脑缺血损伤是临床常见的心脑血管疾病，脑缺血引起的最早损伤就是突触活动的消失，目前没有直接针对缺血条件下突触前囊泡循环的相关报道。我们前期研究发现缺血处理后alpha-Synuclein (α-Syn)在神经元内表达升高，有更多的α-Syn转位到突触前囊泡上；预先干扰α-Syn表达则阻止了缺血引起的突触囊泡胞吞的延迟；高表达α-Syn可促进突触囊泡和线粒体的相互作用，提示α-Syn可延迟突触囊泡的胞吞，并且与线粒体功能密切相关。根据以上结果，本项目拟在细胞和动物模型上，探讨脑缺血损伤时α-Syn延迟突触囊泡胞吞的分子机制；观察α-Syn是否介导线粒体与突触囊泡的相互作用及其分子基础是什么，并观察该互作是否进一步阻滞突触囊泡的胞吞；最后探寻能够同时逆向调节囊泡胞吞受阻和α-Syn病变的生物靶标分子。进行该项目的研究将为进一步阐明脑缺血损伤的机制和寻找脑缺血损伤的临床治疗靶标提供有力的理论依据。

Cerebral ischemic injury is the most common cardiovascular and cerebrovascular diseases. The earliest damage response induced by ischemia is the disappearance of synaptic activities in brain. Up to now, there is few studies focused on presynaptic recycling under ischemic condition. Our preliminary data demonstrated that the ischemia significantly induced the expression of alpha-Synuclein (α-Syn) in neurons and translocation to presynaptic vesicles. Knockdown of α-Syn could block the prolongation of endocytosis induced by ischemia. Overexpression of α-Syn markedly induced the organellar interactome between mitochondria and synaptic vesicles. Based on above findings, we hypothesize that α-Syn may delay the endocytosis of synaptic vesicles, which is closely related to mitochondrial function in ischemic insult. The aim of this project is to study that the novel mechanisms on delay of synaptic vesicles endocytosis induced by α-Syn, whether α-Syn mediates the organellar interactome between mitochondria and synaptic vesicles, if so, what molecule(s) involves in it and what role of this interactome on endocytosis of synaptic vesicles after ischemic treatment. Finally, we will identify the potential target proteins that they can reversely regulate the prolongation of endocytosis induced by ischemia and pathological action by α-Syn using an in vitro and an in vivo ischemic models. Pursuing on this study will help to clarify the mechanisms on brain damage caused by ischemia and provide an effective target to protect brain against ischemic injury.