Hostname: page-component-8448b6f56d-t5pn6 Total loading time: 0 Render date: 2024-04-19T21:50:11.868Z Has data issue: false hasContentIssue false
  • English
  • Français

Molecular pathogenesis of Parkinson disease: insights from genetic studies

Published online by Cambridge University Press:  27 July 2009

Thomas Gasser
Thomas Gasser
Affiliation:
Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler Str. 3, 72076 Tübingen, Germany. Tel: +49 7071 29 86529; Fax: +49 7071 29 4839; E-mail: thomas.gasser@med.uni-tuebingen.de
Get access Rights & Permissions [Opens in a new window]

Abstract

Over the past few years, genetic findings have changed our views on the molecular pathogenesis of Parkinson disease (PD), as mutations in a growing number of genes have been found to cause monogenic forms of the disorder. These mutations cause neuronal dysfunction and neurodegeneration either by a toxic gain of function, as in the case of the dominant forms of monogenic PD caused by mutations in the genes for α-synuclein or LRRK2, or by a loss of an intrinsic protective function, as is likely for the recessive PD genes parkin (PRKN), PINK1 and DJ-1. Evidence is emerging that at least some of the pathways uncovered in the rare monogenic forms of PD may play a direct role in the aetiology of the common sporadic disorder and that variants of the respective genes contribute to the risk of developing the disease. These findings will allow the search for new treatment strategies that focus on the underlying molecular pathophysiology, rather than simply on ameliorating symptoms.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 11 , July 2009 , e22
Copyright
Copyright © Cambridge University Press 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Poewe, W. (2009) Treatments for Parkinson disease–past achievements and current clinical needs. Neurology 72, S65-73CrossRefGoogle ScholarPubMed
2Duvoisin, R.C. (1987) Genetics of Parkinson's disease. Advances in Neurology 45, 307-312Google ScholarPubMed
3Gasser, T. (2007) Update on the genetics of Parkinson's disease. Movement Disorders 22 (Suppl 17), S343-350CrossRefGoogle ScholarPubMed
4Farrer, M.J. et al. (2007) Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia. Parkinsonism & Related Disorders 13, 89-92Google Scholar
5Polymeropoulos, M.H. et al. (1997) Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045-2047CrossRefGoogle ScholarPubMed
6Krüger, R. et al. (1998) Ala30Pro mutation in the gene encoding a-synuclein in Parkinson's disease. Nature Genetics 18, 106-108CrossRefGoogle Scholar
7Zarranz, J.J. et al. (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Annals of Neurology 55, 164-173CrossRefGoogle ScholarPubMed
8Berg, D. et al. (2005) Alpha-synuclein and Parkinson's disease: implications from the screening of more than 1,900 patients. Movement Disorders 20, 1191-1194CrossRefGoogle Scholar
9Golbe, L.I. et al. (1996) Clinical genetic analysis of Parkinson's disease in the Contursi kindred. Annals of Neurology 40, 767-775CrossRefGoogle ScholarPubMed
10Duda, J.E. et al. (2002) Concurrence of alpha-synuclein and tau brain pathology in the Contursi kindred. Acta Neuropathologica 104, 7-11Google Scholar
11Spillantini, M.G. et al. (1997) Alpha-synuclein in Lewy bodies. Nature 388, 839-840Google Scholar
12Goedert, M., Spillantini, M.G. and Davies, S.W. (1998) Filamentous nerve cell inclusions in neurodegenerative diseases. Current Opinion in Neurobiology 8, 619-632CrossRefGoogle ScholarPubMed
13Cookson, M.R. and van der Brug, M. (2007) Cell systems and the toxic mechanism(s) of alpha-synuclein. Experimental Neurology 209, 5-11CrossRefGoogle ScholarPubMed
14Singleton, A.B. et al. (2003) alpha-Synuclein locus triplication causes Parkinson's disease. Science 302, 841CrossRefGoogle ScholarPubMed
15Ibanez, P. et al. (2004) Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease. Lancet 364, 1169-1171CrossRefGoogle ScholarPubMed
16Miller, D.W. et al. (2004) Alpha-synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication. Neurology 62, 1835-1838CrossRefGoogle ScholarPubMed
17Chartier-Harlin, M.C. et al. (2004) Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364, 1167-1169CrossRefGoogle ScholarPubMed
18Jensen, P.H. et al. (1998) Binding of alpha-synuclein to brain vesicles is abolished by familial Parkinson's disease mutation. Journal of Biological Chemistry 273, 26292-26294CrossRefGoogle ScholarPubMed
19Abeliovich, A. et al. (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25, 239-252CrossRefGoogle ScholarPubMed
20Engelender, S. et al. (1999) Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nature Genetics 22, 110-114Google Scholar
21Masliah, E. et al. (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287, 1265-1269Google Scholar
22Kahle, P.J. et al. (2000) Subcellular localization of wild-type and Parkinson's disease-associated mutant alpha-synuclein in human and transgenic mouse brain. Journal of Neuroscience 20, 6365-6373CrossRefGoogle ScholarPubMed
23Feany, M.B. and Bender, W.W. (2000) A Drosophila model of Parkinson's disease. Nature 404, 394-398Google Scholar
24Greene, J.C. et al. (2003) Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proceedings of the National Academy of Sciences of the United States of America 100, 4078-4083Google Scholar
25Auluck, P.K. et al. (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295, 865-868CrossRefGoogle Scholar
26Funayama, M. et al. (2002) A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Annals of Neurology 51, 296-301CrossRefGoogle ScholarPubMed
27Zimprich, A. et al. (2004) Mutations in LRRK2 cause autosomal-dominant Parkinsonism with pleomorphic pathology. Neuron 44, 601-607CrossRefGoogle ScholarPubMed
28Paisan-Ruiz, C. et al. (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44, 595-600Google Scholar
29Di Fonzo, A. et al. (2006) Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease. European Journal of Human Genetics 14, 322-331CrossRefGoogle ScholarPubMed
30Berg, D. et al. (2005) Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease*. Brain 128, 3000-3011CrossRefGoogle ScholarPubMed
31Nichols, W.C. et al. (2005) Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet 365, 410-412Google Scholar
32Di Fonzo, A. et al. (2005) A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet 365, 412-415CrossRefGoogle ScholarPubMed
33Kachergus, J. et al. (2005) Identification of a novel LRRK2 mutation linked to autosomal dominant Parkinsonism: evidence of a common founder across European populations. American Journal of Human Genetics 76, 672-680CrossRefGoogle ScholarPubMed
34Gilks, W.P. et al. (2005) A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 365, 415-416Google ScholarPubMed
35Ozelius, L.J. et al. (2006) LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. New England Journal of Medicine 354, 424-425CrossRefGoogle ScholarPubMed
36Lesage, S. et al. (2006) LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. New England Journal of Medicine 354, 422-423CrossRefGoogle ScholarPubMed
37Goldwurm, S. et al. (2007) Evaluation of LRRK2 G2019S penetrance: relevance for genetic counseling in Parkinson disease. Neurology 68, 1141-1143CrossRefGoogle ScholarPubMed
38Di Fonzo, A. et al. (2006) A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan. Neurogenetics 7, 133-138Google Scholar
39Tan, E.K. et al. (2007) The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence. Human Genetics 120, 857-863Google Scholar
40Funayama, M. et al. (2007) Leucine-rich repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population. Neuroreport 18, 273-275CrossRefGoogle ScholarPubMed
41Gloeckner, C.J. et al. (2006) The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Human Molecular Genetics 15, 223-232CrossRefGoogle ScholarPubMed
42Greggio, E. et al. (2007) Mutations in LRRK2/dardarin associated with Parkinson disease are more toxic than equivalent mutations in the homologous kinase LRRK1. Journal of Neurochemistry 102, 93-102Google Scholar
43Mata, I.F. et al. (2005) Lrrk2 pathogenic substitutions in Parkinson's disease. Neurogenetics 6, 171-177CrossRefGoogle ScholarPubMed
44Bras, J.M. et al. (2005) G2019s dardarin substitution is a common cause of Parkinson's disease in a Portuguese cohort. Movement Disorders 20, 1653-1655CrossRefGoogle Scholar
45Healy, D.G. et al. (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurology 7, 583-590CrossRefGoogle ScholarPubMed
46Dachsel, J.C. et al. (2006) Digenic parkinsonism: investigation of the synergistic effects of PRKN and LRRK2. Neuroscience Letters 410, 80-84CrossRefGoogle ScholarPubMed
47Bosgraaf, L. and Van Haastert, P.J. (2003) Roc, a Ras/GTPase domain in complex proteins. Biochimica et Biophysica Acta 1643, 5-10CrossRefGoogle Scholar
48Smith, W.W. et al. (2005) Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proceedings of the National Academy of Sciences of the United States of America 102, 18676-18681Google Scholar
49West, A.B. et al. (2007) Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Human Molecular Genetics 16, 223-232CrossRefGoogle ScholarPubMed
50Greggio, E. et al. (2006) Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiology of Disease 23, 329-341CrossRefGoogle ScholarPubMed
51Ross, O.A. et al. (2006) Lrrk2 and Lewy body disease. Annals of Neurology 59, 388-393CrossRefGoogle ScholarPubMed
52Dachsel, J.C. et al. (2007) Lrrk2 G2019S substitution in frontotemporal lobar degeneration with ubiquitin-immunoreactive neuronal inclusions. Acta Neuropathologica 113, 601-606CrossRefGoogle ScholarPubMed
53Aharon-Peretz, J., Rosenbaum, H. and Gershoni-Baruch, R. (2004) Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. New England Journal of Medicine 351, 1972-1977CrossRefGoogle ScholarPubMed
54Mata, I.F. et al. (2008) Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Archives of Neurology 65, 379-382Google Scholar
55De Marco, E.V. et al. (2008) Glucocerebrosidase gene mutations are associated with Parkinson's disease in southern Italy. Movement Disorders 23, 460-463CrossRefGoogle ScholarPubMed
56Ziegler, S.G. et al. (2007) Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease. Molecular Genetics and Metabolism 91, 195-200Google Scholar
57Goker-Alpan, O. et al. (2006) Glucocerebrosidase mutations are an important risk factor for Lewy body disorders. Neurology 67, 908-910CrossRefGoogle ScholarPubMed
58Ishikawa, A. and Tsuji, S. (1996) Clinical analysis of 17 patients in 12 Japanese families with autosomal-recessive type juvenile parkinsonism. Neurology 47, 160-166CrossRefGoogle ScholarPubMed
59Ichinose, H. et al. (1994) Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nature Genetics 8, 236-242CrossRefGoogle ScholarPubMed
60Matsumine, H. et al. (1997) Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27. American Journal of Human Genetics 60, 588-596Google ScholarPubMed
61Kitada, T. et al. (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605-608Google Scholar
62Hattori, N. et al. (1998) Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the Parkin gene in affected individuals. Annals of Neurology 44, 935-941CrossRefGoogle Scholar
63Lücking, C.B. et al. (1998) Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism. The European Consortium on Genetic Susceptibility in Parkinson's Disease and the French Parkinson's Disease Genetics Study Group. Lancet 352, 1355-1356CrossRefGoogle Scholar
64Abbas, N. et al. (1999) A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. Human Molecular Genetics 8, 567-574CrossRefGoogle Scholar
65Lücking, C.B. et al. (2000) Association between Early-Onset Parkinson's Disease and Mutations in the Parkin Gene. New England Journal of Medicine 342, 1560-1567CrossRefGoogle ScholarPubMed
66Hedrich, K. et al. (2004) Distribution, type, and origin of Parkin mutations: review and case studies. Movement Disorders 19, 1146-1157Google Scholar
67Lücking, C.B. et al. (2001) Pseudo-dominant inheritance and exon 2 triplication in a family with parkin gene mutations. Neurology 57, 924-927Google Scholar
68Periquet, M. et al. (2003) Parkin mutations are frequent in patients with isolated early-onset parkinsonism. Brain 126, 1271-1278CrossRefGoogle ScholarPubMed
69Periquet, M. et al. (2001) Origin of the Mutations in the parkin Gene in Europe: Exon Rearrangements Are Independent Recurrent Events, whereas Point Mutations May Result from Founder Effects. American Journal of Human Genetics 68, 617-626Google Scholar
70Klein, C. et al. (2000) Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype. Annals of Neurology 48, 65-713.0.CO;2-L>CrossRefGoogle Scholar
71Valente, E.M. et al. (2004) Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158-1160Google Scholar
72Valente, E.M. et al. (2004) PINK1 mutations are associated with sporadic early-onset parkinsonism. Annals of Neurology 56, 336-341CrossRefGoogle ScholarPubMed
73Hatano, Y. et al. (2004) Novel PINK1 mutations in early-onset parkinsonism. Annals of Neurology 56, 424-427Google Scholar
74Bonifati, V. et al. (2005) Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology 65, 87-95CrossRefGoogle ScholarPubMed
75Hedrich, K. et al. (2006) Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit? Archives of Neurology 63, 833-838Google Scholar
76Prestel, J. et al. (2008) Clinical and molecular characterisation of a Parkinson family with a novel PINK1 mutation. Journal of Neurology 255, 643-648CrossRefGoogle ScholarPubMed
77Marongiu, R. et al. (2007) Whole gene deletion and splicing mutations expand the PINK1 genotypic spectrum. Human Mutation 28, 98CrossRefGoogle ScholarPubMed
78Albanese, A. et al. (2005) The PINK1 phenotype can be indistinguishable from idiopathic Parkinson disease. Neurology 64 1958-1960CrossRefGoogle ScholarPubMed
79Ephraty, L. et al. (2007) Neuropsychiatric and cognitive features in autosomal-recessive early parkinsonism due to PINK1 mutations. Movement Disorders 22, 566-569CrossRefGoogle ScholarPubMed
80van Duijn, C.M. et al. (2001) Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. American Journal of Human Genetics 69, 629-634Google Scholar
81Bonifati, V. et al. (2002) Mutations in the DJ-1 gene associated with autosomal recessive early-onset Parkinsonism. Science 299, 256-259Google Scholar
82Abou-Sleiman, P.M. et al. (2003) The role of pathogenic DJ-1 mutations in Parkinson's disease. Annals of Neurology 54, 283-286CrossRefGoogle ScholarPubMed
83Hering, R. et al. (2004) Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7). Human Mutation 24, 321-329CrossRefGoogle ScholarPubMed
84Annesi, G. et al. (2005) DJ-1 mutations and parkinsonism-dementia-amyotrophic lateral sclerosis complex. Annals of Neurology 58, 803-807Google Scholar
85Takahashi, H. et al. (1994) Familial juvenile parkinsonism: clinical and pathologic study in a family. Neurology 44, 437-441CrossRefGoogle ScholarPubMed
86van De Warrenburg, B.P. et al. (2001) Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations. Neurology 56, 555-557CrossRefGoogle Scholar
87Mori, H. et al. (1998) Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q. Neurology 51, 890-892Google Scholar
88Farrer, M. et al. (2001) Lewy bodies and parkinsonism in families with parkin mutations. Annals of Neurology 50, 293-300CrossRefGoogle ScholarPubMed
89Pramstaller, P.P. et al. (2005) Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers. Annals of Neurology 58, 411-422CrossRefGoogle Scholar
90Shimura, H. et al. (2000) Familial parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nature Genetics 25, 302-305CrossRefGoogle ScholarPubMed
91Chung, K.K. et al. (2001) Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nature Medicine 7, 1144-1150CrossRefGoogle ScholarPubMed
92Imai, Y. et al. (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105, 891-902CrossRefGoogle ScholarPubMed
93Zhang, Y. et al. (2000) Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proceedings of the National Academy of Sciences of the United States of America 97, 13354-13359Google Scholar
94Joch, M. et al. (2007) Parkin-mediated monoubiquitination of the PDZ protein PICK1 regulates the activity of acid-sensing ion channels. Molecular Biology of the Cell 18, 3105-3118CrossRefGoogle ScholarPubMed
95Schapira, A.H. (2008) Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurology 7, 97-109CrossRefGoogle ScholarPubMed
96Kuroda, Y. et al. (2006) Parkin enhances mitochondrial biogenesis in proliferating cells. Human Molecular Genetics 15, 883-895CrossRefGoogle ScholarPubMed
97Palacino, J.J. et al. (2004) Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. Journal of Biological Chemistry 279, 18614-18622Google Scholar
98Stichel, C.C. et al. (2007) Mono- and double-mutant mouse models of Parkinson's disease display severe mitochondrial damage. Human Molecular Genetics 16, 2377-2393CrossRefGoogle ScholarPubMed
99Yang, Y. et al. (2006) Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proceedings of the National Academy of Sciences of the United States of America 103, 10793-10798CrossRefGoogle ScholarPubMed
100Mortiboys, H. et al. (2008) Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Annals of Neurology 64, 555-565CrossRefGoogle ScholarPubMed
101Hoepken, H.H. et al. (2007) Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. Neurobiology of Disease 25, 401-411Google Scholar
102Poole, A.C. et al. (2008) The PINK1/Parkin pathway regulates mitochondrial morphology. Proceedings of the National Academy of Sciences of the United States of America 105, 1638-1643Google Scholar
103Lev, N. et al. (2006) Role of DJ-1 in Parkinson's disease. Journal of Molecular Neuroscience 29, 215-225CrossRefGoogle ScholarPubMed
104Canet-Aviles, R.M. et al. (2004) The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proceedings of the National Academy of Sciences of the United States of America 101, 9103-9108CrossRefGoogle ScholarPubMed
105Xiong, H. et al. (2009) Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation. Journal of Clinical Investigation 119, 650-660CrossRefGoogle Scholar
106Najim al Din, A.S. et al. (1994) Pallido-pyramidal degeneration, supranuclear upgaze paresis and dementia: Kufor-Rakeb syndrome. Acta Neurologica Scandinavica 89, 347-352Google Scholar
107Ramirez, A. et al. (2006) Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nature Genetics 38, 1184-1191CrossRefGoogle ScholarPubMed
108Vilarino-Guell, C. et al. (2009) ATP13A2 variability in Parkinson disease. Human Mutation 30, 406-410Google Scholar
109Morgan, N.V. et al. (2006) PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nature Genetics 38, 752-754Google Scholar
110Paisan-Ruiz, C. et al. (2009) Characterization of PLA2G6 as a locus for dystonia-parkinsonism. Annals of Neurology 65, 19-23CrossRefGoogle ScholarPubMed
111Di Fonzo, A. et al. (2009) FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology 72, 240-245Google Scholar
112Gasser, T. et al. (1998) A susceptibility locus for Parkinson's disease maps to chromosome 2p13. Nature Genetics 18, 262-265Google Scholar
113DeStefano, A.L. et al. (2002) PARK3 influences age at onset in Parkinson disease: a genome scan in the GenePD study. American Journal of Human Genetics 70, 1089-1095CrossRefGoogle ScholarPubMed
114Pankratz, N. et al. (2004) Genes influencing Parkinson disease onset: replication of PARK3 and identification of novel loci. Neurology 62, 1616-1618Google Scholar
115Karamohamed, S. et al. (2003) A haplotype at the PARK3 locus influences onset age for Parkinson's disease: the GenePD study. Neurology 61, 1557-1561CrossRefGoogle ScholarPubMed
116Sharma, M. et al. (2006) The sepiapterin reductase gene region reveals association in the PARK3 locus: analysis of familial and sporadic Parkinson's disease in European populations. Journal of Medical Genetics 43, 557-562CrossRefGoogle ScholarPubMed
117Leroy, E. et al. (1998) The ubiquitin pathway in Parkinson's disease. Nature 395, 451-452CrossRefGoogle ScholarPubMed
118Maraganore, D.M. et al. (2004) UCHL1 is a Parkinson's disease susceptibility gene. Annals of Neurology 55, 512-521Google Scholar
119Hicks, A.A. et al. (2002) A susceptibility gene for late-onset idiopathic Parkinson's disease. Annals of Neurology 52, 549-555CrossRefGoogle ScholarPubMed
120Pankratz, N. et al. (2003) Significant linkage of Parkinson disease to chromosome 2q36-37. American Journal of Human Genetics 72, 1053-1057CrossRefGoogle ScholarPubMed
121Prestel, J. et al. (2005) PARK11 is not linked with Parkinson's disease in European families. European Journal of Human Genetics 13, 193-197Google Scholar
122Lautier, C. et al. (2008) Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease. American Journal of Human Genetics 82, 822-833CrossRefGoogle ScholarPubMed
123Bras, J. et al. (2008) Lack of replication of association between GIGYF2 variants and Parkinson disease. Human Molecular Genetics 18, 341-346CrossRefGoogle ScholarPubMed
124Nichols, W.C. et al. (2009) Variation in GIGYF2 is not associated with Parkinson disease. Neurology 72, 1886-92CrossRefGoogle Scholar
125Zimprich, A. et al. (2009) PARK11 gene (GIGYF2) variants Asn56Ser and Asn457Thr are not pathogenic for Parkinson's disease. Parkinsonism & Related Disorders Feb 26; [Epub ahead of print]Google Scholar
126Strauss, K.M. et al. (2005) Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Human Molecular Genetics 14, 2099-2111Google Scholar
127Maraganore, D.M. et al. (2006) Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA: the Journal of the American Medical Association 296, 661-670CrossRefGoogle ScholarPubMed
128Mueller, J.C. et al. (2005) Multiple regions of alpha-synuclein are associated with Parkinson's disease. Annals of Neurology 57, 535-541Google Scholar
129Mizuta, I. et al. (2006) Multiple candidate gene analysis identifies {alpha}-synuclein as a susceptibility gene for sporadic Parkinson's disease. Human Molecular Genetics 15, 1151-1158Google Scholar
130Goris, A. et al. (2007) Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson's disease. Annals of Neurology 62, 145-153CrossRefGoogle ScholarPubMed
131Winkler, S. et al. (2007) alpha-Synuclein and Parkinson disease susceptibility. Neurology 69, 1745-1750CrossRefGoogle ScholarPubMed
132Ross, O.A. et al. (2007) Familial genes in sporadic disease: common variants of alpha-synuclein gene associate with Parkinson's disease. Mechanisms of Ageing and Development 128, 378-382CrossRefGoogle ScholarPubMed
133Myhre, R. et al. (2008) Multiple alpha-synuclein gene polymorphisms are associated with Parkinson's disease in a Norwegian population. Acta Neurologica Scandinavica 118, 320-327Google Scholar
134Pankratz, N. et al. (2009) Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Human Genetics 124, 593-605Google Scholar
135Fuchs, J. et al. (2008) Genetic variability in the SNCA gene influences alpha-synuclein levels in the blood and brain. FASEB Journal 22, 1327-1334Google Scholar
136Healy, D.G. et al. (2004) Tau gene and Parkinson's disease: a case-control study and meta-analysis. Journal of Neurology Neurosurgery and Psychiatry 75, 962-965CrossRefGoogle ScholarPubMed
137Martin, E.R. et al. (2001) Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease. JAMA: the Journal of the American Medical Association 286, 2245-2250CrossRefGoogle ScholarPubMed
138Skipper, L. et al. (2004) Linkage disequilibrium and association of MAPT H1 in Parkinson disease. American Journal of Human Genetics 75, 669-677Google Scholar
139de Silva, R. et al. (2002) The tau locus is not significantly associated with pathologically confirmed sporadic Parkinson's disease. Neuroscience Letters 330, 201-203Google Scholar
140Wenning, G.K. and Jellinger, K.A. (2005) The role of alpha-synuclein and tau in neurodegenerative movement disorders. Current Opinion in Neurology 18, 357-362Google Scholar
141Arima, K. et al. (1999) Cellular co-localization of phosphorylated tau- and NACP/alpha- synuclein-epitopes in lewy bodies in sporadic Parkinson's disease and in dementia with lewy bodies. Brain Research 843, 53-61Google Scholar
142Galpern, W.R. and Lang, A.E. (2006) Interface between tauopathies and synucleinopathies: a tale of two proteins. Annals of Neurology 59, 449-458Google Scholar
143Khan, N.L. et al. (2002) Progression of nigrostriatal dysfunction in a parkin kindred: an [18F]dopa PET and clinical study. Brain 125, 2248-2256CrossRefGoogle Scholar
144Hilker, R. et al. (2001) Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene. Annals of Neurology 49, 367-376Google Scholar
145Pramstaller, P.P. et al. (2002) Phenotypic variability in a large kindred (Family LA) with deletions in the parkin gene. Movement Disorders 17, 424-426Google Scholar
146Lincoln, S.J. et al. (2003) Parkin variants in North American Parkinson's disease: cases and controls. Movement Disorders 18, 1306-1311CrossRefGoogle ScholarPubMed
147Kay, D.M. et al. (2007) Heterozygous parkin point mutations are as common in control subjects as in Parkinson's patients. Annals of Neurology 61, 47-54Google Scholar
148Chiba-Falek, O. et al. (2005) Regulation of alpha-synuclein expression by poly (ADP ribose) polymerase-1 (PARP-1) binding to the NACP-Rep1 polymorphic site upstream of the SNCA gene. American Journal of Human Genetics 76, 478-492CrossRefGoogle Scholar
149Higashi, S. et al. (2007) Localization of Parkinson's disease-associated LRRK2 in normal and pathological human brain. Brain Research 1155, 208-219Google Scholar

Further reading, resources and contacts

The Michael J. Fox Foundation is a private organisation funding and supporting Parkinson disease research: http://www.michaeljfox.org/

The PD-Gene database aims to provide an unbiased, centralised, publicly available and regularly updated collection of genetic association studies in Parkinson disease: http://www.pdgene.org

The European Parkinson's Disease Association (EPDA) is a concerned with the health and welfare of people living with Parkinson disease and their families and carers: http://www.epda.eu.com/

Healy, D.G. et al. (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurology 7, 583-590CrossRefGoogle ScholarPubMed
Gupta, A., Dawson, V.L. and Dawson, T.M. (2008) What causes cell death in Parkinson's disease? Annals of Neurology 64 Suppl 2, S3-15Google Scholar
Hardy, J. (2005) Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: ‘permissive templating’ as a general mechanism underlying neurodegeneration. Biochemical Society Transactions 33, 578-581CrossRefGoogle ScholarPubMed
Healy, D.G. et al. (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurology 7, 583-590CrossRefGoogle ScholarPubMed
Gupta, A., Dawson, V.L. and Dawson, T.M. (2008) What causes cell death in Parkinson's disease? Annals of Neurology 64 Suppl 2, S3-15Google Scholar
Hardy, J. (2005) Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: ‘permissive templating’ as a general mechanism underlying neurodegeneration. Biochemical Society Transactions 33, 578-581CrossRefGoogle ScholarPubMed