{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:36:39Z","timestamp":1792460199831,"version":"4.5.0"},"reference-count":42,"publisher":"National Academy of Sciences","issue":"17","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,4,27]]},"abstract":"<jats:p>Huntington\u2019s disease (HD), an incurable neurodegenerative disorder, has a complex pathogenesis including protein aggregation and the dysregulation of neuronal transcription and metabolism. Here, we demonstrate that inhibition of sirtuin 2 (SIRT2) achieves neuroprotection in cellular and invertebrate models of HD. Genetic or pharmacologic inhibition of SIRT2 in a striatal neuron model of HD resulted in gene expression changes including significant down-regulation of RNAs responsible for sterol biosynthesis. Whereas mutant huntingtin fragments increased sterols in neuronal cells, SIRT2 inhibition reduced sterol levels via decreased nuclear trafficking of SREBP-2. Importantly, manipulation of sterol biosynthesis at the transcriptional level mimicked SIRT2 inhibition, demonstrating that the metabolic effects of SIRT2 inhibition are sufficient to diminish mutant huntingtin toxicity. These data identify SIRT2 inhibition as a promising avenue for HD therapy and elucidate a unique mechanism of SIRT2-inhibitor-mediated neuroprotection. Furthermore, the ascertainment of SIRT2\u2019s role in regulating cellular metabolism demonstrates a central function shared with other sirtuin proteins.<\/jats:p>","DOI":"10.1073\/pnas.1002924107","type":"journal-article","created":{"date-parts":[[2010,4,8]],"date-time":"2010-04-08T22:52:29Z","timestamp":1270767149000},"page":"7927-7932","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":294,"title":["SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis"],"prefix":"10.1073","volume":"107","author":[{"given":"Ruth","family":"Luthi-Carter","sequence":"first","affiliation":[{"name":"Brain Mind Institute, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne, 1015 Lausanne, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Brain Mind Institute, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne, 1015 Lausanne, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judit","family":"Pallos","sequence":"additional","affiliation":[{"name":"Departments of bDevelopmental Biology Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Lambert","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Unit 894, Laboratory of Neuronal Cell Biology and Pathology, 75014 Paris, France;"},{"name":"University of Paris Descartes, EA 4059, 75014 Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Amore","sequence":"additional","affiliation":[{"name":"MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA 02129;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Parker","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Unit 894, Laboratory of Neuronal Cell Biology and Pathology, 75014 Paris, France;"},{"name":"University of Paris Descartes, EA 4059, 75014 Paris, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary","family":"Moffitt","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, King\u2019s College London, London SE1 9RT, United Kingdom; 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