Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein neurotoxicity and is a therapeutic target for Parkinson';s disease

作者：Liu Zhihua; Meray Robin K; Grammatopoulos Tom N; Fredenburg Ross A; Cookson Mark R; Liu Yichin; Logan Todd; Lan**ury Peter T Jr^*

来源：Proceedings of the National Academy of Sciences, 2009, 106(12): 4635-4640.

DOI：10.1073/pnas.0806474106

• farnesylation
• synuclein

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-L1(M)) 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-L1(M) 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-L1(M) 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-L1(M), 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.

• 出版日期2009-3-24