Exposure to long chain polyunsaturated fatty acids triggers rapid multimerization of synucleins

Detergent-stable multimers of alpha -synuclein have been found specifically in the brains of patients with Parkinson's disease and other neurodegenera tive diseases. Here we show that recombinant alpha -synuclein forms multime rs in vitro upon exposure to vesicles containing certain Polyunsaturated fa tty acid (PUFA) acyl groups, including arachidonoyl and docosahexaenoyl. Th is process occurs at physiological concentrations and much faster than in a queous solution. PUFA-induced aggregation involves physical association wit h the vesicle surface via the large apolipoprotein-like lipid-binding domai n that constitutes the majority of the protein. beta- and gamma -synucleins , as well as the Parkinson's disease-associated alpha -synuclein variants A 30P and A53T, show similar tendencies to multimerize in the presence of PUF As. Multimerization does not require the presence of any tyrosine residues in the sequence. The membrane-based interaction of the synucleins with spec ific long chain polyunsaturated phospholipids may be relevant to the protei n family's physiological functions and may also contribute to the aggregati on of alpha -synuclein observed in neurodegenerative disease.