期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：12
页码：4635-4640
DOI：10.1073/pnas.0806474106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is linked to Parkinson's disease (PD) and memory and is selectively expressed in neurons at high levels. Its expression pattern suggests a function distinct from that of its widely expressed homolog UCH-L3. We report here that, in contrast to UCH-L3, UCH-L1 exists in a membrane-associated form (UCH-L1M) in addition to the commonly studied soluble form. C-terminal farnesylation promotes the association of UCH-L1 with cellular membranes, including the endoplasmic reticulum. The amount of UCH-L1M in transfected cells is shown to correlate with the intracellular level of {alpha}-synuclein, a protein whose accumulation is associated with neurotoxicity and the development of PD. Reduction of UCH-L1M in cell culture models of {alpha}-synuclein toxicity by treatment with a farnesyltransferase inhibitor (FTI-277) reduces {alpha}-synuclein levels and increases cell viability. Proteasome function is not affected by UCH-L1M, suggesting that it may negatively regulate the lysosomal degradation of {alpha}-synuclein. Therefore, inhibition of UCH-L1 farnesylation may be a therapeutic strategy for slowing the progression of PD and related synucleinopathies.
