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.
Liu
Yichin
Y
Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Cambridge, MA 02139, USA.
Fallon
Lara
L
Lashuel
Hilal A
HA
Liu
Zhihua
Z
Lansbury
Peter T
PT
D000818:Animals; D001923:Brain Chemistry; D019556:COS Cells; D019281:Dimerization; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D006801:Humans; D008025:Ligases / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics; D011110:Polymorphism, Genetic; D011817:Rabbits; D051381:Rats; D013572:Synaptic Vesicles / Q000737:chemistry; D051843:Synucleins; D013869:Thiolester Hydrolases / Q000032:analysis / Q000235:genetics*; D014162:Transfection; D043222:Ubiquitin Thiolesterase; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein; D013869:Thiolester Hydrolases; D043222:Ubiquitin Thiolesterase; D008025:Ligases