmm.2017.07.002

40. Maciejczyk M, Mikoluc B, Pietrucha B, HeropolitanskaPliszka E, Pac M, Motkowski R, et al. Oxidative stress, mitochondrial abnormalities and antioxidant defense in Ataxia-telangiectasia, Bloom syndrome and Nijmegen breakage syndrome. Redox Biol. 2017; 11: 375-383. doi: 10.1016/j.redox.2016.12.030

41. Choy KR, Watters DJ. Neurodegeneration in ataxia-telangiectasia: Multiple roles of ATM kinase in cellular homeostasis. Dev Dyn. 2018; 247: 33-46. doi: 10.1002/dvdy.24522

42. Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015; 30(12): 1591-601. doi: 10.1002/mds.26424

43. Manual guide. Applied Biosystems user bulletin: Using the SNaPshot® Multiplex System. 2005. URL: https://tools.thermofisher.com/content/sfs/manuals/cms_041203.pdf [date of access: 20.05.2022].

44. Resseguie EA, Staversky RJ, Brookes PS, O’Reilly MA. Hyperoxia activates ATM independent from mitochondrial ROS and dysfunction. Redox Biol. 2015; 5: 176-185. doi: 10.1016/j.redox.2015.04.012

45. Shimura T. ATM-mediated mitochondrial radiation responses of human fibroblasts. Genes (Basel). 2021; 12(7): 1015. doi: 10.3390/genes12071015

46. Lee JH, Paull TT. Cellular functions of the protein kinase ATM and their relevance to human disease. Nat Rev Mol Cell Biol. 2021; 22(12): 796-814. doi: 10.1038/s41580-021-00394-2

47. Lee JH, Mand MR, Kao CH, Zhou Y, Ryu SW, Richards AL, et al. ATM directs DNA damage responses and proteostasis via genetically separable pathways. Sci Signal. 2018; 11(512): eaan5598. doi: 10.1126/scisignal.aan5598

48. Mootha VK, Bunkenborg J, Olsen JV, Hjerrild M, Wisniewski JR, Stahl E, et al. Integrated analysis of protein composition, tissue diversity, and gene regulation in mouse mitochondria. Cell. 2003; 115(5): 629-640. doi: 10.1016/s0092-8674(03)00926-7

49. Brown KD, Rathi A, Kamath R, Beardsley DI, Zhan Q, Mannino JL, et al. The mismatch repair system is required for S-phase checkpoint activation.Nat Genet. 2003; 33: 80-84. doi: 10.1038/ng1052