The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to neuronal cells

Human Molecular Genetics
Elli KyratziLeonidas Stefanis

Abstract

A number of studies have associated the S18Y polymorphic variant of UCH-L1 with protection from sporadic Parkinson's Disease (PD). The mechanism involved in this protective function is unknown, but has generally been assumed to be linked to the ubiquitin-proteasome system (UPS). In the current study, we have investigated the effects of overexpression of UCH-L1 and its variants, including S18Y, in neuronal cells. We find that S18Y, but not WT, UCH-L1 confers a specific antioxidant protective function when expressed at physiological levels in human neuroblastoma cells and primary cortical neurons. In contrast, neither WT nor S18Y UCH-L1 appear to directly impact the proteasome, although they both lead to stabilization of free ubiquitin. Lack of WT mouse UCH-L1 in neurons derived from gad mice led to a decrease of free ubiquitin, but no overall decrease in UPS function or enhanced sensitivity to oxidative stress. 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. Our results furthermore provide indirect evidence for the importance of oxidative stress as a pathogeneti...Continue Reading

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Citations

Feb 5, 2010·Apoptosis : an International Journal on Programmed Cell Death·Qian Huang, Maria E Figueiredo-Pereira
Mar 6, 2009·Proceedings of the National Academy of Sciences of the United States of America·Zhihua LiuPeter T Lansbury
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