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Defining features are Lewy bodies that can be rich in \u03b1-synuclein (\u03b1S), vesicle membranes, and other lipid membranes, coupled with striatal dopamine loss and progressive motor dysfunction. Of these, lipid abnormalities are the least understood. An altered lipid metabolism in PD patient-derived neurons \u2014 carrying mutations in either GBA1, encoding for glucocerebrosidase (GCase), or \u03b1S \u2014 shifted the physiological \u03b1S tetramer\/monomer (T:M) equilibrium, resulting in PD phenotypes. We previously reported inhibition of stearoyl-CoA desaturase (SCD), the rate-limiting enzyme for fatty acid desaturation, stabilized \u03b1S tetramers and improved motor deficits in \u03b1S mice. Here we show that mutant GBA1-PD cultured neurons have increased SCD products (monounsaturated fatty acids [MUFAS]) and reduced \u03b1S T:M ratios that were improved by inhibiting SCD. Oral treatment of symptomatic L444P and E326K Gba1 mutant mice with 5b also improved the \u03b1S T:M homeostasis and dopaminergic striatal integrity. Moreover, SCD inhibition normalized GCase maturation and dampened lysosomal and lipid-rich clustering, key features of neuropathology in GBA-PD. In conclusion, this study supports that brain MUFA metabolism links\n                    <jats:italic>GBA1<\/jats:italic>\n                    genotype and WT \u03b1S homeostasis to downstream neuronal and behavioral impairments, identifying SCD as a therapeutic target for GBA-PD.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.188413","type":"journal-article","created":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T12:00:25Z","timestamp":1748952025000},"source":"Crossref","is-referenced-by-count":10,"title":["Stearoyl-CoA desaturase inhibition normalizes brain lipid saturation, \u03b1-synuclein homeostasis, and motor function in mutant Gba1-Parkinson mice"],"prefix":"10.1172","volume":"10","author":[{"given":"Silke","family":"Nuber","sequence":"first","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts, 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