alpha-synuclein and mevastatin

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

Topics: alpha-Synuclein; Amino Acid Substitution; Animals; beta-Cyclodextrins; Brain Chemistry; Cell Compartmentation; Cell Membrane Permeability; Cells, Cultured; Cholesterol; Detergents; Digitonin; Fumonisins; HeLa Cells; Hippocampus; Humans; Kidney; Lovastatin; Membrane Lipids; Membrane Microdomains; Mevalonic Acid; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Mutation, Missense; Nerve Tissue Proteins; Nystatin; Protein Binding; Rats; Recombinant Fusion Proteins; Sphingolipids; Synucleins; Transfection