Lipid Rafts Mediate the Synaptic Localization of α-Synuclein

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Abstract
α-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, α-synuclein localizes almost exclusively to the nerve terminal. In brain extracts, however, α-synuclein behaves as a soluble, monomeric protein. Using a binding assay to characterize the association of α-synuclein with cell membranes, we find that α-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 α-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 α-synuclein with lipid rafts. Furthermore, we find that both the A30P mutation and raft disruption redistribute α-synuclein away from synapses, indicating an important role for raft association in the normal function of α-synuclein and its role in the pathogenesis of PD.
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