PD (Parkinson's disease) is an aetiologically heterogeneous disorder characterized by a clinical phenotype consisting of resting tremor, rigidity and bradykinesia. Motor symptoms are associated with a progressive loss of dopaminergic neurons, with Lewy body inclusions within surviving neurons. Although heritability studies have shown evidence of familial aggregation, twin studies have provided limited support for a genetic aetiology. Nevertheless, classical linkage methods have nominated 11 regions of the genome and pathogenic mutations have been identified in several genes, including α-synuclein, parkin, ubiquitin C-ter-minal hydrolase L1, oncogene DJ-1, PTEN-induced protein kinase 1 and microtubule-associated protein tau. Most recently, heterozygous mutations in LRRK2 (leucine-rich repeat kinase 2) were found to cause late-onset, autosomal-dominant PD. Despite their consistent clinical phenotype, family members with LRRK2 mutations can have variable α-synuclein and tau pathologies. Lrrk2 is a member of the Roc (Ras of complex proteins) family, with Ras GTPase and MAPKKK (mitogen-activated protein kinase kinase kinase) catalytic domains. Thus its discovery highlights vesicle dynamics and secondary-messenger signalling in disease pathophysiology. To diagnose a disease accurately and effectively treat it, requires an understanding of its molecular pathogenesis. Herein, we provide an overview of the genetics of PD, how these discoveries are revolutionizing long-held beliefs and more importantly how this knowledge may be translated into patient therapy.
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August 2005
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Conference Article|
August 01 2005
Pathophysiology, pleotrophy and paradigm shifts: genetic lessons from Parkinson's disease
O.A. Ross;
O.A. Ross
1Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, U.S.A.
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M.J. Farrer
M.J. Farrer
1
1Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, U.S.A.
1To whom correspondence should be addressed, at Molecular Genetics Laboratory and Core, Morris K. Udall Parkinson's Disease Research Center of Excellence, Birdsall Bldg, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, U.S.A. (email farrer.matthew@mayo.edu).
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Publisher: Portland Press Ltd
Received:
March 30 2005
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2005 The Biochemical Society
2005
Biochem Soc Trans (2005) 33 (4): 586–590.
Article history
Received:
March 30 2005
Citation
O.A. Ross, M.J. Farrer; Pathophysiology, pleotrophy and paradigm shifts: genetic lessons from Parkinson's disease. Biochem Soc Trans 1 August 2005; 33 (4): 586–590. doi: https://doi.org/10.1042/BST0330586
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