α-Synuclein Adopts an α-Helical Conformation in the Presence of Polyunsaturated Fatty Acids To Hinder Micelle Formation^†

α-Synuclein is a small cytosolic protein involved in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. Recent studies suggested a lipid-related function for this brain-enriched protein. Since the brain carries a high level of docosahexaenoic acid (DHA) and since the extent of α-synuclein gene expression increases in response to DHA intake, we have investigated the interaction of α-synuclein with this essential omega-3 fatty acid. We show that α-synuclein allows DHA to be present in a soluble rather than micellar form. Upon interaction with DHA, the normally unstructured α-synuclein rapidly adopts an α-helical conformation. Prolonged exposure to DHA, however, gradually converts α-synuclein into amyloid-like fibrils. These results identify a potential biological function for α-synuclein and define an omega-3-linked pathway leading to α-synuclein aggregation.