Etiology of Parkinson’s Disease – New Advances and New Challenges

Czech version

Authors: S. N. Illarioškin
Authors‘ workplace: Výzkumné centrum neurologie, Ruská akademie lékařských věd, Moskva
Published in: Cesk Slov Neurol N 2015; 78/111(3): 283-291
Category: Review Article

Overview

Etiology of Parkinson’s disease (PD) for many years has been remaining the matter of active discussions and intensive interdisciplinary studies. About 5– 10% of all cases of PD are represented by monogenic forms manifesting predominantly in younger persons, while most cases of the disease are sporadic and have multifactorial nature. The key molecular event in the development of neurodegeneration in PD is the conformational change of a small vesicular protein α‑ synuclein initiating its self‑ fibrilization with forming neurotoxic cytoplasmic aggregates and Lewy bodies/ neurites. Misfolding of α‑ synuclein in PD is caused by specific interaction of environmental factors, genomic factors and characteristics of systemic metabolism, which, in combination, determines the processes of cell detoxication, mitochondrial functioning, synaptic transmission and endosomal transport. In this review, possible exogenous and endogenous triggers of pathological process in PD are discussed in detail. Among the risk factors, special consideration is given to the role of different neurotoxins, prion hypothesis of the development of PD, as well as up‑ to‑ date knowledge about genetics of familial and sporadic cases of PD.

Key words:
Parkinson’s disease – etiology – molecular mechanisms – risk factors – genetics

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Sources

1. Mizuno Y, Hattori N, Kubo S, Sato S, Nishioka K, Hatano T et al. Progress in the pathogenesis and genetics of Parkinson’s disease. Philos Trans R Soc B Biol Sci 2008; 363(1500): 2215– 2227. doi: 10.1098/ rstb.2008.2273.

2. Schiesling C, Kieper N, Seidel K, Kruger R. Review: Familial Parkinson’s disease – genetics, clinical phenotype and neuropathology in relation to the common sporadic form of the disease. Neuropathol Appl Neurobiol 2008; 34(3): 255– 271. doi: 10.1111/ j.1365‑ 2990.2008.00952.x.

3. Singleton AB, Farrer MJ, Bonifati V. The genetics of Parkinson’s disease: progress and therapeutic implications. Mov Disord 2013; 28(1): 14– 23. doi: 10.1002/ mds.25249.

4. Bartels T, Choi JG, Selkoe DJ. α‑ synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 2011; 477(7362): 107– 110. doi: 10.1038/ nature10324.

5. Abeliovich A, Schmitz Y, Fariñas I, Choi‑ Lundberg D, Ho WH, Castillo PE et al. Mice lacking alphα‑ synuclein display functional deficits in the nigrostriatal system. Neuron 2000; 25(1): 239– 252.

6. Lee FJ, Liu F, Pristupa ZB, Niznik HB. Direct binding and functional coupling of alphα‑ synuclein to the dopamine transporters accelerate dopamine‑induced apoptosis. Faseb J 2001; 15(6): 916– 926.

7. Murphy DD, Rueter SM, Trojanowski JQ, Lee VM. Synucleins are developmentally expressed, and alphα‑ synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci 2000; 20(9): 3214– 3220.

8. Breydo L, Wu JW, Uversky VN. α‑ synuclein misfolding and Parkinson‘s disease. Biochim Biophys Acta 2012; 1822(2): 261– 285. doi: 10.1016/ j.bbadis.2011.10.002.

9. Jenner P, Morris HR, Robbins TW, Goedert M, Hardy J,Ben‑ Shlomo Y et al. Parkinson’s disease – the debate on the clinical phenomenology, etiology, pathology and pathogenesis. J Parkinsons Dis 2013; 3(1): 1– 11. doi: 10.3233/ JPD‑ 130175.

10. Lim KL, Zhang CW. Molecular events underlying Parkinson‘s disease – an interwoven tapestry. Frontiers Neurol 2013; 4: 33. doi: 10.3389/ fneur.2013.00033.

11. Obeso JA, Rodriguez‑ Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M et al. Missing pieces in the Parkinson’s disease puzzle. Nat Med 2010; 16(6): 653– 661. doi: 10.1038/ nm.2165.

12. Saiki S, Sato S, Hattori N. Molecular pathogenesis of Parkinson‘s disease: update. J Neurol Neurosurg Psychiatry 2012; 83(4): 430– 436. doi: 10.1136/ jnnp‑ 2011‑ 301205.

13. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. Alphα‑ synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 1998; 95(11): 6469– 6473.

14. Gatto NM, Rhodes SL, Manthripragada AD, Bronstein J,Cockburn M, Farrer M et al. α‑ synuclein gene may interact with environmental factors in increasing risk of Parkinson’s disease. Neuroepidemiology 2010; 35(3): 191– 195. doi: 10.1159/ 000315157.

15. Lin MK, Farrer MJ. Genetics and genomics of Parkinson‘s disease. Genome Med 2014; 6(6): 48. doi: 10.1186/ gm566.

16. Schapira AH, Jenner P. Etiology and pathogenesis of Parkinson‘s disease. Mov Disord 2011; 26(6): 1049– 1055. doi: 10.1002/ mds.23732.

17. Vargas KJ, Makani S, Davis T, Westphal CH, Castillo PE, Chandra SS. Synucleins regulate the kinetics of synaptic vesicle endocytosis. J Neurosci 2014; 34(28): 9364– 9376. doi: 10.1523/ JNEUROSCI.4787‑ 13.2014.

18. Veldman BA, Wijn AM, Knoers N, Praamstra P, Horstink MW. Genetic and environmental risk factors in Parkinson’s disease. Clin Neurol Neurosurg 1998; 100(1): 15– 26.

19. Menšíková K, Kaňovský P, Kaiserová M, Nestrašil I, Bareš M. Proměnlivá tvář parkinsonské neurodegenerace. Cesk Slov Neurol N 2013; 76/ 109(1): 26– 34.

20. Priyadarshi A, Khuder SA, Schaub EA, Priyadarshi SS.Environmental risk factors and Parkinson’s disease: a meta‑analysis. Environ Res 2001; 86(2): 122– 127.

21. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson‘s disease: a review of the evidence. Eur J Epidemiol 2011; 26 (Suppl 1):S1– S58. doi: 10.1007/ s10654‑ 011‑ 9581‑ 6.

22. Betarbet R, Sherer TB, MacKenzie G, Garcia‑ Osuna M, Panov AV, Greenamyre JT et al. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 2000; 3(12): 1301– 1306.

23. Meredith GE, Sonsalla PK, Chesselet MF. Animal models of Parkinson’s disease progression. Acta Neuropathol 2008; 115(4): 385– 398. doi: 10.1007/ s00401‑ 008‑ 0350‑ x.

24. Ossowska K, Smiałowska M, Kuter K, Wierońska J, Zieba B, Wardas J et al. Degeneration of dopaminergic mesocortical neurons and activation of compensatory processes induced by a long‑term paraquat administration in rats: implications for Parkinson‘s disease. Neuroscience 2006; 141(4): 2155– 2165.

25. Dick FD, De Palma G, Ahmadi A, Scott NW, Prescott GJ,Bennett J et al. Environmental risk factors for Parkinson’s disease and parkinsonism: the Geoparkinson study. Occup Environ Med 2007; 64(10): 666– 672.

26. Gatto NM, Cockburn M, Bronstein J, Manthripragada AD,Ritz B. Well‑water consumption and Parkinson’s disease in rural California. Environ Health Persp 2009; 117(12): 1912– 1918. doi: 10.1289/ ehp.0900852.

27. Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Richardson RJ. The risk of Parkinson’s disease with exposure to pesticides, farming, well water, and rural living. Neurology 1998; 50(5): 1346– 1350.

28. Kamel F, Tanner C, Umbach D, Hoppin J, Alavanja M, Blair A et al. Pesticide exposure and self‑ reported Parkinson’s disease in the agricultural health study. Am J Epidemiol 2007; 165(4): 364– 374.

29. Costello S, Cockburn M, Bronstein J, Zhang X, Ritz B. Parkinson‘s disease and residential exposure to maneb and paraquat from agricultural applications in the central valley of California. Am J Epidemiol 2009; 169(8): 919– 926. doi: 10.1093/ aje/ kwp006.

30. Tanner CM, Kamel F, Ross GW, Hoppin JA, Goldman SM,Korell M et al. Rotenone, paraquat, and Parkinson‘s disease. Environ Health Perspect 2011; 119(6): 866– 872. doi: 10.1289/ ehp.1002839.

31. Corrigan FM, Wienburg CL, Shore RF, Daniel SE, Mann D.Organochlorine insecticides in substantia nigra in Parkinson‘s disease. J Toxicol Environ Health A 2000; 59(4): 229– 234.

32. Fleming L, Mann JB, Bean J, Briggle T, Sanchez‑ Ramos JR.Parkinson‘s disease and brain levels of organochlorine pesticides. Ann Neurol 1994; 36(1): 100– 103.

33. Chorfa A, Lazizzera C, Bétemps D, Morignat E, Dussurgey S, Andrieu T et al. A variety of pesticides trigger in vitro α‑ synuclein accumulation, a key event in Parkinson‘s disease. Arch Toxicol 2014 [Epub ahead of print].

34. Uversky VN, Li J, Fink AL. Pesticides directly accelerate the rate of alphα‑ synuclein fibril formation: a possible factor in Parkinson‘s disease. FEBS Lett 2001; 500(3): 105– 108.

35. Franco R, Li SM, Rodriguez‑ Rocha H, Burns M, Panayiotidis MI. Molecular mechanisms of pesticide‑induced neurotoxicity: relevance to Parkinson‘s disease. Chem Biol Interact 2010; 188(2): 289– 300. doi: 10.1016/ j.cbi.2010.06.003.

36. Langston JW, Forno LS, Tetrud J, Reeves AG, Kaplan JA, Karluk D. Evidence of active nerve cell degeneration in the substantia nigra in humans years after 1- methyl4- phenyl‑ 1,2,3,6- tetrahydropyridine exposure. Ann Neurol 1999; 46(4): 598– 605.

37. Perese DA, Ulman J, Viola J, Ewing SE, Bankiewicz KS. A 6- hydroxydopamine‑induced selective parkinsonian rat model. Brain Res 1989; 494(2): 285– 293.

38. Powers KM, Smith‑ Weller T, Franklin GM, Longstreth WT jr, Swanson PD, Checkoway H. Parkinson’s disease risks associated with dietary iron, manganese, and other nutrient intakes. Neurology 2003; 60(11): 1761– 1766.

39. Uversky VN, Li J, Bower K, Fink AL. Synergistic effects of pesticides and metals on the fibrillation of alphα‑ synuclein: implications for Parkinson‘s disease. Neurotoxicology 2002; 23(4– 5): 527– 536.

40. Werneck AL, Alvarenga H. Genetics, drugs and environmental factors in Parkinson’s disease. A case‑ control study. Arq Neuropsiquiatr 1999; 57(2B): 347– 355.

41. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN,Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24(2): 197– 211.

42. Del Tredici K, Braak H. Lewy pathology and neurodegeneration in premotor Parkinson‘s disease. Mov Disord 2012; 27(5): 597–607. doi: 10.1002/ mds.24921.

43. Adler CH, Dugger BN, Hinni ML, Lott DG, Driver‑ Dunckley E, Hidalgo J et al. Submandibular gland needle biopsy for the diagnosis of Parkinson disease. Neurology 2014; 82(10): 858– 864. doi: 10.1212/ WNL.0000000000000204.

44. Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White CL et al. Multi‑organ distribution of phosphorylated α‑ synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 2010; 119(6): 689– 702. doi: 10.1007/ s00401‑ 010‑ 0664‑ 3.

45. Folgoas E, Lebouvier T, Leclair‑ Visonneau L, Cersosimo MG, Barthelaix A, Derkinderen P et al. Diagnostic value of minor salivary glands biopsy for the detection of Lewy pathology. Neurosci Lett 2013; 551: 62– 64. doi: 10.1016/ j.neulet.2013.07.016.

46. Lebouvier T, Neunlist M, Bruley des Varannes S, Coron E,Drouard A, N‘Guyen JM, Chaumette T et al. Colonic biopsies to assess the neuropathology of Parkinson’s disease and its relationship with symptoms. PLoS One 2010; 5(9): e12728. doi: 10.1371/ journal.pone.0012728.

47. Phillips RJ, Walter GC, Wilder SL, Baronowsky EA, Powley TL. Alphα‑ synuclein‑immunopositive myenteric neurons and vagal preganglionic terminals: autonomic pathway implicated in Parkinson’s disease? Neuroscience 2008; 153(3): 733– 750. doi: 10.1016/ j.neuroscience.2008.02.074.

48. Paillusson S, Clairembault T, Biraud M, Neunlist M, Derkinderen P. Activity‑ dependent secretion of alhα‑ synuclein by enteric neurons. J Neurochem 2013; 125(4): 512– 517. doi: 10.1111/ jnc.12131.

49. Jellinger KA. Synuclein deposition and non‑motor symptoms in Parkinson disease. J Neurol Sci 2011; 310(1– 2): 107– 111. doi: 10.1016/ j.jns.2011.04.012.

50. Hellenbrand W, Seidler A, Boeing H, Robra BP, Vieregge P, Nischan P et al. Diet and Parkinson’s disease. I: a possible role for the past intake of specific foods and food groups. Results from a self‑ administered food‑ frequency questionnaire in a case‑ control study. Neurology 1996; 47(3): 636– 643.

51. Ross GW, Petrovitch H. Current evidence for neuroprotective effects of nicotine and caffeine against Parkinson’s disease. Drugs Aging 2001; 18(11): 797– 806.

52. Tan LC, Koh WP, Yuan JM, Wang R, Au WL, Tan JH et al. Differential effects of black versus green tea on risk of Parkinson’s disease in the Singapore Chinese Health Study. Am J Epidemiol 2008; 167(5): 553– 560.

53. Hong DP, Fink AL, Uversky VN. Smoking and Parkinson’s disease: does nicotine affect alphα‑ synuclein fibrillation? Biochim Biophys Acta 2009; 1794(2): 282– 290. doi: 10.1016/ j.bbapap.2008.09.026.

54. Olanow CW. Do prions cause Parkinson disease? The evidence accumulates. Ann Neurol 2014; 75(3): 331– 333. doi: 10.1002/ ana.24098.

55. Olanow CW, McNaught K. Parkinson’s disease, proteins, and prions: milestones. Mov Disord 2011; 26(6): 1056– 1071. doi: 10.1002/ mds.23767.

56. Luk KC, Song C, O‘Brien P, Stieber A, Branch JR, Brunden KR et al. Exogenous alpha‑ synuclein fibrils seed the formation of Lewy body‑like intracellular inclusions in cultured cells. Proc Natl Acad Sci U S A 2009; 106(47): 20051– 20056. doi: 10.1073/ pnas.0908005106.

57. Volpicelli‑ Daley L, Luk K, Patel T, Tanik S, Riddle D, Stieber A et al. Exogenous α‑ synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 2011; 72(1): 57– 71. doi: 10.1016/ j.neuron.2011.08.033.

58. Moore DJ, West AB, Dawson VL, Dawson TM. Molecular pathophysiology of Parkinson’s disease. Ann Rev Neurosci 2005; 28: 57– 87.

59. Conway KA, Harper JD, Lansbury PT jr. Fibrils formed in vitro from α‑ synuclein and two mutant forms linked to Parkinson’s disease are typical amyloid. Biochemistry 2000; 39(10): 2552– 2563.

60. Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. Lewy body‑like pathology in long‑ term embryonic nigral transplants in Parkinson‘s disease. Nat Med 2008; 14(5): 504– 506. doi: 10.1038/ nm1747.

61. Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJet al. Lewy bodies in grafted neurons in subjects with Parkinson‘s disease suggest host‑to‑ graft disease propagation. Nat Med 2008; 14(5): 501– 503. doi: 10.1038/ nm1746.

62. Danzer KM, Kranich LR, Ruf WP, Cagsal‑ Getkin O, Winslow AR, Zhu L et al. Exosomal cell‑ to‑ cell transmission of α‑ synuclein oligomers. Mol Neurodegener 2012; 7: 42. doi: 10.1186/ 1750‑ 1326‑ 7‑ 42.

63. Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L et al. Inclusion formation and neuronal cell death through neuron‑ to‑ neuron transmission of alphα‑ synuclein. Proc Natl Acad Sci USA 2009; 106(31): 13010– 13015. doi: 10.1073/ pnas.0903691106.

64. Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M, Margaritis LH et al. Cell‑ produced α‑ synuclein is secreted in a calcium‑ dependent manner by exosomes and impacts neuronal survival. J Neurosci 2010; 30(20): 6838– 6851. doi: 10.1523/ JNEUROSCI.5699‑ 09.2010.

65. Angot E, Steiner JA, Hansen C, Li JY, Brundin P. Are synucleinopathies prion‑like disorders? Lancet Neurol 2010; 9(11): 1128– 1138. doi: 10.1016/ S1474‑ 4422(10)70213‑ 1.

66. Tokuda T, Qureshi MM, Ardah MT, Varghese S, Shehab SA, Kasai T et al. Detection of elevated levels of alphα‑ synuclein oligomers in CSF from patients with Parkinson disease. Neurology 2010; 75(20): 1766– 1772. doi: 10.1212/ WNL.0b013e3181fd613b.

67. Luk KC, Lee VM. Modeling Lewy pathology propagation in Parkinson‘s disease. Parkinsonism Relat Disord 2014; 20 (Suppl 1): S85– S87. doi: 10.1016/ S1353‑ 8020(13)70022‑ 1.

68. Luk K, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski J et al. Pathological α‑ synuclein transmission initiates Parkinson‑like neurodegeneration in non‑transgenic mice. Science 2012; 338(6109): 949– 953. doi: 10.1126/ science.1227157.

69. Masuda‑ Suzukake M, Nonaka T, Hosokawa M, Oikawa T,Arai T, Akiyama H et al. Prion‑like spreading of pathological α‑ synuclein in brain. Brain 2013; 136(4): 1128– 1138. doi: 10.1093/ brain/ awt037.

70. Luk KC, Kehm VM, Zhang B, O‘Brien P, Trojanowski JQ, Lee VM. Intracerebral inoculation of pathological α‑ synuclein initiates a rapidly progressive neurodegenerative α‑ synucleinopathy in mice. J Exp Med 2012; 209(5): 975– 986. doi: 10.1084/ jem.20112457.

71. Mougenot AL, Nicot S, Bencsik A, Morignat E, Verchère J, Lakhdar L et al. Prion‑like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol Aging 2012; 33(9): 2225– 2228. doi: 10.1016/ j.neurobiolaging.2011.06.022.

72. Recasens A, Dehay B, Bové J, Carballo‑ Carbajal I, Dovero S, Pérez‑ Villalba A et al. Lewy body extracts from Parkinson’s disease brains trigger α‑ synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 2014; 75(3): 351– 362. doi: 10.1002/ ana.24066.

73. Watts JC, Giles K, Oehler A, Middleton L, Dexter DT, Gentleman SM et al. Transmission of multiple system atrophy prions to transgenic mice. Proc Natl Acad Sci USA 2013; 110(48): 19555–19560.

74. Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A, Zhang Bet al. Distinct alphα‑ synuclein strains differentially promote tau inclusions in neurons. Cell 2013; 154(1): 103– 117. doi: 10.1016/ j.cell.2013.05.057.

75. Guo JL, Lee VMY. Cell‑ to‑ cell transmission of pathogenic proteins in neurodegenerative diseases. Nat Med 2014; 20(2): 130– 138. doi: 10.1038/ nm.3457.

76. Jucker M, Walker LC. Self‑ propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 2013; 501(7465): 45– 51. doi: 10.1038/ nature12481.

77. Irwin DJ, Abrams JY, Schonberger LB, Leschek EW, Mills JL, Lee VM et al. Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver‑ derived human growth hormone. JAMA Neurol 2013; 70(4): 462– 468. doi: 10.1001/ jamaneurol.2013.1933.

78. Tran HT, Chung CH, Iba M, Zhang B, Trojanowski JQ, Luk KC et al. α‑ synuclein immunotherapy blocks uptake and templated propagation of misfolded α‑ synuclein and neurodegeneration. Cell Rep 2014; 7(6): 2054– 2065. doi: 10.1016/ j.celrep.2014.05.033.

79. Jordan BD. Chronic traumatic brain injury associated with boxing. Semin Neurol 2000; 20(2): 179– 185.

80. Gershanik OS. Trauma and Parkinson’s disease. Handb Clin Neurol 2007; 84: 487– 499. doi: 10.1016/ S0072‑ 9752(07)84057‑ 7.

81. Taylor CA, Saint‑ Hilaire MH, Cupples LA, Thomas CA, Burchard AE, Feldman RG et al. Environmental, medical, and family history risk factors for Parkinson’s disease: a New England‑based case control study. Am J Med Genet 1999; 88(6): 742– 749.

82. Jafari S, Etminan M, Aminzadeh F, Samii A. Head injury and risk of Parkinson disease: a systematic review and meta‑analysis. Mov Disord 2013; 28(9): 1222– 1229. doi: 10.1002/ mds.25458.

83. Irwin DJ, Trojanowski JQ. Many roads to Parkinson’s disease neurodegeneration: head trauma – a road more traveled than we know? Mov Disord 2013; 28(9): 1167– 1170. doi: 10.1002/ mds.25551.

84. Uryu K, Giasson BI, Longhi L, Martinez D, Murray I, Conte V et al. Age‑ dependent synuclein pathology following traumatic brain injury in mice. Exp Neurol 2003; 184(1): 214– 224.

85. Kasten M, Chade A, Tanner CM. Epidemiology of Parkinson’s disease. Handb Clin Neurol 2007; 83: 129– 151. doi: 10.1016/ S0072‑ 9752(07)83006‑ 5.

86. Schulz JB, Lindenau J, Seyfried J, Dichgans J. Glutathione, oxidative stress and neurodegeneration. Eur J Biochem 2000; 267(16): 4904– 4911.

87. Sulzer D, Surmeier DJ. Neuronal vulnerability, pathogenesis, and Parkinson‘s disease. Mov Disord 2013; 28(6): 41– 50. doi: 10.1002/ mds.25095.

88. Chai C, Lim KL. Genetic insights into sporadic Parkinson’s disease pathogenesis. Curr Genomics 2013; 14(8): 486– 501. doi: 10.2174/ 1389202914666131210195808.

89. Piccini P, Burn DJ, Ceravolo R, Maraganore D, Brooks DJ.The role of inheritance in sporadic Parkinsons’ disease: evidence from a longitudinal study of dopaminergic function in twins. Ann Neurol 1999; 45(5): 577– 582.

90. Simón‑ Sánchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D et al. Genome‑ wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 2009; 41(12): 1308– 1312. doi: 10.1038/ ng.487.

91. Bonifati V. Genetics of Parkinson‘s disease – state of the art, 2013. Parkinsonism Relat Disord 2014; 20 (Suppl 1): S23– S28. doi: 10.1016/ S1353‑ 8020(13)70009‑ 9.

92. Ibáñez P, Lesage S, Janin S, Lohmann E, Durif F, Destée A et al. Alphα‑ synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms. Arch Neurol 2009; 66(1): 102– 108. doi: 10.1001/ archneurol.2008.555.

93. Kilarski LL, Pearson JP, Newsway V, Majounie E, Knipe MD, Misbahuddin A et al. Systematic review and UK‑based study of PARK2 (parkin), PINK1, PARK7 (DJ‑ 1) and LRRK2 in early‑ onset Parkinson’s disease. Mov Disord 2012; 27(12): 1522– 1529. doi: 10.1002/ mds.25132.

94. Wang Y, Clark LN, Louis ED, Mejia‑ Santana H, Harris J, Cote LJ et al. Risk of Parkinson disease in carriers of parkin mutations:estimation using the kin‑cohort method. Arch Neurol 2008; 65(4): 467– 474. doi: 10.1001/ archneur.65.4.467.

95. Lim KL, Ng XH, Grace LG, Yao TP. Mitochondrial dynamics and Parkinson’s disease: focus on parkin. Antioxid Redox Signal 2012; 16(9): 935– 949. doi: 10.1089/ ars.2011.4105.

96. Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 2008; 183(5): 795– 803. doi: 10.1083/ jcb.200809125.

97. Canet‑ Avilés RM, Wilson MA, Miller DW, Ahmad R, McLendon C, Bandyopadhyay S et al. The Parkinson’s disease protein DJ‑ 1 is neuroprotective due to cyctein‑sulfinic acid‑driven mitochondrial localization. Proc Natl Acad Sci U S A 2004; 101(24): 9103– 9108.

98. Thomas KJ, McCoy MK, Blackinton J, Beilina A, van der Brug M, Sandebring A et al. DJ‑ 1 acts in parallel to the PINK1/ parkin pathway to control mitochondrial function and autophagy. Hum Mol Genet 2011; 20(1): 40– 50. doi: 10.1093/ hmg/ ddq430.

99. Healy DG, Falchi M, O‘Sullivan SS, Bonifati V, Durr A, Bressman S et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2‑associated Parkinson’s disease: a case‑ control study. Lancet Neurol 2008; 7(7): 583– 590. doi: 10.1016/ S1474‑ 4422(08)70117‑ 0.

100. Kračunová K, Kovačovicová M, Baldovič M, Valkovič P, Kádaši L, Benetin J. The Incidence of Mutation on the Leucine‑ rich Repeat Kinase 2 Gene in Patients with Parkinson’s Disease in Slovakia. Cesk Slov Neurol N 2011; 74/ 107(4): 443– 445.

101. Vilariño‑ Güell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, Lincoln SJ et al. VPS35 mutations in Parkinson disease. Am J Hum Genet 2011; 89(1): 162– 167. doi: 10.1016/ j.ajhg.2011.06.001.

102. Zimprich A, Benet‑ Pagès A, Struhal W, Graf E, Eck SH, Offman MN et al. A mutation in VPS35, encoding a subunit of the retromer complex, causes late‑ onset Parkinson disease. Am J Hum Genet 2011; 89(1): 168– 175. doi: 10.1016/ j.ajhg.2011.06.008.

103. Sharma M, Ioannidis JP, Aasly JO, Annesi G, Brice A,Bertram L et al. A multi‑centre clinico‑ genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease‑associated variants. J Med Genet 2012; 49(11): 721– 726. doi: 10.1136/ jmedgenet‑ 2012‑ 101155.

104. Kay DM, Factor SA, Samii A, Higgins DS, Griffith A, Roberts JW et al. Genetic association between alphα‑ synuclein and idiopathic Parkinson’s disease. Am J Med Genet B Neuropsychiatr Genet 2008; 147B(7): 1222– 1230. doi: 10.1002/ ajmg.b.30758.

105. Maraganore DM, de Andrade M, Elbaz A, Farrer MJ,Ioannidis JP, Krüger R et al. Collaborative analysis of alphα‑ synuclein gene promoter variability and Parkinson disease. JAMA 2006; 296(6): 661– 670.

106. Parsian AJ, Racette BA, Zhao JH, Sinha R, Patra B, Perlmutter JS et al. Association of alphα‑ synuclein gene haplotypes with Parkinson’s disease. Parkinsonism Relat Disord 2007; 13(6): 343– 347.

107. Mueller JC, Fuchs J, Hofer A, Zimprich A, Lichtner P, Illig T et al. Multiple regions of alphα‑ synuclein are associated with Parkinson’s disease. Ann Neurol 2005; 57(4): 535– 541.

108. Rhinn H, Qiang L, Yamashita T, Rhee D, Zolin A, Vanti Wet al. Alternative alphα‑ synuclein transcript usage as a convergent mechanism in Parkinson’s disease pathology. Nat Commun 2012; 3: 1084. doi: 10.1038/ ncomms2032.

109. Sidransky E, Nalls MA, Aasly JO, Aharon‑ Peretz J, Annesi G, Barbosa ER et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 2009; 361(17): 1651– 1661. doi: 10.1056/ NEJMoa0901281.

110. Westbroek W, Gustafson AM, Sidransky E. Exploring the link between glucocerebrosidase mutations and parkinsonism. Trends Mol Med 2011; 17(9): 485– 493. doi: 10.1016/ j.molmed.2011.05.003.

111. Alonso‑ Navarro H, Jimenez‑ Jimenez FJ, Garcia‑ Martin E, Agundez JA. Genomic and pharmacogenomics biomarkers of Parkinson’s disease. Curr Drug Metab 2014; 15(2): 129– 181.

112. International Parkinson Disease Genomics Consortium. Imputation of sequence variants for identification of genetic risks for Parkinson‘s disease: a meta‑analysis of genome‑ wide association studies. Lancet 2011; 377(9766): 641– 649. doi: 10.1016/ S0140‑ 6736(10)62345‑ 8.

113. International Parkinson‘s Disease Genomics Consortium (IPDGC); Wellcome Trust Case Control Consortium 2 (WTCCC2). A two‑stage meta‑analysis identifies several new loci for Parkinson‘s disease. PLoS Genet 2011; 7(6): e1002142. doi: 10.1371/ journal.pgen.1002142.

114. Lill CM, Roehr JT, McQueen MB, Kavvoura FK, Bagade S, Schjeide BM et al. Comprehensive research synopsis and systematic meta‑analyses in Parkinson’s disease genetics: the PDGene database. PLoS Genet 2012; 8(3): e1002548. doi: 10.1371/ journal.pgen.1002548.

115. Pastor P. Genetic heterogeneity in Parkinson disease: the meaning of GWAS and replication studies. Neurology 2012; 79(7): 619– 620. doi: 10.1212/ WNL.0b013e318264e3d2.

116. Imamura K, Hishikawa N, Sawada M, Nagatsu T, Yoshida M, Hashizume Y. Distribution of major histocompatibility complex class II‑ positive microglia and cytokine profile of Parkinson’s disease brains. Acta Neuropathol 2003; 106(6): 518– 526.

117. Ouchi Y, Yoshikawa E, Sekine Y, Futatsubashi M, Kanno T, Ogusu T et al. Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann Neurol 2005; 57(2): 168– 175.

118. Moehle MS, Webber PJ, Tse T, Sukar N, Standaert DG, DeSilva TM et al. LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci 2012; 32(5): 1602– 1611. doi: 10.1523/ JNEUROSCI.5601‑ 11.2012.

119. Elbaz A, Levecque C, Clavel J, Vidal JS, Richard F, Amouyel P et al. CYP2D6 polymorphism, pesticide exposure, and Parkinson’s disease. Ann Neurol 2004; 55(3): 430– 434.

120. De Palma G, Dick FD, Calzetti S, Scott NW, Prescott GJ,Osborne A et al. A case‑ control study of Parkinson‘s disease and tobacco use: gene‑ tobacco interactions. Mov Disord 2010; 25(7): 912– 919. doi: 10.1002/ mds.22980.

121. Goldman SM, Kamel F, Bhudikanok F. Alphα‑ synuclein (SNCA) genotype modifies the association between head injury and Parkinson’s disease (PD). Neurology 2009; 72 (Suppl 3): S23.005.

122. Hirsch EC, Jenner P, Przedborski S. Pathogenesis of Parkinson’s disease. Mov Disord 2013; 28(1): 24– 30. doi: 10.1002/ mds.25032.

123. Rubinsztein DC. The roles of intracellular protein‑degradation pathways in neurodegeneration. Nature 2006; 443(7113): 780– 786.

124. Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML et al. PGC‑ 1α, a potential therapeutic target for early intervention in Parkinson‘s disease. Sci Transl Med 2010; 2(52): 52– 73. doi: 10.1126/scitranslmed.3001059.