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The Journal of Neuroscience, November 23, 2005, 25(47):10913-10921; doi:10.1523/JNEUROSCI.2922-05.2005

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Neurobiology of Disease
Neural Activity Controls the Synaptic Accumulation of -Synuclein

Doris L. Fortin,¹ Venu M. Nemani,¹ Susan M. Voglmaier,¹ Malcolm D. Anthony,¹ Timothy A. Ryan,² and Robert H. Edwards¹

¹Departments of Neurology and Physiology, Graduate Programs in Biomedical Sciences, Cell Biology, and Neuroscience, University of California, San Francisco, San Francisco, California 94143-2140, and ²Department of Biochemistry, Weill Medical College of Cornell University, New York, New York 10021

The presynaptic protein -synuclein has a central role in Parkinson's disease (PD). However, the mechanism by which the protein contributes to neurodegeneration and its normal function remain unknown. -Synuclein localizes to the nerve terminal and interacts with artificial membranes in vitro but binds weakly to native brain membranes. To characterize the membrane association of -synuclein in living neurons, we used fluorescence recovery after photobleaching. Despite its enrichment at the synapse, -synuclein is highly mobile, with rapid exchange between adjacent synapses. In addition, we find that -synuclein disperses from the nerve terminal in response to neural activity. Dispersion depends on exocytosis, but unlike other synaptic vesicle proteins, -synuclein dissociates from the synaptic vesicle membrane after fusion. Furthermore, the dispersion of -synuclein is graded with respect to stimulus intensity. Neural activity thus controls the normal function of -synuclein at the nerve terminal and may influence its role in PD.

Key words: -synuclein; membrane association; synaptic vesicle; neural activity; Parkinson's disease; synapsin

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Received July 14, 2005; revised September 30, 2005; accepted October 7, 2005.

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