PrPSc蓄积诱导神经元损伤是Prion疾病引起机体神经症状及以死亡告终的根本原因。而线粒体动力学失衡和功能障碍是PrPSc引起神经元凋亡的关键因素，但具体调控机制尚不清楚。最新研究报道，Retromer功能丧失是引起多种神经退行性疾病的关键因素之一，而VPS35是Retromer发挥功能的核心蛋白。而且已有蛋白组学研究结果提示，Retromer可能负责转运维持线粒体动力学平衡（融合/裂变）的关键蛋白。因此，本课题主要利用CRISPR/Cas9、慢病毒过表达载体等技术，靶向于Retromer-VPS35在PrPSc引起神经元线粒体动力学失衡的调控机制进行研究，试图筛选Retromer-VPS35负责转运的与线粒体融合/裂变相关的主要蛋白，并对其关键信号通路进行研究分析，以此探索PrPSc引起神经元损伤的分子机制，进而为揭示Prion疾病的致病机制和寻找治疗靶位点提供科学依据和理论支持。

Accumulation of PrPSc induces neuronal damage is the root cause of neurological symptoms and death in Prion disease. Mitochondrial dynamics disruption and dysfunction are the key factors for neuronal apoptosis induced by PrPSc, but the molecular mechanism of specific regulation is still unclear. Recent studies have reported that loss of Retromer function is one of the key factors causing a variety of neurodegenerative diseases, and VPS35 is the core protein that Retromer functions. Moreover, the results of proteomics studies suggest that Retromer may be responsible for transporting key proteins that maintain mitochondrial dynamics balance (fusion/fission). Therefore, this study will mainly employ with CRISPR/Cas9, lentiviral overexpression vectors and other techniques, targeting the regulatory mechanism of Retromer-VPS35 in PrPSc-induced neuronal mitochondrial dynamics disruption, attempting to filtrate Retromer-VPS35 is responsible for the transport of major proteins involved in mitochondrial fusion/fission, and its key signaling pathways are studied to explore the molecular mechanism of PrPSc-induced neuronal damage. And then the results will provide scientific evidence and theoretical support for revealing the pathogenesis and finding therapeutic targets in Prion disease.