Alpha-synuclein impairs triglyceride metabolism and mitochondrial structure in aging nematodes

In the nematode Caenorhabditis elegans, researchers found that alpha-synuclein progressively alters lipid metabolism during aging. The protein reduces total triacylglycerols and disrupts the structures of both lipid droplets and mitochondria. These structural defects depend on the ability of alpha-synuclein to bind lipids and condense into inclusions. While reducing triacylglycerols, alpha-synuclein also proportionally increases long-chain unsaturated fatty acids. Modifying these lipid pathways countered the damage in worms. Genetically blocking the synthesis of long-chain unsaturated fatty acids alleviated alpha-synuclein-induced loss of motility. Supplementing the nematodes with medium-chain triglycerides also improved toxicity phenotypes. Noting that Parkinson's disease cohorts show lower plasma triacylglycerols, the researchers conclude that alpha-synuclein condensation impairs lipid balance to drive cellular toxicity.