Condensate-driven triglyceride reduction links α-synuclein to mitochondrial dysfunction.
Condensate-driven triglyceride reduction links α-synuclein to mitochondrial dysfunction.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Groningen, NL · Author affiliation
European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. t.zhang@mail.hzau.edu.cn.Location evidence
Wuhan, CN · Author affiliation
College of Food Science and Technology, Huazhong Agricultural University, Wuhan, China. t.zhang@mail.hzau.edu.cn.Location evidence
GR · Author affiliation · country only
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece.Location evidence
Jiangnan, CN · Author affiliation
State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China.Location evidence
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Original 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.