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.
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.
Doris L
DL
Fortin
Matthew D
MD
Troyer
Ken
K
Nakamura
Shin-ichiro
S
Kubo
Malcolm D
MD
Anthony
Robert H
RH
Edwards
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