Identification of Glycerol 3-phosphate acyltransferase as a potent modifier of α-Synuclein-induced toxicity

Abstract

Although multiple cellular pathways have been implicated in a-Synuclein (a-syn)-associated Parkinson’s disease (PD), the role of lipid metabolism remains elusive. Using the Drosophila system as a genetic screening tool, we identified mino, which encodes the mitochondrial isoform of the lipid synthesis enzyme glycerol 3-phosphate acyltransferase (GPAT), as a potent modifier of a-syn. Silencing the expression of mino significantly suppresses a-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 found that mino modulates the levels of mitochondrial reactive oxygen speciesand lipid peroxidation. Importantly, treatment of a-syn-expressing flies with FSG67, a GPAT inhibitor, reproduces the benefits of mino knockdown. FSG67 also inhibited a-syn aggregation and lipid peroxidation in mouse primary neurons transfected with a-syn preformed fibrils. Our study elucidates an important factor contributing to a-syn toxicity and offers a novel therapeutic direction for PD.