Parkinson's disease (PD) is a serious public health problem for the United States. Although dramatic advances have been made in the clinical management of Parkinson's disease, understanding of the mechanisms that underlie its neurodegeneration is incomplete. Such knowledge will be necessary for future development of therapeutics that impede or halt the progression of Parkinson's disease. The long-term objectives of this project are to determine the mechanisms by which oxidation products of dopamine and related catechols, catechol thioethers, may be converted to neurotoxins that contribute to nigrostriatal oxidative damage and neurodegeneration.
The Specific Aims of this projects are: (1) to determine the potency of endogenous catechol thioether produced in the mercapturic acid pathway and the mechanisms by which they may contribute to dopaminergic neurodegeneration in whole mitochondria, cultured dopaminergic neurons, brain regions of aged control and genetically engineered mice with deficiencies in anti-oxidant defenses, (2) to determine the activities of mercapturic acid pathway enzymes and the concentration of catechol mercapturates in brain regions and CSF from patients with Parkinson's disease, other nigrostriatal neurodegenerative diseases, and aged-matched controls, and (3) to determine the mechanisms by which environmental toxicants epidemiological linked with an increased risk of Parkinson's disease may augment neurotoxicity form catechol thioethers. This new information will determine the extent to which catechol thioethers produced in the mercapturic acid pathway may contribute to Parkinson's disease progression, interact with aging and environmental toxicants implicated in Parkinson's disease, and serve as intra vitam biomarkers of nigrostriatal degeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010196-05
Application #
6654426
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Lawler, Cindy P
Project Start
2000-04-01
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
5
Fiscal Year
2003
Total Cost
$270,018
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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