Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Substitution
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Animals
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Brain Chemistry
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Cell Compartmentation
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Cell Membrane Permeability / drug effects
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Cells, Cultured / metabolism
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Cells, Cultured / ultrastructure
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Cholesterol / biosynthesis
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Cholesterol / physiology
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Detergents / pharmacology
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Digitonin / pharmacology
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Fumonisins / pharmacology
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HeLa Cells / metabolism
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HeLa Cells / ultrastructure
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Hippocampus / cytology
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Humans
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Kidney
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Lovastatin / analogs & derivatives*
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Lovastatin / pharmacology
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Membrane Lipids / physiology
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Membrane Microdomains / drug effects
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Membrane Microdomains / physiology*
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Mevalonic Acid / pharmacology
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Mice
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Mice, Transgenic
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Mutation, Missense
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Nystatin / pharmacology
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Protein Binding / drug effects
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Rats
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Recombinant Fusion Proteins / analysis
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Recombinant Fusion Proteins / metabolism
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Sphingolipids / biosynthesis
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Sphingolipids / physiology
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Synucleins
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Transfection
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alpha-Synuclein
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beta-Cyclodextrins / pharmacology
Substances
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Detergents
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Fumonisins
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Membrane Lipids
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Nerve Tissue Proteins
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Recombinant Fusion Proteins
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SNCA protein, human
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Snca protein, mouse
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Snca protein, rat
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Sphingolipids
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Synucleins
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alpha-Synuclein
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beta-Cyclodextrins
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methyl-beta-cyclodextrin
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Nystatin
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mevastatin
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fumonisin B1
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Cholesterol
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Lovastatin
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Digitonin
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Mevalonic Acid