Lipid rafts mediate the synaptic localization of alpha-synuclein.
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.
Fortin
Doris L
DL
Department of Neurology, Graduate Programs in Biomedical Sciences, Cell Biology and Neuroscience, University of California San Francisco School of Medicine, San Francisco, California 94143-2140, USA.
Troyer
Matthew D
MD
Nakamura
Ken
K
Kubo
Shin-ichiro
S
Anthony
Malcolm D
MD
Edwards
Robert H
RH
D019943:Amino Acid Substitution; D000818:Animals; D001923:Brain Chemistry; D002451:Cell Compartmentation; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured / Q000378:metabolism / Q000648:ultrastructure; D002784:Cholesterol / Q000096:biosynthesis / Q000502:physiology; D003902:Detergents / Q000494:pharmacology; D004072:Digitonin / Q000494:pharmacology; D037341:Fumonisins / Q000494:pharmacology; D006367:HeLa Cells / Q000378:metabolism / Q000648:ultrastructure; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007668:Kidney; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008563:Membrane Lipids / Q000502:physiology; D021962:Membrane Microdomains / Q000187:drug effects / Q000502:physiology*; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009761:Nystatin / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000378:metabolism; D013107:Sphingolipids / Q000096:biosynthesis / Q000502:physiology; D051843:Synucleins; D014162:Transfection; D051844:alpha-Synuclein; D047392:beta-Cyclodextrins / Q000494:pharmacology
D003902:Detergents; D037341:Fumonisins; D008563:Membrane Lipids; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; C497606:Snca protein, rat; D013107:Sphingolipids; D051843:Synucleins; D051844:alpha-Synuclein; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D009761:Nystatin; C012258:mevastatin; C056933:fumonisin B1; D002784:Cholesterol; D008148:Lovastatin; D004072:Digitonin; D008798:Mevalonic Acid