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A key therapeutic target in PD is \u03b1\u2010synuclein (\u03b1S), which is both genetically implicated and accumulates in Lewy bodies rich in vesicles and other lipid membranes. Reestablishing \u03b1S homeostasis is a central goal in PD. Based on previous lipidomic analyses, we conducted a mouse trial of a stearoyl\u2013coenzyme A desaturase (SCD) inhibitor (\u201c5b\u201d) that prevented \u03b1S\u2010positive vesicular inclusions and cytotoxicity in cultured human neurons.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Oral dosing and brain activity of 5b were established in nontransgenic mice. 5b in drinking water was given to mice expressing wild\u2010type human \u03b1S (WT) or an amplified familial PD \u03b1S mutation (E35K\u2009+\u2009E46K\u2009+\u2009E61K [\"3K\"]) beginning near the onset of nigral and cortical neurodegeneration and the robust PD\u2010like motor syndrome in 3K. Motor phenotypes, brain cytopathology, and SCD\u2010related lipid changes were quantified in 5b\u2010 versus placebo\u2010treated mice. Outcomes were compared to effects of crossing 3K to SCD1\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>5b treatment reduced \u03b1S hyperphosphorylation in E46K\u2010expressing human neurons, in 3K neural cultures, and in both WT and 3K \u03b1S mice. 5b prevented subtle gait deficits in WT \u03b1S mice and the PD\u2010like resting tremor and progressive motor decline of 3K \u03b1S mice. 5b also increased \u03b1S tetramers and reduced proteinase K\u2010resistant lipid\u2010rich aggregates. Similar benefits accrued from genetically deleting 1 SCD allele, providing target validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Prolonged reduction of brain SCD activity prevented PD\u2010like neuropathology in multiple PD models. Thus, an orally available SCD inhibitor potently ameliorates PD phenotypes, positioning this approach to treat human \u03b1\u2010synucleinopathies. ANN NEUROL 2021;89:74\u201390<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.25920","type":"journal-article","created":{"date-parts":[[2020,9,30]],"date-time":"2020-09-30T02:44:47Z","timestamp":1601433887000},"page":"74-90","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["A Stearoyl\u2013Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in\n                    <scp>\u03b1<\/scp>\n                    \u2010Synuclein Mice"],"prefix":"10.1002","volume":"89","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2124-6865","authenticated-orcid":false,"given":"Silke","family":"Nuber","sequence":"first","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Department of Neurology Brigham and Women's Hospital and Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice 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Friedrich\u2010Alexander University Erlangen\u2010Nuremberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Lambrecht","sequence":"additional","affiliation":[{"name":"Division of Molecular Neurology Friedrich\u2010Alexander University Erlangen\u2010Nuremberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Winkler","sequence":"additional","affiliation":[{"name":"Division of Molecular Neurology Friedrich\u2010Alexander University Erlangen\u2010Nuremberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6265-9087","authenticated-orcid":false,"given":"Andreas","family":"Weihofen","sequence":"additional","affiliation":[{"name":"Neurodegenerative Diseases Research Unit Biogen  Cambridge MA 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