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

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.

• Authors: Yichin Liu, Lara Fallon, Hilal A Lashuel, Zhihua Liu, Peter T Lansbury Jr
• Journal: Cell (Cell) Vol. 111 Issue 2 Pg. 209-18 (Oct 18 2002) ISSN: 0092-8674 [Print] United States
• PMID: 12408865 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

• 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, genetics)
• Transfection
• Ubiquitin Thiolesterase
• alpha-Synuclein