Parkinson?s disease (PD) is characterized by the presence of Lewy bodies, the cytoplasmic neuronal inclusions, in the substantia nigra. One major component of the Lewy bodies was identified to be the fibril a-synuclein, thus linked the accumulation of this protein to the pathogenesis of PD. Failure to regulate the concentration of a-synuclein can contribute to the build-up and consequently fibrillization of the protein. The objective of this proposed research is to investigate the degradation process of a-synuclein through the ubiquitin/proteasome pathway. Neuronal ubiquitin C-terminal hydrolase (UCH-L1) hydrolyzes C-terminal ester and amides of ubiquitin and is believed to play a key role in processing polyubiquitin and/or ubiquitylated proteolytic peptide. A mutation (I93M) of the enzyme has been linked to a rare early-onset form of PD, at the same time a polymorphism of the enzyme (S18Y) was indicated to reduce the risk of PD. By direct comparing the specific activities of the wild-type and mutant UCH-L1 enzymes using techniques in biochemistry, biophysics and molecular biology, we hope we will have a better understanding of the degradation pathway of a-synuclein and the role of the UCH-L1 in the proteasome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS042415-03
Application #
6699300
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Murphy, Diane
Project Start
2001-12-01
Project End
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
3
Fiscal Year
2004
Total Cost
$47,296
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115