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

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 α-synuclein, a protein whose accumulation is associated with neurotoxicity and the development of PD. Reduction of UCH-L1M in cell culture models of α-synuclein toxicity by treatment with a farnesyltransferase inhibitor (FTI-277) reduces α-synuclein levels and increases cell viability. Proteasome function is not affected by UCH-L1M, suggesting that it may negatively regulate the lysosomal degradation of α-synuclein. Therefore, inhibition of UCH-L1 farnesylation may be a therapeutic strategy for slowing the progression of PD and related synucleinopathies.