Fortin Doris L, Nemani Venu M, Voglmaier Susan M, Anthony Malcolm D, Ryan Timothy A, Edwards Robert H
Department of Neurology, Graduate Program in Biomedical Sciences, University of California, San Francisco, California 94143-2140, USA.
J Neurosci. 2005 Nov 23;25(47):10913-21. doi: 10.1523/JNEUROSCI.2922-05.2005.
The presynaptic protein alpha-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. Alpha-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 alpha-synuclein in living neurons, we used fluorescence recovery after photobleaching. Despite its enrichment at the synapse, alpha-synuclein is highly mobile, with rapid exchange between adjacent synapses. In addition, we find that alpha-synuclein disperses from the nerve terminal in response to neural activity. Dispersion depends on exocytosis, but unlike other synaptic vesicle proteins, alpha-synuclein dissociates from the synaptic vesicle membrane after fusion. Furthermore, the dispersion of alpha-synuclein is graded with respect to stimulus intensity. Neural activity thus controls the normal function of alpha-synuclein at the nerve terminal and may influence its role in PD.
突触前蛋白α-突触核蛋白在帕金森病（PD）中起核心作用。然而，该蛋白导致神经退行性变的机制及其正常功能仍不清楚。α-突触核蛋白定位于神经末梢，在体外可与人工膜相互作用，但与天然脑膜的结合较弱。为了表征α-突触核蛋白在活神经元中的膜结合情况，我们采用了光漂白后荧光恢复技术。尽管α-突触核蛋白在突触处富集，但其流动性很高，在相邻突触之间快速交换。此外，我们发现α-突触核蛋白会响应神经活动从神经末梢分散开来。分散依赖于胞吐作用，但与其他突触囊泡蛋白不同，α-突触核蛋白在融合后从突触囊泡膜上解离。此外，α-突触核蛋白的分散程度与刺激强度相关。因此，神经活动控制着α-突触核蛋白在神经末梢的正常功能，并可能影响其在帕金森病中的作用。
