Lipid rafts mediate the synaptic localization of alpha-synuclein

• Published in: The Journal of neuroscience Vol. 24; no. 30; pp. 6715 - 6723
• Main Authors: Fortin, Doris L, Troyer, Matthew D, Nakamura, Ken, Kubo, Shin-ichiro, Anthony, Malcolm D, Edwards, Robert H
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 28.07.2004
• Subjects: alpha-Synuclein; Amino Acid Substitution; Animals; beta-Cyclodextrins - pharmacology; Brain Chemistry; Cell Compartmentation; Cell Membrane Permeability - drug effects; Cells, Cultured - metabolism; Cells, Cultured - ultrastructure; Cholesterol - biosynthesis; Cholesterol - physiology; Detergents - pharmacology; Digitonin - pharmacology; Fumonisins - pharmacology; HeLa Cells - metabolism; HeLa Cells - ultrastructure; Hippocampus - cytology; Humans; Kidney; Lovastatin - analogs & derivatives; Lovastatin - pharmacology; Membrane Lipids - physiology; Membrane Microdomains - drug effects; Membrane Microdomains - physiology; Mevalonic Acid - pharmacology; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Mutation, Missense; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurobiology of Disease; Nystatin - pharmacology; Protein Binding - drug effects; Rats; Recombinant Fusion Proteins - analysis; Recombinant Fusion Proteins - metabolism; Sphingolipids - biosynthesis; Sphingolipids - physiology; Synucleins; Transfection
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1594-04.2004

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.