The investigation of familial Parkinson's disease-related syndromes is likely to provide insight into the pathogenesis of sporadic Parkinsons's disease (PD) and may suggest novel therapeutics. Mutations in the amino-terminal repeat domain of a-Synuclein (alpha-Syn) underlie rare autosomal-dominant, familial forms of PD. Familial, autosomal-recessive mutations in Parkin lead to both juvenile and adult-onset forms of PD. Furthermore, Parkin appears to possess a ubiquitin-ligase activity, implicating it in the protein degradation process. Mounting evidence implicates altered protein ubiquitination and degradation by the ubiquitin/proteasome pathway (UPP) in human neurodegenerative disorders. Both pathological and genetic data link altered protein degradation pathways with PD. A pathological hallmark of PD, the Lewy Body (LB), appears to represent intracellular inclusions composed of multiple proteins including ubiquitin, a-Synuclein (alpha-Syn), ubiquitin carboxy-terminal hydrolase (UCH-L1), and Parkin. Both Parkin and UCH-L1 are implicated in protein ubiquitination, whereas alpha-Syn appears to be a substrate of ubiquitination. The goal of this proposal is to gain an understanding of the mechanisms of action of the PD-related genes alpha-Syn, Parkin. Of particular interest are potential relationships among these molecules. I propose to combine complementary biochemical, cellular, and genetic approaches to this end.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research (K02)
Project #
1K02AG021944-01
Application #
6598598
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Finkelstein, Judith A
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$107,622
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032