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Human Molecular Genetics Advance Access originally published online on April 14, 2008
Human Molecular Genetics 2008 17(14):2160-2171; doi:10.1093/hmg/ddn115
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Elli Kyratzi1, Maria Pavlaki1 and Leonidas Stefanis1,2,*

1 Division of Basic Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece 2 Second Department of Neurology, University of Athens Medical School, Athens, Greece

* To whom correspondence should be addressed at: Division of Basic Neurosciences, Biomedical Research Foundation, Academy of Athens, Soranou Efessiou 4, 11527 Athens, Greece. E-mail: lstefanis{at}bioacademy.gr; ls76{at}columbia.edu

Received January 31, 2008; Accepted April 8, 2008

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 pathogenetic factor in certain forms of sporadic PD.


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