Neurobiology of Disease Lipid Rafts Mediate the Synaptic Localization of -Synuclein

-Synuclein contributes to the pathogenesis of Parkinson’s disease (PD), but its precise role in the disorder and its normal function remain poorly understood. Consistent with a presumed role in neurotransmitter release and its prominent deposition in the dystrophic neurites of PD, -synuclein localizes almost exclusively to the nerve terminal. In brain extracts, however, -synuclein behaves as a soluble, monomeric protein. Using a binding assay to characterize the association of -synuclein with cell membranes, we find that -synuclein binds saturably and with high affinity to characteristic intracellular structures that double label for components of lipid rafts. Biochemical analysis demonstrates the interaction of -synuclein with detergent-resistant membranes and reveals a shift in electrophoretic mobility of the raft-associated protein. In addition, the A30P mutation associated with PD disrupts the interaction of -synuclein with lipid rafts. Furthermore, we find that both the A30P mutation and raft disruption redistribute -synuclein away from synapses, indicating an important role for raft association in the normal function of -synuclein and its role in the pathogenesis of PD.