Parkinson's disease (PD) is characterized by the presence of Lewy bodies (the cytoplasmic neuronal inclusions) and the significant loss of dopaminergic neurons in the substantia nigra, a-synuclein was identified as one major fibril component of the Lewy bodies, thus linked the accumulation of this protein to the pathogenesis of PD. Failure to regulate the concentration of a-synuclein, for example by dysfunction of the pathogenesis of PD. Failure to regulate the concentration of a-synuclein, for example by dysfunction of degradation process, can also contribute to the build-up and consequently fibrillation of the protein. A gene, PARK5, has been linked to PD are involved in proteasomal degradation pathway and it is an ubiquitin C terminal hydrolase (UCH-L 1) that hydrolyzes C-terminal ester and amides of ubiquitin and is believed to play a key role in processing polyubiquitin and/or ubiquity lated proteolytic peptide. A rare mutation (193M) of UCH L 1 that yields a 50% reduction in its hydrolytic activity has been tentatively linked to a rare early onset form of PD, at the same time a polymorphism of the enzyme (S 18Y) was indicated to reduce the risk of PD. The assumption that each enzyme expresses a single enzymatic activity in vivo, however, is challenged by the linkage of UCH-L 1 to PD. UCH-L 1, especially those variants linked to higher susceptibility to PD, causes the accumulation of a-synuclein in cultured cells, an effect that cannot be explained by its recognized hydrolase activity. UCH-L1 exhibits a second, dimerization-dependent, ubiquityl ligase activity. The polymorphic variant of UCH-L1 that is associated with decreased PD risk (S 18Y) has reduced ligase activity, but comparable hydrolase activity as the wild-type enzyme. Thus the ligase activity, as welt as the hydrolase activity of UCH-L1 may play a role in proteasomal protein degradation, a critical process for molecules (""""""""molecular probes"""""""") that can be used to perturb UCH-L1 ligase activity in cell culture and animal models of PD. This """"""""chemical genetic"""""""" strategy is complementary to traditional genetic approaches (e.g., knockouts and trasngenics) for understanding protein function but has a distinct advantage in that the probes are potential lead compounds for the development of novel PD therapetutics. The program detailed below will seek probes with the following activities: (1) inhibitors ofUCH-L1 dimerization, (2) inhibitors of UCH-L1 ligase activity, and (3) repressors and activators of UCH-L1 expression.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Murphy, Diane
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Meray, Robin K; Lansbury Jr, Peter T (2007) Reversible monoubiquitination regulates the Parkinson disease-associated ubiquitin hydrolase UCH-L1. J Biol Chem 282:10567-75