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Abstract Background Parkinson’s disease (PD) is mainly characterized by the pathological feature of α-synuclein (α-syn) aggregation, with the exact disease pathogenesis unclear. During the onset and progression of PD, synaptic dysfunction including dysregulation of axonal transport, impaired exocytosis and endocytosis are identified as crucial events of PD pathogenesis. It has been reported that overexpression of α-syn impairs clathrin-mediated endocytosis (CME) in the synapses. However, the underlying mechanisms remained unknown. Methods In this study, we investigated the molecular events underlying the synaptic dysfunction induced by overexpression of wild-type human α-syn and its mutant form, involving series of proteins participating in CME. Results We found that excessive human α-syn causes impaired fission and uncoating of clathrin-coated vesicles (CCVs) during synaptic vesicle recycling, leading to reduced clustering of synaptic vesicles near the active zone and increased size of plasma membrane and number of endocytic intermediates. Furthermore, overexpressed human α-syn induced changes of CME associated proteins, among which synaptojanin1 (SYNJ1) showed significant reduction in various brain regions. Overexpression of SYNJ1 in the primary neuron of α-syn transgenic mice recovered the synaptic vesicle density and clustering. Using fluorescence-conjugated transferrin, we demonstrated that SYNJ1 re-boosted the CME activity by restoring the phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] homeostasis. Conclusions In summary, our data suggested that overexpression of α-syn disrupts synaptic function through interfering with vesicle recycling, which could be alleviated by re-availing of SYNJ1. Our study unrevealed a molecular mechanism of the synaptic dysfunction in PD pathogenesis and provided a potential therapeutic target for treating PD.
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