α-Synuclein acts as a cholesteryl-ester sensor on lipid droplets regulating organelle size and abundance

Abstract

AbstractWhile aggregated alpha-Synuclein (αSyn) is commonly associated with Parkinson’s disease, its physiological function as a membrane-binding protein is poorly understood. Here, we show that endogenous αSyn binds lipid droplets (LDs) in multiple human cell lines and in stem cell-derived dopaminergic neurons. LD-binding encompasses αSyn residues 1-100, which masks their detection by immunofluorescence microscopy, probably explaining the scarcity of similar observations in earlier studies. αSyn-LD interactions are highly temperature-sensitive and selective for cholesteryl-ester-rich LDs. They promote the formation of αSyn multimers that dissociate from LDs at non-permissive temperatures. αSyn remains LD-bound throughout starvation-induced lipolysis, whereas siRNA-knockdown diminishes LD abundance and compromises cell viability upon nutrient depletion, without affecting LD biosynthesis. Reciprocally, excess αSyn stimulates LD accumulation in dependence of lipid availability, restricts organelle size and ensures intracellular LD organization, which strictly depends on functional membrane-binding. Supporting a general role of αSyn in cellular lipid and cholesterol metabolism, our results point to additional loss-of-function similarities between Parkinson’s, Alzheimer’s and Gaucher’s disease.