寡聚型α-突触共核蛋白致小胶质细胞异常迁移的机制研究

The pathogenesis of Parkinson's disease (PD) remains unclear,and more evidences suggested that microglial cells play an important role.Alpha-synuclein,especially its oligomer is a key cause of PD,the relationship between oligomeric alpha-synuclein and microglia has been tremendously studied.Our previous study indicated that oligomeric alpha-synuclein could not only activate microglia,also induce microglial migration,which cause more dopaminergic neurons death and disease progress.Our further study demonstrated that monocyte chemotactic protein 1(MCP-1) was involved in the migration of microglia initiated by oligomeric alpha-synuclein.To understand the exact mechanism of oligomeric alpha-synuclein inducing the migration of microglia,we utilize quantative proteomic approaches to identify cell signal transduction proteins modulating the expression of MCP-1 and the migration process,basing on the preliminary data.The proposal will not only help us to understand how oligomeric alpha-synuclen inducing the abnormal migration of microglia,also provide a new valuable clue to the mechanism of disease progress.

帕金森病（PD）病因和进展机制尚不明确，小胶质细胞与PD发病密切相关。突触共核蛋白（alpha-synuclein）特别是其寡聚体作为PD重要的致病因素之一，其与小胶质细胞的关系受到重多关注，我们的前期研究发现寡聚型alpha-synuclein不仅可激活小胶质细胞，还可促使该细胞发生一定程度迁移，从而导致更多的多巴胺（DA）能神经元死亡，疾病持续进展；进一步研究表明单核细胞趋化蛋白-1（MCP-1）参与该迁移过程。为探讨寡聚型alpha-synuclein导致小胶质细胞迁移的具体机制，我们在研究寡聚型alpha-synuclein促使小胶质细胞发生迁移行为的基础上，应用定量蛋白质组学方法找出调控MCP-1表达变化继而影响小胶质细胞迁移的目标蛋白质，明确寡聚型alpha-synuclein 和小胶质细胞异常迁移及继发神经元损伤的具体机制。本项目将为PD发病和疾病进展研究提供有价值的新线索。

α-突触核蛋白（α-synuclein）对小胶质细胞的持续激活与迁移在帕金森病（PD）的发病过程中起着重要作用，其具体机制尚不明确。我们通过对中神经来源外泌体进行质谱分析鉴定出CXCL12，进一步发现PD患者神经来源外泌体中CXCL12升高且与α-synuclein水平正相关。在小胶质细胞系、原代小胶质细胞及A53T转基因小鼠中均观察到α-synuclein可明显促进CXCL12的分泌，小胶质细胞膜上CXCR4表达增高。进一步我们发现α-synuclein可通过激活TLR4-IKB-NF-kB通路促进 CXCL12分泌。而CXCL12作为趋化因子，可通过与其受体CXCR4结合从而诱导小胶质细胞发生迁移。本项目的开展为PD的发病机制、探索PD新的治疗途径提供有价值的新线索。