Neural Activity Controls the Synaptic Accumulation of α-Synuclein

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Abstract
The presynaptic protein α-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. α-Synuclein localizes to the nerve terminal and interacts with artificial membranesin vitrobut binds weakly to native brain membranes. To characterize the membrane association of α-synuclein in living neurons, we used fluorescence recovery after photobleaching. Despite its enrichment at the synapse, α-synuclein is highly mobile, with rapid exchange between adjacent synapses. In addition, we find that α-synuclein disperses from the nerve terminal in response to neural activity. Dispersion depends on exocytosis, but unlike other synaptic vesicle proteins, α-synuclein dissociates from the synaptic vesicle membrane after fusion. Furthermore, the dispersion of α-synuclein is graded with respect to stimulus intensity. Neural activity thus controls the normal function of α-synuclein at the nerve terminal and may influence its role in PD.