Parkinson's disease is a prevalent neurodegenerative disorder characterized by tremors, rigidity, and bradykinesia. These symptoms are thought to arise from the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Recently, mutations of the parkin gene, which encodes a ubiquitin-protein ligase, were found to underlie a familial form of Parkinson's disease known as autosomal recessive juvenile Parkinson's disease (AR-JP). While this advance provides clues to the mechanism responsible for pathology in AR-JP, the cellular targets of the parkin ubiquitin-protein ligase activity and the specific biochemical pathways affected by parkin mutations remain largely unknown. To address these issues, the objectives of this proposal are to create a Drosophila melanogaster model of AR-JP through mutational analysis of a Drosophila parkin ortholog, and to use this fly AR-JP model to investigate the molecular mechanisms of neuronal dysfunction underlying parkin deficiency. Two main hypotheses will be explored in this proposal: (a) parkin sequesters alpha-synuclein protein into Lewy bodies and this function represents a cellular mechanism of alpha-synuclein detoxification; (b) neurodegeneration triggered by parkin mutations results from accumulation of parkin substrate(s). To accomplish the objectives of this proposal, the following specific aims will be pursued: (1) Generate and characterize Drosophila parkin (D-parkin) mutants; (2) Determine whether altered D-parkin expression affects the time course and extent of alpha-synuclein induced neurodegeneration and Lewy body formation; (3) Identify modifiers of a D-parkin mutant phenotype; (4) Isolate D-parkin-binding components and investigate structure-function relationships in D-parkin. Results from this work should clarify the relationship between parkin dysfunction and neurodegeneration, and possibly reveal strategies for treatment of Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041780-03
Application #
6639794
Study Section
Special Emphasis Panel (ZNS1-SRB-W (02))
Program Officer
Murphy, Diane
Project Start
2001-05-01
Project End
2005-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
3
Fiscal Year
2003
Total Cost
$220,176
Indirect Cost
Name
University of Washington
Department
Genetics
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Trinh, Kien; Moore, Katherine; Wes, Paul D et al. (2008) Induction of the phase II detoxification pathway suppresses neuron loss in Drosophila models of Parkinson's disease. J Neurosci 28:465-72
Greene, Jessica C; Whitworth, Alexander J; Andrews, Laurie A et al. (2005) Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis. Hum Mol Genet 14:799-811
Whitworth, Alexander J; Theodore, Dorothy A; Greene, Jessica C et al. (2005) Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease. Proc Natl Acad Sci U S A 102:8024-9
Greene, Jessica C; Whitworth, Alexander J; Kuo, Isabella et al. (2003) Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci U S A 100:4078-83