Glycerol 3-phosphate acyltransferase exacerbates α-synuclein-induced toxicity by increasing lipid peroxidation

Although multiple cellular pathways have been implicated in α-Synuclein (α-syn)-associated Parkinson’s disease (PD), the role of lipid metabolism remains elusive. In this study, we identify Drosophila mino, which encodes the mitochondrial isoform of the lipid synthesis enzyme glycerol 3-phosphate acyltransferase (GPAT), as a potent modifier of α-syn. Silencing the expression of mino significantly suppresses α-syn-induced PD phenotypes in Drosophila, including dopaminergic neuronal loss and locomotion defects as well as circadian rhythm-related activities, whereas mino overexpression yields opposite effects. Mechanistically, we find that mino modulates the levels of mitochondrial reactive oxygen species and lipid peroxidation. Importantly, treatment of α-syn-expressing flies with FSG67, a GPAT inhibitor of glycerol 3-phosphate acyltransferase, reproduces the benefits of mino knockdown. FSG67 also inhibits α-syn aggregation and lipid peroxidation in mouse primary neurons treated with α-syn preformed fibrils. Our study elucidates an important factor contributing to α-syn toxicity and offers a therapeutic direction for PD. The role of lipid metabolism in Parkinson's disease is poorly understood. Here, Ren and co-authors identify a key enzyme in this process, mitochondrial glycerol 3-phosphate acyltransferase, as a critical driver of α-synuclein toxicity.