{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T15:25:07Z","timestamp":1789226707308,"version":"build-2803163510"},"posted":{"date-parts":[[2025,10,23]]},"group-title":"Cell Biology","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,18]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  Inclusions of \u03b1-Synuclein (\u03b1Syn) characterize multiple age-related neurodegenerative diseases, including Parkinson\u2019s disease (PD) and Multiple System Atrophy (MSA). While interactions between \u03b1Syn and lipids are known to contribute to \u03b1Syn pathobiology, the precise cellular mechanisms that link lipids to \u03b1Syn toxicity have yet to be elucidated. Through lipidomic profiling of\n                  <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                  , we found that \u03b1Syn progressively alters lipid metabolism in aging worms. \u03b1Syn strongly reduces overall content of triacylglycerols (TAG) and disrupts the structure of lipid droplets (LD). These pathological changes depend on \u03b1Syn\u2019s properties to condensate and form inclusions. Apart from lowering TAG levels, \u03b1Syn also increases the proportion of long-chain unsaturated fatty acids (LCUFAs). Consequently, genetic inhibition of LCUFA biosynthesis alleviates \u03b1Syn-induced loss of\n                  <jats:italic>C. elegans<\/jats:italic>\n                  motility. Strikingly, bypassing lipid metabolic defects by supplementing Medium Chain Fatty Acids (MCFAs) restores the \u03b1Syn-impaired mitochondrial response and rescues motility. These results link \u03b1Syn condensation to impaired TAG metabolism, which reduces mitochondrial function and enhances overall toxicity. Together with the finding that plasma TAGs are lowered in Parkinson patient cohorts, these results suggest that restoring TAG metabolism could alleviate \u03b1Syn-induced toxicity in Parkinson\u2019s and other age-related synucleinopathies.\n                <\/jats:p>","DOI":"10.1101\/2025.10.22.682553","type":"posted-content","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T16:05:19Z","timestamp":1761235519000},"source":"Crossref","is-referenced-by-count":2,"title":["Condensate-Driven Triglyceride Depletion Links \u03b1-Synuclein to Mitochondrial Dysfunction"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8653-5089","authenticated-orcid":false,"given":"Tao","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Eugenia","family":"Goya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Herron-Bedoya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorien C.","family":"van der Weerd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dikaia","family":"Tsagkari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Couzijn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lale","family":"G\u00fcng\u00f6rd\u00fc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9e I.","family":"Seinstra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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