{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T13:29:32Z","timestamp":1792589372725,"version":"4.5.0"},"reference-count":65,"publisher":"National Academy of Sciences","issue":"12","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,3,24]]},"abstract":"<jats:p>\n                    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\n                    <jats:sup>M<\/jats:sup>\n                    ) 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\n                    <jats:sup>M<\/jats:sup>\n                    in transfected cells is shown to correlate with the intracellular level of \u03b1-synuclein, a protein whose accumulation is associated with neurotoxicity and the development of PD. Reduction of UCH-L1\n                    <jats:sup>M<\/jats:sup>\n                    in cell culture models of \u03b1-synuclein toxicity by treatment with a farnesyltransferase inhibitor (FTI-277) reduces \u03b1-synuclein levels and increases cell viability. Proteasome function is not affected by UCH-L1\n                    <jats:sup>M<\/jats:sup>\n                    , suggesting that it may negatively regulate the lysosomal degradation of \u03b1-synuclein. Therefore, inhibition of UCH-L1 farnesylation may be a therapeutic strategy for slowing the progression of PD and related synucleinopathies.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0806474106","type":"journal-article","created":{"date-parts":[[2009,3,4]],"date-time":"2009-03-04T21:40:29Z","timestamp":1236202829000},"page":"4635-4640","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":133,"title":["Membrane-associated farnesylated UCH-L1 promotes \u03b1-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease"],"prefix":"10.1073","volume":"106","author":[{"given":"Zhihua","family":"Liu","sequence":"first","affiliation":[{"name":"Center for Neurologic Diseases, Brigham and Women's Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139;"},{"name":"Link Medicine Corporation, 161 First Street, Cambridge, MA 02142; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin K.","family":"Meray","sequence":"additional","affiliation":[{"name":"Center for Neurologic Diseases, Brigham and Women's Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139;"},{"name":"Link Medicine Corporation, 161 First Street, Cambridge, MA 02142; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom N.","family":"Grammatopoulos","sequence":"additional","affiliation":[{"name":"Link Medicine Corporation, 161 First Street, Cambridge, MA 02142; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross A.","family":"Fredenburg","sequence":"additional","affiliation":[{"name":"Link Medicine Corporation, 161 First Street, Cambridge, MA 02142; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Cookson","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics, National Institutes of Health, Building 35, 9000 Rockville Pike, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichin","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Neurologic Diseases, Brigham and Women's Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd","family":"Logan","sequence":"additional","affiliation":[{"name":"Link Medicine Corporation, 161 First Street, Cambridge, MA 02142; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Peter T.","family":"Lansbury","sequence":"additional","affiliation":[{"name":"Center for Neurologic Diseases, Brigham and Women's Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139;"},{"name":"Link Medicine Corporation, 161 First Street, Cambridge, MA 02142; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,3,24]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/12647"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2006.060301"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)65169-3"},{"key":"e_1_3_3_4_2","first-page":"1278","article-title":"PGP9.5 overexpression in esophageal squamous cell carcinoma","volume":"50","author":"Takase T","year":"2003","unstructured":"T Takase, et al., PGP9.5 overexpression in esophageal squamous cell carcinoma. 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