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Abstract
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.