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.
