Lipid Rafts Mediate the Synaptic Localization of α-Synuclein

TLDR

α‑Synuclein is linked to Parkinson’s disease, yet its precise role remains unclear; it localizes almost exclusively to nerve terminals but is soluble and monomeric in brain extracts. A binding assay revealed that α‑synuclein binds saturably and with high affinity to intracellular structures that co‑label for lipid‑raft components. Biochemical analysis showed α‑synuclein associates with detergent‑resistant membranes, shifts electrophoretic mobility, and that the A30P mutation or raft disruption abolishes this interaction, redistributing the protein away from synapses and underscoring the importance of raft association for its normal function and PD pathogenesis.

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.