α-Synuclein Inhibits Intersynaptic Vesicle Mobility and Maintains Recycling-Pool Homeostasis

Although the presynaptic protein alpha-synuclein is a recognized player in neurodegeneration, its precise physiologic function(s) and/or role in human disease remains unclear. An emerging consensus from previous studies in lower-order systems is that alpha-synuclein interferes with vesicle-trafficking pathways; however putative neuronal correlates are unknown. Here we explore consequences of alpha-synuclein modulation in cultured mouse hippocampal neurons; coupling alpha-synuclein overexpression and knock-out model-systems with contemporary imaging paradigms. Our studies reveal an unexpected role of alpha-synuclein in attenuating the mobility of recycling pool (RP) vesicles between presynaptic boutons-called superpool trafficking-and also in maintaining the overall size of RPs at synapses. While an excess of alpha-synuclein led to smaller RPs and inhibited intersynaptic trafficking, an absence of alpha-synuclein triggered converse changes with larger RPs and enhanced intersynaptic trafficking. The data collectively suggest a model where alpha-synuclein maintains RP homeostasis by modulating intersynaptic vesicular dynamics, and provide a putative neuronal correlate of alpha-synuclein-induced impairments in vesicle-trafficking previously reported in lower-order systems.