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The rate of \u03b1\u2010syn aggregation, as well as the secondary structure of \u03b1\u2010syn oligomers and fibrils, can be uniquely altered by lipids. However, the role of saturation of fatty acids (FAs) in such lipids in the aggregation properties of \u03b1\u2010syn remains unclear. In this study, we investigated the effect of saturation of FAs in phosphatidylcholine (PC) and cardiolipin (CL), as well as a mixture of these phospholipids on the rate of \u03b1\u2010syn aggregation. We found that although saturation plays very little if any role in the rate of protein aggregation and morphology of \u03b1\u2010syn aggregates, it determined the secondary structure of \u03b1\u2010syn oligomers and fibrils. Furthermore, we found that aggregates formed in the presence of both saturated and unsaturated PC and CL, as well as mixtures of these phospholipids, exert significantly higher cell toxicity compared to the protein aggregates formed in the lipid\u2010free environment. To extend these findings, we conducted in vivo studies using <jats:italic>C. elegans<\/jats:italic>, where we assessed the effect of lipid\u2010modified \u03b1\u2010syn aggregates on organismal survival and neurotoxicity. Our results suggest that the saturation of FAs in phospholipids present in the plasma and mitochondrial membranes can be a key determinant of the secondary structure and, consequently, the toxicity of \u03b1\u2010syn oligomers and fibrils. These findings provide new insights into the role of lipids in Parkinson's disease pathogenesis and highlight potential targets for therapeutic intervention.<\/jats:p>","DOI":"10.1002\/pro.70121","type":"journal-article","created":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T04:29:31Z","timestamp":1744950571000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The role of phospholipid saturation and composition in \u03b1\u2010synuclein aggregation and toxicity: A dual in vitro and in vivo approach"],"prefix":"10.1002","volume":"34","author":[{"given":"Aidan P.","family":"Holman","sequence":"first","affiliation":[{"name":"Interdisciplinary Faculty of Toxicology Texas A&amp;M University  College Station Texas USA"},{"name":"Department of Biochemistry and Biophysics Texas A&amp;M University  College Station Texas 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