黏结合蛋白多糖syndecan介导AUTS2综合征神经发育缺陷的机制研究及干预策略

AUTS2综合征是由AUTS2基因突变引起的一种罕见神经发育疾病。鉴于其有明确的遗传学病因，是研究神经发育疾病机制的绝佳模型。目前已知AUTS2基因突变可导致神经元迁移受损，但其分子机理仍不明确。本课题组前期利用AUTS2综合征患儿的体细胞建立了人源干细胞分化的神经元模型，并RNAseq分析对比了正常人与患者来源的神经元表达谱差异，发现黏结合蛋白多糖syndecan相关通路为主要受影响通路，遂提出syndecan介导AUTS2突变所致神经元迁移缺陷这一假说。本项目拟以人源干细胞分化的神经元为模型，探究AUTS2综合征中syndecan介导的神经元迁移缺陷及相关细胞骨架调节机制。因syndecan可受食物来源的DHA调节，本项目将进一步尝试外源补充DHA对神经元迁移缺陷进行挽救。本研究将明确AUTS2综合征发病机制中的关键因子并提供可能的干预策略。

AUTS2 syndrome is a rare neurodevelopmental disorder caused by mutations of AUTS2 gene. With a definite genetic etiology, it provides an ideal model for research of neurodevelopmental disorders. AUTS2 mutations were known to cause defects of neuronal migration, while the exact molecular mechanism is unclear. Our group has established induced-pluripotent stem cell lines (iPS) derived from AUTS2 patients, and subsequent RNAseq analysis of differentiated neurons revealed syndecan in multiple pathways enriched by differentially-expressed genes between normal and diseased neurons. We propose that syndecan mediates the defects of neuronal migration caused by AUTS2 mutations. In this study, we will utilize the established human iPS-neuron model to explore the syndecan-mediated mechanism of cytoskeletal regulation and neuronal migration defects in AUTS2 syndrome. As syndecan expression is regulated by food-derived DHA, we will further investigate if DHA supplements could rescue the migration defects in diseased neurons. The results of this study will provide key therapeutic targets and potential interventional strategy for AUTS2 syndrome.