Synaptotagmin-11 inhibits neural endocytosis and mediates parkin-linked Parkinson's disease

讲座名称: Synaptotagmin-11 inhibits neural endocytosis and mediates parkin-linked Parkinson's disease
讲座时间: 2016-10-28
讲座人: 王昌河
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校区: 兴庆校区
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讲座内容: 报告题目:Synaptotagmin-11 inhibits neural endocytosis and mediates parkin-linked Parkinson's disease 报告时间:10月28日(周五)下午2:00 报告地点:生命学院308报告厅 报告人:王昌河 报告内容:Loss-of-function mutations in Parkin are the most common causes of autosomal recessive Parkinson’s disease (PD). Many putative substrates of parkin have been reported; their pathogenic roles, however, remain obscure due to poor characterization, particularly in vivo. Here, we show that synaptotagmin-11 is a physiological substrate of parkin and plays a critical role in mediating parkin-linked neurotoxicity. We find that synaptotagmin-11 inhibits synaptic vesicle (SV) endocytosis by impairing the replenishment of synaptic releasable vesicle pools. Increased expression of synaptotagmin-11 in the substantia nigra pars compacta (SNpc) impairs striatal dopamine release, causes late-onset degeneration of dopaminergic neurons, and induces progressive contralateral motor abnormalities. Parkin deficiency induces synaptotagmin-11 accumulation and PD-related neurotoxicity, which is fully reversed by synaptotagmin-11 knockdown in the SNpc or specific deletion in dopaminergic neurons. Thus, parkin dysfunction-induced neurotoxicity in PD requires synaptotagmin-11 accumulation in SNpc dopaminergic neurons. These findings reveal a parkin-synaptotagmin-11 pathogenic pathway and synaptotagmin-11 activity as a novel therapeutic target for PD.  
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