Parkinson's disease: Genetics and pathogenesis

Annual Review of Pathology: Mechanisms of Disease

Volumn 6, Issue , 2011, Pages 193-222

  Shulman, Joshua M ^a,c,d   De Jager, Philip L ^a,c,d   Feany, Mel B ^b,c  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

^c HARVARD MEDICAL SCHOOL   (United States)

^d BROAD INSTITUTE OF MIT AND HARVARD   (United States)

Author keywords

animal model; GBA; genome wide association study; Lewy body; LRRK2; MAPT; parkin; synuclein

Indexed keywords

ALPHA SYNUCLEIN; GLUCOSYLCERAMIDASE; LEUCINE RICH REPEAT KINASE 2; TAU PROTEIN;

ARTICLE; CLINICAL ASSESSMENT; CLINICAL FEATURE; DISEASE COURSE; GENETIC ASSOCIATION; GENETICS; HUMAN; NEUROPROTECTION; NONHUMAN; PARKINSON DISEASE; PARKINSONISM; PATHOGENESIS; PATHOLOGY; PRIORITY JOURNAL; TRANSLATIONAL RESEARCH;

ANIMALS; GENETIC PREDISPOSITION TO DISEASE; HUMANS; LEWY BODIES; PARKINSON DISEASE;

EID: 79751509762     PISSN: 15534006     EISSN: 15534014     Source Type: Book Series    
DOI: 10.1146/annurev-pathol-011110-130242     Document Type: Article

References (171)

1. Parkinson J. 1817. An Essay on the Shaking Palsy. London:Whittingham & Rowland
2. Lewy FH. 1912. Paralysis agitans. I. Pathologische anatomie. In Handbuch der Neurologie, ed. M Lewandowsky, pp. 920-33. Berlin: Springer
3. de Lau LML, Breteler MMB. 2006. Epidemiology of Parkinson's disease. Lancet Neurol. 5:525-35
4. Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, et al. 2003. Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity. Am. J. Epidemiol. 157:1015-22 (Pubitemid 36628805)
5. Hawkes CH. 2008. The prodromal phase of sporadic Parkinson's disease: Does it exist and if so how long is it? Mov. Disord. 23:1799-807
6. Elbaz A, Bower JH, Peterson BJ, Maraganore DM, McDonnell SK, et al. 2003. Survival study of Parkinson disease in Olmsted County, Minnesota. Arch. Neurol. 60:91-96 (Pubitemid 36078114)
7. Fahn S. 2003. Description of Parkinson's disease as a clinical syndrome. Ann. N.Y. Acad. Sci. 991:1-14 (Pubitemid 36793796)
8. Rodriguez-Oroz MC, Jahanshahi M, Krack P, Litvan I, Macias R, et al. 2009. Initial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms. Lancet Neurol. 8:1128-39
9. Langston J. 2006. The Parkinson's complex: Parkinsonism is just the tip of the iceberg. Ann. Neurol. 59:591-96
10. ChaudhuriKR, Schapira AHV. 2009. Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 8:464-74
11. Hely MA,Morris JGL,ReidWGJ, Trafficante R. 2005. Sydney Multicenter Study of Parkinson's disease: non-L-dopa-responsive problems dominate at 15 years. Mov. Disord. 20:190-99 (Pubitemid 40361122)
12. Langston JW, Ballard P, Tetrud JW, Irwin I. 1983. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979-80 (Pubitemid 13189531)
13. Priyadarshi A, Khuder SA, Schaub EA, Shrivastava S. 2000. A meta-analysis of Parkinson's disease and exposure to pesticides. Neurotoxicology 21:435-40
14. Hernán MA,Takkouche B, Caamaño-Isorna F,Gestal-Otero JJ. 2002.Ameta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson's disease. Ann. Neurol. 52:276-84 (Pubitemid 35001493)
15. Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, et al. 2009. Neuropathological assessment of Parkinson's disease: refining the diagnostic criteria. Lancet Neurol. 8:1150-57
16. Spillantini M, Murrell J, GoedertM, FarlowM, Klug A, et al. 1998. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. USA 95:7737-41 (Pubitemid 28293323)
17. Jellinger KA. 2009. A critical evaluation of current staging of α-synuclein pathology in Lewy body disorders. Biochim. Biophys. Acta 1792:730-40
18. Pavese N, Brooks DJ. 2009. Imaging neurodegeneration in Parkinson's disease. Biochim. Biophys. Acta 1792:722-29
19. Braak H, Del Tredici K. 2008. Invited article: Nervous system pathology in sporadic Parkinson disease. Neurology 70:1916-25 (Pubitemid 351684646)
20. Braak H, Del Tredici K, Rub U, de Vos R, Jansen Steur E, et al. 2003. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24:197-211 (Pubitemid 36007810)
21. Halliday G, Hely M, Reid W, Morris J. 2008. The progression of pathology in longitudinally followed patients with Parkinson's disease. Acta Neuropathol. 115:409-15
22. Zaccai J, Brayne C, McKeith I, Matthews F, Ince PG, et al. 2008. Patterns and stages of α- synucleinopathy: relevance in a population-based cohort. Neurology 70:1042-48 (Pubitemid 351451312)
23. Dickson DW, Fujishiro H, DelleDonne A, Menke J, Ahmed Z, et al. 2008. Evidence that incidental Lewy body disease is presymptomatic Parkinson's disease. Acta Neuropathol. 115:437-44
24. McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, et al. 2005. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863-72 (Pubitemid 43970103)
25. Ballatore C, Lee V, Trojanowski J. 2007. Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat. Rev. Neurosci. 8:663-72 (Pubitemid 47283144)
26. Pickering-Brown SM. 2010. Review: Recent progress in frontotemporal lobar degeneration. Neuropathol. Appl. Neurobiol. 36:4-16
27. Schneider JA, Li J-L, Li Y, Wilson RS, Kordower JH, et al. 2006. Substantia nigra tangles are related to gait impairment in older persons. Ann. Neurol. 59:166-73 (Pubitemid 43042883)
28. Geddes JF, Hughes AJ, Lees AJ, Daniel SE. 1993. Pathological overlap in cases of parkinsonism associated with neurofibrillary tangles. A study of recent cases of postencephalitic parkinsonism and comparison with progressive supranuclear palsy and Guamanian parkinsonism-dementia complex. Brain 116:281-302 (Pubitemid 23087048)
29. Ince PG, Codd GA. 2005. Return of the cycad hypothesis-does the amyotrophic lateral sclerosis/ parkinsonism dementia complex (ALS/PDC) of Guam have new implications for global health? Neuropathol. Appl. Neurobiol. 31:345-53 (Pubitemid 41059855)
30. Marder K, Levy G, Louis E, Mejia-Santana H, Cote L, et al. 2003. Familial aggregation of early- and late-onset Parkinson's disease. Ann. Neurol. 54:507-13 (Pubitemid 37176547)
31. Sveinbjörnsdottir S, Hicks AA, Jonsson T, Pétursson H, Guǧmundsson G, et al. 2000. Familial aggregation of Parkinson's disease in Iceland. N. Engl. J. Med. 343:1765-70
32. Tanner C, Ottman R, Goldman S, Ellenberg J, Chan P, et al. 1999. Parkinson disease in twins: an etiologic study. J. Am. Med. Assoc. 281:341-46 (Pubitemid 29061038)
33. Gasser T. 2009. Mendelian forms of Parkinson's disease. Biochim. Biophys. Acta 1792:587-96
34. Hirschhorn J, Daly M. 2005. Genome-wide association studies for common diseases and complex traits. Nat. Rev. Genet. 6:95-108 (Pubitemid 40179532)
35. Satake W, Nakabayashi Y,Mizuta I, Hirota Y, Ito C, et al. 2009. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat. Genet. 41:1303-7
36. Simón-Sánchez J, Schulte C, Bras J, Sharma M, Gibbs J, et al. 2009. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat. Genet. 41:1308-12
37. Hardy J, Lewis P, Revesz T, Lees A, Paisan-Ruiz C. 2009. The genetics of Parkinson's syndromes: a critical review. Curr. Opin. Genet. Dev. 19:254-65
38. Klein C, Schneider SA, Lang AE. 2009. Hereditary parkinsonism: Parkinson disease look-alikes-an algorithm for clinicians to "PARK" genes and beyond. Mov. Disord. 24:2042-58
39. Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, et al. 1998. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. Nat. Genet. 18:106-8
40. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, et al. 1997. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276:2045-47 (Pubitemid 27443610)
41. Zarranz JJ, Alegre J, G Gómez -Esteban JC, Lezcano E, Ros R, et al. 2004. The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann Neurol. 55:164-73 (Pubitemid 38166992)
42. Bostantjopoulou S, Katsarou Z, Papadimitriou A, Veletza V, Hatzigeorgiou G, et al. 2001. Clinical features of Parkinsonian patients with the α-synuclein (G209A) mutation. Mov. Disord. 16:1007-13 (Pubitemid 36041212)
43. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, et al. 1997. α-Synuclein in Lewy bodies. Nature 388:839-40
44. Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, et al. 2003. α-Synuclein locus triplication causes Parkinson's disease. Science 302:841 (Pubitemid 37339619)
45. Chartier-Harlin M-C, Kachergus J, Roumier C, Mouroux V, Douay X, et al. 2004. α-Synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364:1167-69 (Pubitemid 39296604)
46. Farrer M, Kachergus J, Forno L, Lincoln S, Wang D-S, et al. 2004. Comparison of kindreds with parkinsonism and á-synuclein genomic multiplications. Ann. Neurol. 55:174-79 (Pubitemid 38166993)
47. Fuchs J, Nilsson C, Kachergus J, Munz M, Larsson E-M, et al. 2007. Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology 68:916-22 (Pubitemid 46568503)
48. Nishioka K, Ross OA, Ishii K, Kachergus JM, Ishiwata K, et al. 2009. Expanding the clinical phenotype of SNCA duplication carriers. Mov. Disord. 24:1811-19
49. Chiba-Falek O, Nussbaum RL. 2001. Effect of allelic variation at the NACP-Rep1 repeat upstream of the α-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system. Hum. Mol. Genet. 10:3101-9 (Pubitemid 34083496)
50. Krüger R, Vieira-Saecker AM, Kuhn W, Berg D, Müller T, et al. 1999. Increased susceptibility to sporadic Parkinson's disease by a certain combined α-synuclein/apolipoprotein E genotype. Ann. Neurol. 45:611-17 (Pubitemid 29217589)
51. Mellick GD, Maraganore DM, Silburn PA. 2005. Australian data and meta-analysis lend support for α-synuclein (NACP-Rep1) as a risk factor for Parkinson's disease. Neurosci. Lett. 375:112-16
52. Pals P, Lincoln S, Manning J, Heckman M, Skipper L, et al. 2004. α-Synuclein promoter confers susceptibility to Parkinson's disease. Ann. Neurol. 56:591-95 (Pubitemid 39319355)
53. Maraganore D, de Andrade M, Elbaz A, Farrer M, Ioannidis J, et al. 2006. Collaborative analysis of α-synuclein gene promoter variability and Parkinson disease. J. Am. Med. Assoc. 296:661-70 (Pubitemid 44200637)
54. Edwards TL, Scott WK, Almonte C, Burt A, Powell EH, et al. 2010. Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann. Hum. Genet. 74:97-109
55. Pankratz N, Wilk JB, Latourelle JC, DeStefano AL, Halter C, et al. 2009. Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum. Genet. 124:593-605
56. Waxman EA, Giasson BI. 2009. Molecular mechanisms of α-synuclein neurodegeneration. Biochim. Biophys. Acta 1792:616-24
57. Abeliovich A, Schmitz Y, Fariñas I, Choi-Lundberg D, Ho WH, et al. 2000. Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239-52 (Pubitemid 30316525)
58. Serpell L, Berriman J, Jakes R, GoedertM, Crowther R. 2000. Fiber diffraction of synthetic α-synuclein filaments shows amyloid-like cross-β conformation. Proc. Natl. Acad. Sci. USA 97:4897-902 (Pubitemid 30238654)
59. Conway KA, Harper JD, Lansbury PT. 1998. Accelerated in vitro fibril formation by a mutant α - synuclein linked to early-onset Parkinson disease. Nat. Med. 4:1318-20 (Pubitemid 28512115)
60. Paisán-Ruíz C, Jain S, Evans EW, GilksWP, Simón J, et al. 2004. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44:595-600 (Pubitemid 39531224)
61. Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, et al. 2004. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601-7 (Pubitemid 39531225)
62. Zabetian CP, Samii A, Mosley AD, Roberts JW, Leis BC, et al. 2005. A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations. Neurology 65:741-44 (Pubitemid 41285855)
63. Biskup S, West AB. 2009. Zeroing in on LRRK2-linked pathogenic mechanisms in Parkinson's disease. Biochim. Biophys. Acta 1792:625-33
64. Di Fonzo A, Rohé CF, Ferreira J, Chien HF, Vacca L, et al. 2005. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet 365:412-15 (Pubitemid 40179228)
65. Gilks W, Abou-Sleiman P, Gandhi S, Jain S, Singleton A, et al. 2005. A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 365:415-16 (Pubitemid 40179229)
66. Khan NL, Jain S, Lynch JM, PaveseN,Abou-Sleiman P, et al. 2005. Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain 128:2786-96 (Pubitemid 41746633)
67. Nichols WC, Pankratz N, Hernandez D, Paisán-Ruíz C, Jain S, et al. 2005. Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet 365:410-12 (Pubitemid 40179227)
68. Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, et al. 2008. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol. 7:583-90
69. Bras JM, Guerreiro RJ, Ribeiro MH, Januario C, Morgadinho A, et al. 2005. G2019S dardarin substitution is a common cause of Parkinson's disease in a Portuguese cohort. Mov. Disord. 20:1653-55
70. Lesage S, Ibanez P, Lohmann E, Pollak P, Tison F, et al. 2005. G2019S LRRK2 mutation in French and North African families with Parkinson's disease. Ann. Neurol. 58:784-87 (Pubitemid 41552556)
71. Ozelius LJ, Senthil G, Saunders-Pullman R, Ohmann E, Deligtisch A, et al. 2006. LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N. Engl. J. Med. 354:424-25 (Pubitemid 43145083)
72. Goldwurm S, Di Fonzo A, Simons EJ, Rohé CF, Zini M, et al. 2005. The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor. J. Med. Genet. 42:e65
73. Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, et al. 2005. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am. J. Hum. Genet. 76:672-80 (Pubitemid 40432174)
74. Kay DM, Kramer P, Higgins D, Zabetian CP, Payami H. 2005. Escaping Parkinson's disease: a neurologically healthy octogenarian with the LRRK2 G2019S mutation. Mov. Disord. 20:1077-78 (Pubitemid 41419535)
75. Ross OA, Toft M, Whittle AJ, Johnson JL, Papapetropoulos S, et al. 2006. Lrrk2 and Lewy body disease. Ann. Neurol. 59:388-93 (Pubitemid 43202496)
76. Funayama M, Hasegawa K, Ohta E, Kawashima N, Komiyama M, et al. 2005. An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. Ann. Neurol. 57:918-21 (Pubitemid 40798631)
77. Wszolek ZK, Pfeiffer RF, Tsuboi Y, Uitti RJ, McComb RD, et al. 2004. Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology 62:1619-22 (Pubitemid 38608210)
78. Di Fonzo A, Wu-Chou Y-H, Lu C-S, van Doeselaar M, Simons EJ, et al. 2006. A common missense variant in the LRRK2 gene,Gly2385Arg, associated with Parkinson's disease risk inTaiwan. Neurogenetics 7:133-38 (Pubitemid 44078290)
79. Funayama M, Li Y, Tomiyama H, Yoshino H, Imamichi Y, et al. 2007. Leucine-rich repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population. Neuroreport 18:273-75
80. Ross OA, Wu Y-R, Lee M-C, Funayama M, Chen M-L, et al. 2008. Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease. Ann. Neurol. 64:88-92
81. Biskup S, Mueller JC, Sharma M, Lichtner P, Zimprich A, et al. 2005. Common variants of LRRK2 are not associated with sporadic Parkinson's disease. Ann. Neurol. 58:905-8 (Pubitemid 41746880)
82. Biskup S, Moore DJ, Celsi F, Higashi S, West AB, et al. 2006. Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann. Neurol. 60:557-69 (Pubitemid 44871798)
83. West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, et al. 2005. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc.Natl. Acad. Sci. USA102:16842-47 (Pubitemid 41688864)
84. DePaolo J, Goker-Alpan O, Samaddar T, Lopez G, Sidransky E. 2009. The association between mutations in the lysosomal protein glucocerebrosidase and parkinsonism. Mov. Disord. 24:1571-78
85. Neudorfer O, Giladi N, Elstein D, Abrahamov A, Turezkite T, et al. 1996. Occurrence of Parkinson's syndrome in type I Gaucher disease. Q. J. Med. 89:691-94 (Pubitemid 26319021)
86. Tayebi N, Callahan M, Madike V, Stubblefield BK, Orvisky E, et al. 2001. Gaucher disease and parkinsonism: a phenotypic and genotypic characterization. Mol. Genet. Metab. 73:313-21 (Pubitemid 32846370)
87. Goker-Alpan O, Schiffmann R, LaMarca ME, Nussbaum RL, McInerney-Leo A, et al. 2004. Parkinsonism among Gaucher disease carriers. J. Med. Genet. 41:937-40 (Pubitemid 40007255)
88. Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. 2004. Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N. Engl. J. Med. 351:1972-77 (Pubitemid 39447138)
89. Lwin A, Orvisky E, Goker-Alpan O, LaMarca ME, Sidransky E. 2004. Glucocerebrosidase mutations in subjects with parkinsonism. Mol. Genet. Metab. 81:70-73 (Pubitemid 38064435)
90. ClarkLN, Ross BM,WangY,Mejia-SantanaH,Harris J, et al. 2007. Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease. Neurology 69:1270-77 (Pubitemid 47429028)
91. Gan-Or Z, Giladi N, Rozovski U, Shifrin C, Rosner S, et al. 2008. Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology 70:2277-83
92. Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, et al. 2009. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N. Engl. J. Med. 361:1651-61
93. Neumann J, Bras J, Deas E, O'Sullivan SS, Parkkinen L, et al. 2009. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain 132:1783-94
94. Eblan MJ, Scholz S, Stubblefield B, Gutti U, Goker-Alpan O, et al. 2006. Glucocerebrosidase mutations are not found in association with LRRK2 G2019S in subjects with parkinsonism. Neurosci. Lett. 404:163-65 (Pubitemid 44041786)
95. Pittman AM, Fung H-C, De Silva R. 2006. Untangling the tau gene association with neurodegenerative disorders. Hum. Mol. Genet. 15:R188-95
96. HuttonM, Lendon C, Rizzu P, BakerM, Froelich S, et al. 1998. Association ofmissense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702-5
97. Healy DG, Abou-Sleiman PM, Lees AJ, Casas JP, Quinn N, et al. 2004. Tau gene and Parkinson's disease: a case-control study and meta-analysis. J. Neurol. Neurosurg. Psychiatry 75:962-65 (Pubitemid 38869606)
98. Zabetian CP, Hutter CM, Factor SA, Nutt JG, Higgins DS, et al. 2007. Association analysis of MAPT H1 haplotype and subhaplotypes in Parkinson's disease. Ann. Neurol. 62:137-44 (Pubitemid 47546499)
99. Caffrey TM, Joachim C, Paracchini S, Esiri MM, Wade-Martins R. 2006. Haplotype-specific expression of exon 10 at the human MAPT locus. Hum. Mol. Genet. 15:3529-37 (Pubitemid 44884120)
100. Myers AJ, Pittman AM, Zhao AS, Rohrer K, Kaleem M, et al. 2007. The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts. Neurobiol. Dis. 25:561-70
101. Fung HC, XiromerisiouG,Gibbs JR,Wu YR, Eerola J, et al. 2006. Association of tau haplotype-tagging polymorphisms with Parkinson's disease in diverse ethnic Parkinson's disease cohorts. Neurodegener. Dis. 3:327-33 (Pubitemid 46034209)
102. Maraganore D, de Andrade M, Lesnick T, Strain K, Farrer M, et al. 2005. High-resolution wholegenome association study of Parkinson disease. Am. J. Hum. Genet. 77:685-93 (Pubitemid 41513273)
103. Evangelou E,MaraganoreDM, Ioannidis JPA. 2007. Meta-analysis in genome-wide association datasets: strategies and application in Parkinson disease. PLoS ONE 2:e196
104. Surmeier DJ. 2007. Calcium, ageing, and neuronal vulnerability in Parkinson's disease. Lancet Neurol. 6:933-38 (Pubitemid 47405004)
105. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, et al. 1998. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605-8 (Pubitemid 28207717)
106. Lücking CB, Dürr A, Bonifati V, Vaughan J, De Michele G, et al. 2000. Association between early-onset Parkinson's disease and mutations in the parkin gene. N. Engl. J. Med. 342:1560-67 (Pubitemid 30340501)
107. Periquet M, Latouche M, Lohmann E, Rawal N, De Michele G, et al. 2003. Parkin mutations are frequent in patients with isolated early-onset parkinsonism. Brain 126:1271-78 (Pubitemid 36644374)
108. Khan NL, Graham E, Critchley P, Schrag AE, Wood NW, et al. 2003. Parkin disease: a phenotypic study of a large case series. Brain 126:1279-92 (Pubitemid 36644375)
109. Khan NL, Katzenschlager R, Watt H, Bhatia KP,Wood NW, et al. 2004. Olfaction differentiates parkin disease from early-onset parkinsonism and Parkinson disease. Neurology 62:1224-26 (Pubitemid 38456528)
110. Mori H, Kondo T, Yokochi M, Matsumine H, Nakagawa-Hattori Y, et al. 1998. Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q. Neurology 51:890-92 (Pubitemid 28449284)
111. van de Warrenburg BP, Lammens M, Lücking CB, Denèfle P, Wesseling P, et al. 2001. Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations. Neurology 56:555-57 (Pubitemid 32172889)
112. Farrer M, Chan P, Chen R, Tan L, Lincoln S, et al. 2001. Lewy bodies and parkinsonism in families with parkin mutations. Ann Neurol. 50:293-300 (Pubitemid 32848731)
113. Pramstaller PP, Schlossmacher MG, JacquesTS, Scaravilli F, Eskelson C, et al. 2005. Lewy body Parkinson's disease in a large pedigree with 77 parkin mutation carriers. Ann. Neurol. 58:411-22 (Pubitemid 41266627)
114. Valente EM, Abou-Sleiman PM, Caputo V,Muqit MMK,Harvey K, et al. 2004. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304:1158-60 (Pubitemid 38661852)
115. Bonifati V, Rohé CF, Breedveld GJ, Fabrizio E, De Mari M, et al. 2005. Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology 65:87-95 (Pubitemid 40967781)
116. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, et al. 2003. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256-59 (Pubitemid 36131051)
117. Canet- Avilés RM, Wilson MA, Miller DW, Ahmad R, McLendon C, et al. 2004. The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc. Natl. Acad. Sci. USA 101:9103-8 (Pubitemid 38781618)
118. Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, et al. 2001. Ubiquitination of a new form of α-synuclein by parkin from human brain: implications for Parkinson's disease. Science 293:263-69 (Pubitemid 32694735)
119. Klein C, Lohmann-Hedrich K, Rogaeva E, Schlossmacher M, Lang A. 2007. Deciphering the role of heterozygous mutations in genes associated with parkinsonism. Lancet Neurol. 6:652-62 (Pubitemid 46921058)
120. Hilker R, Klein C, GhaemiM, Kis B, Strotmann T, et al. 2001. Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene. Ann. Neurol. 49:367-76 (Pubitemid 32202791)
121. Abou-Sleiman PM, Muqit MMK, McDonald NQ, Yang YX, Gandhi S, et al. 2006. A heterozygous effect for PINK1 mutations in Parkinson's disease? Ann. Neurol. 60:414-19 (Pubitemid 44684977)
122. KayDM, MoranD,Moses L, Poorkaj P, Zabetian CP, et al. 2007. Heterozygous parkin point mutations are as common in control subjects as in Parkinson's patients. Ann. Neurol. 61:47-54 (Pubitemid 46214243)
123. Lincoln SJ, Maraganore DM, Lesnick TG, Bounds R, de Andrade M, et al. 2003. Parkin variants in North American Parkinson's disease: cases and controls. Mov. Disord. 18:1306-11 (Pubitemid 38263315)
124. Oliveira SA, Scott WK, Nance MA,Watts RL, Hubble JP, et al. 2003. Association study of parkin gene polymorphisms with idiopathic Parkinson disease. Arch. Neurol. 60:975-80 (Pubitemid 36858357)
125. West AB, Maraganore D, Crook J, Lesnick T, Lockhart PJ, et al. 2002. Functional association of the parkin gene promoter with idiopathic Parkinson's disease. Hum. Mol. Genet. 11:2787-92 (Pubitemid 35214904)
126. Ungerstedt U. 1968. 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur. J. Pharmacol. 5:107-10
127. Betarbet R, Sherer T,MacKenzie G, Garcia-Osuna M, Panov A, et al. 2000. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat. Neurosci. 3:1301-6
128. DauerW, Przedborski S. 2003. Parkinson's disease: mechanisms and models. Neuron 39:889-909 (Pubitemid 37130207)
129. Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, et al. 2000. Dopaminergic loss and inclusion body formation in á-synuclein mice: implications for neurodegenerative disorders. Science 287:1265-69 (Pubitemid 30112148)
130. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, et al. 2002. Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron 34:521-33 (Pubitemid 34628750)
131. LeeMK, StirlingW, Xu Y, Xu X,Qui D, et al. 2002. Humanaα-synuclein- harboring familial Parkinson's disease-linked Ala-53→excl;úThr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. Proc. Natl. Acad. Sci. USA 99:8968-73 (Pubitemid 34693667)
132. Kirik D, Rosenblad C, Burger C, Lundberg C, Johansen TE, et al. 2002. Parkinson-like neurodegeneration induced by targeted overexpression of α-synuclein in the nigrostriatal system. J. Neurosci. 22:2780-91 (Pubitemid 37465827)
133. Klein RL, King MA, Hamby ME, Meyer EM. 2002. Dopaminergic cell loss induced by human A30P α-synuclein gene transfer to the rat substantia nigra. Hum. Gene Ther. 13:605-12 (Pubitemid 34264311)
134. Lo Bianco C, Ridet J-L, Schneider BL, Deglon N, Aebischer P. 2002. α-Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson's disease. Proc. Natl. Acad. Sci. USA 99:10813-18
135. Lauwers E, Debyser Z, Van Dorpe J, De Strooper B, Nuttin B, et al. 2003. Neuropathology and neurodegeneration in rodent brain induced by lentiviral vector-mediated overexpression of α-synuclein. Brain Pathol. 13:364-72 (Pubitemid 36975826)
136. Kirik D, Annett LE, Burger C, Muzyczka N, Mandel RJ, et al. 2003. Nigrostriatal α-synucleinopathy induced by viral vector-mediated overexpression of human α-synuclein: a new primate model of Parkinson's disease. Proc. Natl. Acad. Sci. USA 100:2884-89 (Pubitemid 36297593)
137. Lo Bianco C, Schneider BL, Bauer M, Sajadi A, Brice A, et al. 2004. Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an α-synuclein ratmodel of Parkinson's disease. Proc. Natl. Acad. Sci. USA 101:17510-15 (Pubitemid 39657434)
138. von Coelln R, Thomas B, Andrabi SA, Lim KL, Savitt JM, et al. 2006. Inclusion body formation and neurodegeneration are parkin independent in amousemodel ofα-synucleinopathy. J. Neurosci. 26:3685-96
139. Outeiro TF, Lindquist S. 2003. Yeast cells provide insight into α-synuclein biology and pathobiology. Science 302:1772-75 (Pubitemid 37505742)
140. Willingham S, Outeiro TF, DeVit MJ, Lindquist SL, Muchowski PJ. 2003. Yeast genes that enhance the toxicity of a mutant huntingtin fragment or of α-synuclein. Science 302:1769-72 (Pubitemid 37505741)
141. Lakso M, Vartiainen S, Moilanen A, Sirvio J, Thomas J, et al. 2003. Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human α-synuclein. J. Neurochem. 86:165-72 (Pubitemid 36753857)
142. Feany M, BenderW. 2000. A Drosophila model of Parkinson's disease. Nature 404:394-98 (Pubitemid 30164341)
143. Auluck P, Chan H, Trojanowski J,Lee V, Bonini N. 2002. Chaperone suppression of α-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295:865-68 (Pubitemid 34118369)
144. Periquet M, Fulga T, Myllykangas L, Schlossmacher MG, Feany MB. 2007. Aggregated α-synuclein mediates dopaminergic neurotoxicity in vivo. J. Neurosci. 27:3338-46 (Pubitemid 46474139)
145. Chen L, FeanyMB. 2005. α-Synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat. Neurosci. 8:657-63 (Pubitemid 40594208)
146. Chen L, Periquet M,Wang X, Negro A, McLean PJ, et al. 2009. Tyrosine and serine phosphorylation of α-synuclein have opposing effects on neurotoxicity and soluble oligomer formation. J. Clin. Investig. 119:3257-65
147. Karpinar DP, Balija MBG, Kügler S, Opazo F, Rezaei-Ghaleh N, et al. 2009. Pre-fibrillar α-synuclein variants with impaired β-structure increase neurotoxicity in Parkinson's disease models. EMBO J. 28:3256-68
148. HashimotoM, Rockenstein E, ManteM,Mallory M, Masliah E. 2001. β-Synuclein inhibits α-synuclein aggregation: a possible role as an antiparkinsonian factor. Neuron 32:213-23 (Pubitemid 33030190)
149. Lo Bianco C, Shorter J, Régulier E, Lashuel H, Iwatsubo T, et al. 2008. Hsp104 antagonizesα-synuclein aggregation and reduces dopaminergic degeneration in a rat model of Parkinson disease. J. Clin. Investig. 118:3087-97
150. Greene JC, Whitworth AJ, Kuo I, Andrews LA, Feany MB, et al. 2003. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc. Natl. Acad. Sci. USA 100:4078-83 (Pubitemid 36418160)
151. Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, et al. 2006. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441:1162-66 (Pubitemid 43990738)
152. Park J, Lee SB, Lee S, Kim Y, Song S, et al. 2006. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441:1157-61 (Pubitemid 43990737)
153. Deng H, DodsonMW,Huang H,GuoM. 2008. TheParkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc. Natl. Acad. Sci. USA 105:14503-8
154. Poole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ, et al. 2008. The PINK1/parkin pathway regulates mitochondrial morphology. Proc. Natl. Acad. Sci. USA 105:1638-43 (Pubitemid 351346567)
155. Yang Y, Ouyang Y, Yang L, Beal MF,McQuibban A, et al. 2008. Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc. Natl. Acad. Sci. USA 105:7070-75 (Pubitemid 351754531)
156. Kitada T, Tong Y, GautierCA, Shen J. 2009. Absence of nigral degeneration in aged parkin/DJ-1/PINK1 triple knockout mice. J. Neurochem. 111:696-702
157. MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, et al. 2006. The familial parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 52:587-93 (Pubitemid 44781171)
158. Lin X, Parisiadou L, Gu X-L, Wang L, Shim H, et al. 2009. Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant α-synuclein. Neuron 64:807-27
159. Hicks AA, Pétursson H, Jónsson T, Stefánsson H, Jóhannsdóttir HS, et al. 2002. A susceptibility gene for late-onset idiopathic Parkinson's disease. Ann. Neurol. 52:549-55 (Pubitemid 35246857)
160. Pankratz N, NicholsWC, Uniacke SK, Halter C, Rudolph A, et al. 2003. Significant linkage of Parkinson disease to chromosome 2q36-37. Am. J. Hum. Genet. 72:1053-57 (Pubitemid 36403326)
161. Pankratz N, NicholsWC, Uniacke SK, Halter C, Murrell J, et al. 2003. Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families. Hum. Mol. Genet. 12:2599-608 (Pubitemid 37304683)
162. Gasser T, M?uller-Myhsok B, Wszolek ZK, Oehlmann R, Calne DB, et al. 1998. A susceptibility locus for Parkinson's disease maps to chromosome 2p13. Nat. Genet. 18:262-65 (Pubitemid 28117265)
163. Ramirez A, Heimbach A, Gründemann J, Stiller B, Hampshire D, et al. 2006. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat. Genet. 38:1184-91 (Pubitemid 44470365)
164. Shojaee S, Sina F, Banihosseini SS, Kazemi MH, Kalhor R, et al. 2008. Genome-wide linkage analysis of a Parkinsonian-pyramidal syndrome pedigree by 500 K SNP arrays. Am. J. Hum. Genet. 82:1375-84
165. Morgan NV, Westaway SK, Morton JEV, Gregory A, Gissen P, et al. 2006. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat. Genet. 38:752-54 (Pubitemid 43980594)
166. Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, et al. 2001. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat. Genet. 28:345-49 (Pubitemid 32702423)
167. Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW. 1993. TheWilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat. Genet. 5:327-37 (Pubitemid 23351302)
168. BakerM,Mackenzie I, Pickering-Brown S, Gass J, Rademakers R, et al. 2006. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916-19 (Pubitemid 44285946)
169. CrutsM, Gijselinck I, van der Zee J, Engelborghs S,Wils H, et al. 2006. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920-24 (Pubitemid 44285947)
170. Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, et al. 1996. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat. Genet. 14:269-76
171. Ichinose H, Ohye T, Takahashi E, Seki N, Hori T, et al. 1994. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat. Genet. 8:236-42 (Pubitemid 24338734)