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PMID: 15282274 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Lipid rafts mediate the synaptic localization of alpha-synuclein.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 24 ·No. 30 ·2004-07-28 ·Pages 6715-23

Fortin DL, Troyer MD, Nakamura K, Kubo S, Anthony MD, Edwards RH

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.

MeSH Terms
Amino Acid Substitution Animals Brain Chemistry Cell Compartmentation Cell Membrane Permeability/drug effects Cells, Cultured/metabolism,ultrastructure Cholesterol/biosynthesis,physiology Detergents/pharmacology Digitonin/pharmacology Fumonisins/pharmacology HeLa Cells/metabolism,ultrastructure Hippocampus/cytology Humans Kidney Lovastatin/analogs & derivatives,pharmacology Membrane Lipids/physiology Membrane Microdomains/drug effects,physiology Mevalonic Acid/pharmacology Mice Mice, Inbred C3H Mice, Inbred C57BL Mice, Transgenic Mutation, Missense Nerve Tissue Proteins/chemistry,genetics,metabolism Nystatin/pharmacology Protein Binding/drug effects Rats Recombinant Fusion Proteins/analysis,metabolism Sphingolipids/biosynthesis,physiology Synucleins Transfection alpha-Synuclein beta-Cyclodextrins/pharmacology
Chemicals
Detergents Fumonisins Membrane Lipids Nerve Tissue Proteins Recombinant Fusion Proteins SNCA protein, human Snca protein, mouse Snca protein, rat Sphingolipids Synucleins alpha-Synuclein beta-Cyclodextrins methyl-beta-cyclodextrin Nystatin mevastatin fumonisin B1 Cholesterol Lovastatin Digitonin Mevalonic Acid
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Fortin Doris L
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
Nakamura Ken
Kubo Shin-ichiro
Anthony Malcolm D
Edwards Robert H
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.1594-04.2004
Published
2004-07-28
Pages
6715-23
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6729723
Subset
IM
External Links
PubMed source DOI: 10.1523/JNEUROSCI.1594-04.2004 PMC Full Text View journal details
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