Since a substitution of serine by tyrosine at codon 18, exon 3 (S18Y polymorphism) of the UCH-L1 gene exhibits a protective effect against the development of degenerative disease such as sporadic Parkinson's disease (PD) in several different ethnic groups, we hypothesized that UCH-L1 gene S18Y polymorphism may have that same effect on the pathologic process of AD.
We propose that aberrant interactions of UCH-L1 variants with CMA machinery, at least partly, underlie the pathogenesis of I93MUCH-L1-associated PD, and possibly of sporadic PD.
A protective effect of a UCH-L1 variant, S18Y, was suggested since the common variant was found to be inversely associated with sporadic Parkinson's disease (PD).
A polymorphic variation of serine to tyrosine at codon 18 in the ubiquitin C-terminal hydrolase-L1 gene is associated with a reduced risk of sporadic Parkinson's disease in a Japanese population.
We conclude that the S18Y variant of UCH-L1 confers a novel antioxidant function that is not present in the WT form and that this function may underlie the protective effects of this variant in certain PD populations.
Taken together, these results suggest that further studies of altered UCH-L1 hydrolase function may provide new insights into a possible common pathogenic mechanism between familial and sporadic Parkinson's disease.