Condensate-driven triglyceride reduction links α-synuclein to mitochondrial dysfunction

Abstract α-Synuclein (αSyn) inclusions characterize multiple age-related neurodegenerative diseases, including Parkinson’s disease (PD). While interactions between αSyn and lipids are known to contribute to αSyn pathobiology, the precise cellular mechanisms linking lipids to αSyn toxicity have yet to be elucidated. Through lipidomic profiling of Caenorhabditis elegans , we find that αSyn progressively alters lipid metabolism in aging worms. αSyn reduces the overall content of triacylglycerols (TAG) and disrupts the structure of lipid droplets (LD) and mitochondria. These pathological changes depend on αSyn’s properties to bind lipid and to condensate into inclusions. Apart from lowering TAG levels, αSyn proportionally increases long-chain unsaturated fatty acids (LCUFAs). Consequently, genetic inhibition of LCUFA biosynthesis alleviates αSyn-induced loss of C. elegans motility. Supplementing Medium-Chain Triglyceride (MCT) on the other hand also improves αSyn-associated toxicity phenotypes. These results link αSyn lipid binding and condensation to impaired TAG metabolism, which drives cellular toxicity. Combined with observed lower plasma TAGs in Parkinson cohorts, our findings reveal contributions of TAG remodelling to αSyn toxicity and point at MCT-supplementation as a mechanism-based therapeutic opportunity in age-related synucleinopathies.