The overall goal of these experiments is to determine the effects of PD-linked mutations on the properties of the gene products and to use this information to discover methods to test possible explanations for pathogenicity. We expect that this work will generate new therapeutic strategies for the treatment of Parkinson's disease (PD). Our emphasis will be on protein fibrillogenesis, since fibrillar cytoplasmic aggregates, or Lewy bodies, are diagnostic for PD and a major fibrillar component of Lewy bodies is also the product of a gene linked to early-onset PD. Three mutations, in two different genes, encoding alpha-synuclein (alphaS) and ubiquitin C-hydrolase (UCH), have been linked to early-onset PD. We have shown that the two alphaS mutations effect the oligomerization properties of the protein; both favor oligomerization. It is a central goal of the proposed research to understand the structural basis for oligomerization and fibrillization and the relationship between this process and disease (the latter will require a collaboration between this project and project 3). We are also very interested in the ubiquitin-dependent degradation of alphaS, especially since UCH may be involved in that pathway. Finally, the possibility that mutant UCH may also be a fibrillogenic protein is under investigation. Protein (UCH and alphaS) fibrillization will be a target for medium-throughput screening assays to be run in the Center core facility (Core B). A gene linked to juvenile-onset parkinsonism, parkin, will be the subject of future biochemical and biophysical investigations. This protein contains an N-terminal ubiquitin homology domain, which suggests its involvement (like UCH) in the degradative process. We intend to characterize wild-type and mutant forms of Parkin. The fact that this disease is inherited in an autosomal recessive manner suggests that gain of function due to toxic oligomers may not be involved.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS038375-02
Application #
6341052
Study Section
Special Emphasis Panel (ZNS1)
Project Start
2000-08-01
Project End
2001-07-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
$294,553
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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