The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility

The assumption that each Enzyme expresses a single enzymatic activity in vivo is challenged by the linkage of the neuronal Enzyme ubiquitin C-terminal hydrolase-L1 (UCH-L1) to Parkinson's disease (PD). UCH-L1, especially those variants linked to higher susceptibility to PD, causes the accumulation of alpha-synuclein in cultured cells, an effect that cannot be explained by its recognized hydrolase activity. UCH-L1 is shown here to exhibit a second, dimerization-dependent, ubiquityl Ligase activity. A polymorphic variant of UCH-L1 that is associated with decreased PD risk (S18Y) has reduced Ligase activity but comparable hydrolase activity as the wild-type Enzyme. Thus, the Ligase activity as well as the hydrolase activity of UCH-L1 may play a role in proteasomal protein degradation, a critical process for neuronal health.