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

Yichin Liu, Lara Fallon, Hilal A. Lashuel, Zhihua Liu, Peter T. Lansbury

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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 α-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.

Original languageEnglish
Pages (from-to)209-218
Number of pages10
JournalCell
Volume111
Issue number2
DOIs
Publication statusPublished - 18 Oct 2002

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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