Lipid rafts mediate the synaptic localization of alpha-
synuclein.Fortin DL, Troyer MD, Nakamura K, Kubo S, Anthony MD,
Edwards RH.
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.


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.


PMID: 15282274 [PubMed - indexed for MEDLINE]