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

Cell. 2002 Oct 18;111(2):209-18. doi: 10.1016/s0092-8674(02)01012-7.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain Chemistry
  • COS Cells
  • Dimerization
  • Gene Dosage
  • Genetic Predisposition to Disease
  • Humans
  • Ligases / metabolism*
  • Models, Molecular
  • Mutation
  • Nerve Tissue Proteins / metabolism*
  • Parkinson Disease / genetics
  • Polymorphism, Genetic
  • Rabbits
  • Rats
  • Synaptic Vesicles / chemistry
  • Synucleins
  • Thiolester Hydrolases / analysis
  • Thiolester Hydrolases / genetics*
  • Transfection
  • Ubiquitin Thiolesterase
  • alpha-Synuclein


  • Nerve Tissue Proteins
  • SNCA protein, human
  • Snca protein, rat
  • Synucleins
  • alpha-Synuclein
  • Thiolester Hydrolases
  • Ubiquitin Thiolesterase
  • Ligases