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The Journal of Neuroscience, July 28, 2004, 24(30):6715-6723; doi:10.1523/JNEUROSCI.1594-04.2004

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Neurobiology of Disease
Lipid Rafts Mediate the Synaptic Localization of -Synuclein

Doris L. Fortin, Matthew D. Troyer, Ken Nakamura, Shin-ichiro Kubo, Malcolm D. Anthony, and Robert H. Edwards

Departments of Neurology and Physiology, Graduate Programs in Biomedical Sciences, Cell Biology and Neuroscience, University of California San Francisco School of Medicine, San Francisco, California 94143-2140

-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, -synuclein localizes almost exclusively to the nerve terminal. In brain extracts, however, -synuclein behaves as a soluble, monomeric protein. Using a binding assay to characterize the association of -synuclein with cell membranes, we find that -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 -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 -synuclein with lipid rafts. Furthermore, we find that both the A30P mutation and raft disruption redistribute -synuclein away from synapses, indicating an important role for raft association in the normal function of -synuclein and its role in the pathogenesis of PD.

Key words: synuclein; Parkinson's disease; neurodegeneration; lipid raft; nerve terminal; synaptic localization

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Received April 26, 2004; revised May 22, 2004; accepted June 10, 2004.

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