Hostname: page-component-586b7cd67f-gb8f7 Total loading time: 0 Render date: 2024-11-25T09:28:50.127Z Has data issue: false hasContentIssue false

Role of LRRK2 kinase dysfunction in Parkinson disease

Published online by Cambridge University Press:  13 June 2011

Azad Kumar
Affiliation:
Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Mark R. Cookson*
Affiliation:
Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
*
*Corresponding author: Mark R. Cookson, Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, MD 20892-3707, USA. E-mail: [email protected]

Abstract

Parkinson disease is a common and usually sporadic neurodegenerative disorder. However, a subset of cases are inherited and, of these, mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most frequent genetic cause of disease. Here, we will discuss recent progress in understanding how LRRK2 mutations lead to disease and how this might have therapeutic implications. The effect of mutations on LRRK2 enzyme function provides clues as to which functions of the protein are important to disease. Recent work has focused on the kinase and GTP-binding domains of LRRK2, and it is assumed that these will be therapeutically important, although there is a substantial amount of work to be done to address this hypothesis.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2011. This is a work of the US Government and is not subject to copyright protection in the USA

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

1Cookson, M.R. (2005) The biochemistry of Parkinson's disease. Annual Reviews of Biochemistry 74, 29-52CrossRefGoogle ScholarPubMed
2Cookson, M.R. and Bandmann, O. (2010) Parkinson's disease: insights from pathways. Human Molecular Genetics 19, R21-R27CrossRefGoogle ScholarPubMed
3Hardy, J. (2010) Genetic analysis of pathways to Parkinson disease. Neuron 68, 201-206CrossRefGoogle ScholarPubMed
4Cookson, M.R. (2010) The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nature Reviews. Neuroscience 11, 791-797CrossRefGoogle ScholarPubMed
5Taymans, J.M. and Cookson, M.R. (2010) Mechanisms in dominant parkinsonism: the toxic triangle of LRRK2, alpha-synuclein, and tau. Bioessays 32, 227-235CrossRefGoogle ScholarPubMed
6Manning, G. et al. (2002) The protein kinase complement of the human genome. Science 298, 1912-1934CrossRefGoogle ScholarPubMed
7Marin, I., van Egmond, W.N. and van Haastert, P.J. (2008) The Roco protein family: a functional perspective. FASEB Journal 22, 3103-3110CrossRefGoogle Scholar
8Gotthardt, K. et al. (2008) Structure of the Roc-COR domain tandem of C. tepidum, a prokaryotic homologue of the human LRRK2 Parkinson kinase. EMBO Journal 27, 2239-2249CrossRefGoogle ScholarPubMed
9Berger, Z., Smith, K.A. and Lavoie, M.J. (2010) Membrane localization of LRRK2 is associated with increased formation of the highly active LRRK2 dimer and changes in its phosphorylation. Biochemistry 49, 5511-5523CrossRefGoogle ScholarPubMed
10Dzamko, N. et al. (2010) Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14–3–3 binding and altered cytoplasmic localization. Biochemical Journal 430, 405-413CrossRefGoogle Scholar
11Giasson, B.I. et al. (2006) Biochemical and pathological characterization of Lrrk2. Annals of Neurology 59, 315-322CrossRefGoogle ScholarPubMed
12Greggio, E. et al. (2006) Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiology of Disease 23, 329-341CrossRefGoogle ScholarPubMed
13Nichols, R.J. et al. (2010) 14–3–3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization. Biochemical Journal 430, 393-404CrossRefGoogle ScholarPubMed
14West, A.B. et al. (2005) Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proceedings of the National Academy of Sciences of the United States of America 102, 16842-16847CrossRefGoogle ScholarPubMed
15Deng, J. et al. (2008) Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase. Proceedings of the National Academy of Sciences of the United States of America 105, 1499-1504CrossRefGoogle ScholarPubMed
16Guo, L. et al. (2007) The Parkinson's disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase that stimulates kinase activity. Experimental Cell Research 313, 3658-3670CrossRefGoogle ScholarPubMed
17Lewis, P.A. et al. (2007) The R1441C mutation of LRRK2 disrupts GTP hydrolysis. Biochemical and Biophysical Research Communications 357, 668-671CrossRefGoogle ScholarPubMed
18Li, X. et al. (2007) Leucine-rich repeat kinase 2 (LRRK2)/PARK8 possesses GTPase activity that is altered in familial Parkinson's disease R1441C/G mutants. Journal of Neurochemistry 103, 238-247CrossRefGoogle ScholarPubMed
19Ito, G. et al. (2007) GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease. Biochemistry 46, 1380-1388CrossRefGoogle Scholar
20Liu, M. et al. (2010) Kinetic mechanistic studies of wild-type leucine-rich repeat kinase 2: characterization of the kinase and GTPase activities. Biochemistry 49, 2008-2017CrossRefGoogle ScholarPubMed
21Gloeckner, C.J. et al. (2010) Phosphopeptide analysis reveals two discrete clusters of phosphorylation in the N-terminus and the Roc domain of the Parkinson-disease associated protein kinase LRRK2. Journal of Proteome Research 9, 1738-1745CrossRefGoogle ScholarPubMed
22Greggio, E. et al. (2009) The Parkinson's disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites. Biochemical and Biophysical Research Communications 389, 449-454CrossRefGoogle ScholarPubMed
23Kamikawaji, S., Ito, G. and Iwatsubo, T. (2009) Identification of the autophosphorylation sites of LRRK2. Biochemistry 48, 10963-10975CrossRefGoogle ScholarPubMed
24Pungaliya, P.P. et al. (2010) Identification and characterization of a leucine-rich repeat kinase 2 (LRRK2) consensus phosphorylation motif. PLoS One 5, e13672CrossRefGoogle ScholarPubMed
25Greggio, E. et al. (2008) The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. Journal of Biological Chemistry 283, 16906-16914CrossRefGoogle ScholarPubMed
26Jorgensen, N.D. et al. (2009) The WD40 domain is required for LRRK2 neurotoxicity. PLoS One 4, e8463CrossRefGoogle ScholarPubMed
27Klein, C.L. et al. (2009) Homo- and heterodimerization of ROCO kinases: LRRK2 kinase inhibition by the LRRK2 ROCO fragment. Journal of Neurochemistry 111, 703-715CrossRefGoogle ScholarPubMed
28Ko, H.S. et al. (2009) CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity. Proceedings of the National Academy of Sciences of the United States of America 106, 2897-2902CrossRefGoogle ScholarPubMed
29Lu, B. et al. (2010) Expression, purification and preliminary biochemical studies of the N-terminal domain of leucine-rich repeat kinase 2. Biochimica et Biophysica Acta 1804, 1780-1784CrossRefGoogle ScholarPubMed
30Sen, S., Webber, P.J. and West, A.B. (2009) Dependence of leucine-rich repeat kinase 2 (LRRK2) kinase activity on dimerization. Journal of Biological Chemistry 284, 36346-36356CrossRefGoogle ScholarPubMed
31Alegre-Abarrategui, J. et al. (2009) LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Human Molecular Genetics 18, 4022-4034CrossRefGoogle Scholar
32Hatano, T. et al. (2007) Leucine-rich repeat kinase 2 associates with lipid rafts. Human Molecular Genetics 16, 678-690CrossRefGoogle ScholarPubMed
33Miklossy, J. et al. (2006) LRRK2 expression in normal and pathologic human brain and in human cell lines. Journal of Neuropathology and Experimental Neurology 65, 953-963CrossRefGoogle ScholarPubMed
34Biskup, S. et al. (2006) Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Annals of Neurology 60, 557-569CrossRefGoogle ScholarPubMed
35Higashi, S. et al. (2009) Abnormal localization of leucine-rich repeat kinase 2 to the endosomal-lysosomal compartment in lewy body disease. Journal of Neuropathology and Experimental Neurology 68, 994-1005CrossRefGoogle Scholar
36Funayama, 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
37Paisan-Ruiz, C. et al. (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44, 595-600CrossRefGoogle ScholarPubMed
38Zimprich, A. et al. (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601-607CrossRefGoogle ScholarPubMed
39Funayama, M. et al. (2005) An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. Annals of Neurology 57, 918-921CrossRefGoogle ScholarPubMed
40Gilks, W.P. et al. (2005) A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 365, 415-416Google ScholarPubMed
41Goldwurm, S. 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. Journal of Medical Genetics 42, e65CrossRefGoogle ScholarPubMed
42Infante, J. et al. (2006) LRRK2 G2019S is a common mutation in Spanish patients with late-onset Parkinson's disease. Neuroscience Letters 395, 224-226CrossRefGoogle ScholarPubMed
43Kachergus, 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
44Lesage, 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
45Lesage, S. et al. (2005) G2019S LRRK2 mutation in French and North African families with Parkinson's disease. Annals of Neurology 58, 784-787CrossRefGoogle ScholarPubMed
46Lesage, S. et al. (2005) LRRK2 haplotype analyses in European and North African families with Parkinson disease: a common founder for the G2019S mutation dating from the 13th century. American Journal of Human Genetics 77, 330-332CrossRefGoogle ScholarPubMed
47Ozelius, 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
48Rajput, A. et al. (2006) Parkinsonism, Lrrk2 G2019S, and tau neuropathology. Neurology 67, 1506-1508CrossRefGoogle ScholarPubMed
49Kumari, U. and Tan, E.K. (2009) LRRK2 in Parkinson's disease: genetic and clinical studies from patients. FEBS Journal 276, 6455-6463CrossRefGoogle ScholarPubMed
50Greggio, E. and Cookson, M.R. (2009) Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions. ASN Neuro 1, e0002CrossRefGoogle ScholarPubMed
51Daniels, V. et al. (2011) Insight into the mode of action of the LRRK2 Y1699C pathogenic mutant. Journal of Neurochemistry 116, 304-315CrossRefGoogle ScholarPubMed
52West, 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
53Haugarvoll, K. and Wszolek, Z.K. (2009) Clinical features of LRRK2 parkinsonism. Parkinsonism and Related Disorders 15 (Suppl 3), S205-S208CrossRefGoogle ScholarPubMed
54Alcalay, R.N. et al. (2010) Frequency of known mutations in early-onset Parkinson disease: implication for genetic counseling: the consortium on risk for early onset Parkinson disease study. Archives of Neurology 67, 1116-1122CrossRefGoogle Scholar
55Goldstein, D.S. et al. (2007) Neurocirculatory and nigrostriatal abnormalities in Parkinson disease from LRRK2 mutation. Neurology 69, 1580-1584CrossRefGoogle ScholarPubMed
56Wider, C., Dickson, D.W. and Wszolek, Z.K. (2010) Leucine-rich repeat kinase 2 gene-associated disease: redefining genotype-phenotype correlation. Neurodegenerative Diseases 7, 175-179CrossRefGoogle ScholarPubMed
57Cookson, M.R., Hardy, J. and Lewis, P.A. (2008) Genetic neuropathology of Parkinson's disease. International Journal Clinical Experimental Pathology 1, 217-231Google ScholarPubMed
58Kay, D.M. et al. (2005) Escaping Parkinson's disease: a neurologically healthy octogenarian with the LRRK2 G2019S mutation. Movement Disorders 20, 1077-1078CrossRefGoogle ScholarPubMed
59Dachsel, J.C. and Farrer, M.J. (2010) LRRK2 and Parkinson disease. Archives of Neurology 67, 542-547CrossRefGoogle ScholarPubMed
60Clark, L.N. et al. (2006) Frequency of LRRK2 mutations in early- and late-onset Parkinson disease. Neurology 67, 1786-1791CrossRefGoogle ScholarPubMed
61Ruiz-Martinez, J. et al. (2010) Penetrance in Parkinson's disease related to the LRRK2 R1441G mutation in the Basque country (Spain). Movement Disorders 25, 2340-2345CrossRefGoogle Scholar
62Gehrke, S. et al. (2010) Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466, 637-641CrossRefGoogle ScholarPubMed
63Imai, Y. et al. (2008) Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO Journal 27, 2432-2443CrossRefGoogle ScholarPubMed
64Kanao, T. et al. (2010) Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila. Human Molecular Genetics 19, 3747-3758CrossRefGoogle ScholarPubMed
65Lee, S. et al. (2010) LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction. Journal of Neuroscience 30, 16959-16969CrossRefGoogle ScholarPubMed
66Lee, S.B. et al. (2007) Loss of LRRK2/PARK8 induces degeneration of dopaminergic neurons in Drosophila. Biochemical and Biophysical Research Communications 358, 534-539CrossRefGoogle ScholarPubMed
67Lin, C.H. et al. (2010) LRRK2 G2019S mutation induces dendrite degeneration through mislocalization and phosphorylation of tau by recruiting autoactivated GSK3ss. Journal of Neuroscience 30, 13138-13149CrossRefGoogle ScholarPubMed
68Liu, Z. et al. (2008) A Drosophila model for LRRK2-linked parkinsonism. Proceedings of the National Academy of Sciences of the United States of America 105, 2693-2698CrossRefGoogle ScholarPubMed
69Ng, C.H. et al. (2009) Parkin protects against LRRK2 G2019S mutant-induced dopaminergic neurodegeneration in Drosophila. Journal of Neuroscience 29, 11257-11262CrossRefGoogle ScholarPubMed
70Tain, L.S. et al. (2009) Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nature Neuroscience 12, 1129-1135CrossRefGoogle ScholarPubMed
71Venderova, K. et al. (2009) Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease. Human Molecular Genetics 18, 4390-4404CrossRefGoogle Scholar
72Hsu, C.H. et al. (2010) MKK6 binds and regulates expression of Parkinson's disease-related protein LRRK2. Journal of Neurochemistry 112, 1593-1604CrossRefGoogle ScholarPubMed
73Saha, S. et al. (2009) LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans. Journal of Neuroscience 29, 9210-9218CrossRefGoogle ScholarPubMed
74Sakaguchi-Nakashima, A. et al. (2007) LRK-1, a C. elegans PARK8-related kinase, regulates axonal-dendritic polarity of SV proteins. Current Biology 17, 592-598CrossRefGoogle Scholar
75Samann, J. et al. (2009) Caenorhabditits elegans LRK-1 and PINK-1 act antagonistically in stress response and neurite outgrowth. Journal of Biological Chemistry 284, 16482-16491CrossRefGoogle ScholarPubMed
76Yao, C. et al. (2010) LRRK2-mediated neurodegeneration and dysfunction of dopaminergic neurons in a Caenorhabditis elegans model of Parkinson's disease. Neurobiology of Disease 40, 73-81CrossRefGoogle Scholar
77Wang, D. et al. (2008) Dispensable role of Drosophila ortholog of LRRK2 kinase activity in survival of dopaminergic neurons. Molecular Neurodegeneration 3, 3CrossRefGoogle ScholarPubMed
78Marin, I. (2008) Ancient origin of the Parkinson disease gene LRRK2. Journal of Molecular Evolution 67, 41-50CrossRefGoogle ScholarPubMed
79Andres-Mateos, E. et al. (2009) Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Journal of Neuroscience 29, 15846-15850CrossRefGoogle ScholarPubMed
80Lin, X. et al. (2009) Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. Neuron 64, 807-827CrossRefGoogle ScholarPubMed
81Tong, Y. et al. (2010) Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of alpha-synuclein, and apoptotic cell death in aged mice. Proceedings of the National Academy of Sciences of the United States of America 107, 9879-9884CrossRefGoogle ScholarPubMed
82Tong, Y. et al. (2009) R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice. Proceedings of the National Academy of Sciences of the United States of America 106, 14622-14627CrossRefGoogle ScholarPubMed
83Li, X. et al. (2010) Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson's disease mutation G2019S. Journal of Neuroscience 30, 1788-1797CrossRefGoogle ScholarPubMed
84Li, Y. et al. (2009) Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nature Neuroscience 12, 826-828CrossRefGoogle ScholarPubMed
85Melrose, H.L. et al. (2010) Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. Neurobiology of Disease 40, 503-517CrossRefGoogle ScholarPubMed
86Winner, B. et al. (2011) Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice. Neurobiology of Disease 41, 706-716CrossRefGoogle ScholarPubMed
87Lee, B.D. et al. (2010) Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease. Nature Medicine 16, 998-1000CrossRefGoogle ScholarPubMed
88Dusonchet, J. et al. (2011) A rat model of progressive nigral neurodegeneration induced by the Parkinson's disease-associated G2019S mutation in LRRK2. Journal of Neuroscience 31, 907-912CrossRefGoogle ScholarPubMed
89Dachsel, J.C. et al. (2010) A comparative study of Lrrk2 function in primary neuronal cultures. Parkinsonism and Related Disorders 16, 650-655CrossRefGoogle ScholarPubMed
90MacLeod, D. et al. (2006) The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 52, 587-593CrossRefGoogle ScholarPubMed
91Parisiadou, L. et al. (2009) Phosphorylation of ezrin/radixin/moesin proteins by LRRK2 promotes the rearrangement of actin cytoskeleton in neuronal morphogenesis. Journal of Neuroscience 29, 13971-13980CrossRefGoogle ScholarPubMed
92Nuytemans, K. et al. (2010) Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Human Mutation 31, 763-780CrossRefGoogle Scholar
93Satake, W. et al. (2009) Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nature Genetics 41, 1303-1307CrossRefGoogle ScholarPubMed
94Simon-Sanchez, J. et al. (2009) Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nature Genetics 41, 1308-1312CrossRefGoogle ScholarPubMed
95Smith, W.W. et al. (2006) Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nature Neuroscience 9, 1231-1233CrossRefGoogle ScholarPubMed
96Liu, M. et al. (2010) Development of a mechanism-based high-throughput screen assay for leucine-rich repeat kinase 2 – discovery of LRRK2 inhibitors. Analytical Biochemistry 404, 186-192CrossRefGoogle ScholarPubMed
97Nichols, R.J. et al. (2009) Substrate specificity and inhibitors of LRRK2, a protein kinase mutated in Parkinson's disease. Biochemical Journal 424, 47-60CrossRefGoogle ScholarPubMed
98Reichling, L.J. and Riddle, S.M. (2009) Leucine-rich repeat kinase 2 mutants I2020T and G2019S exhibit altered kinase inhibitor sensitivity. Biochemical and Biophysical Research Communications 384, 255-258CrossRefGoogle ScholarPubMed
99Deng, X. et al. (2011) Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2. Nature Chemical Biology 7, 203–25CrossRefGoogle ScholarPubMed

Further reading, resources and contacts

Cookson, M.R. (2010). The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nature Reviews Neuroscience 11, 791-797CrossRefGoogle ScholarPubMed
Greggio, E. and Cookson, M.R. (2009) Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions. ASN Neuro 1, e0002CrossRefGoogle ScholarPubMed
General information about PD research can be found at PDOnline: http://www.pdonlineresearch.org/.Google Scholar
Up-to-date information on inherited forms of PD can be obtained from the OMIM (online inheritance in man) website: http://www.ncbi.nlm.nih.gov/omim.Google Scholar
Additional data on the association of specific genetic variants with PD can be found at pdgene: http://www.pdgene.org.Google Scholar
General information about PD research can be found at PDOnline: http://www.pdonlineresearch.org/.Google Scholar
Up-to-date information on inherited forms of PD can be obtained from the OMIM (online inheritance in man) website: http://www.ncbi.nlm.nih.gov/omim.Google Scholar
Additional data on the association of specific genetic variants with PD can be found at pdgene: http://www.pdgene.org.Google Scholar