Membrane-associated farnesylated UCH-L1 promotes alpha-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-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.
Liu
Zhihua
Z
Center for Neurologic Diseases, Brigham and Women's Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA.
Meray
Robin K
RK
Grammatopoulos
Tom N
TN
Fredenburg
Ross A
RA
Cookson
Mark R
MR
Liu
Yichin
Y
Logan
Todd
T
Lansbury
Peter T
PT
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D019556:COS Cells; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D002522:Chlorocebus aethiops; D003545:Cysteine / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000201:enzymology; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000201:enzymology* / Q000628:therapy*; D054876:Prenylation / Q000187:drug effects*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D051844:alpha-Synuclein / Q000633:toxicity*
C096856:FTI 277; C482860:UCHL1 protein, human; D051844:alpha-Synuclein; D008715:Methionine; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex; D003545:Cysteine