PQBP1调控神经元轴树突生长发育的机制研究

Mental retardation (MR) is a common neurodevelopmental disease. Clinical genetic analysis showed that PQBP1 mutation is closely related with mental retardation. However, the pathogenesis of PQBP1 mutation is not fully understood. Our previous study showed the abnormal development of axon and dendrite in Pqbp1 cKO mice. Actin plays an important role in axonal and dendritic development. Moreover, we find that PQBP1 interacts with N-WASP, which functions in actin polymerization. In this proposal, we will utilize a combination of the approach in cell biology, genetics, biochemistry, molecular biology, neurobiology and image to investigate the regulation of PQBP1 in the activity, distribution and stability of N-WASP and the mechanism of PQBP1 in actin polymerization. The study may provide a new perspective for revealing the mechanism of mental retardation caused by PQBP1 mutation, which is of great significance for the future of drug design.

智力迟滞（Mental Retardation, MR或Intellect Disability, ID)是一种常见的神经发育疾病。临床遗传分析显示多聚谷氨酰胺结合蛋白1（PQBP1)基因突变与智力发育迟滞密切相关，但其致病机理目前还不完全清楚。我们前期的研究显示Pqbp1敲除小鼠大脑中轴突和树突生长异常。肌动蛋白在神经元轴树突生长中起着重要作用。我们发现PQBP1与肌动蛋白聚合调控分子N-WASP相互作用。在本申请项目中，我们将利用细胞生物学，遗传学，神经生物学和影像学的手段，研究PQBP1通过对N-WASP的活性、分布和稳定性的调控，进而影响肌动蛋白聚合的机制。本项目的研究可能为揭示PQBP1突变导致的智力障碍提供新的视角，对今后的药物设计有非常重要的意义。

智力迟滞（Mental Retardation, MR或Intellect Disability, ID)是一种常见的神经发育疾病。临床遗传分析显示多聚谷氨酰胺结合蛋白1（PQBP1)基因突变与智力发育迟滞密切相关，但其致病机理目前还不完全清楚。本研究中，我们发现PQBP1与肌动蛋白聚合调控分子N-WASP相互作用。PQBP1通过WW结构域与N-WASP的PPP结构域结合，影响N-WASP的活性。PQBP1缺失不影响N-WASP的表达与定位。利用肽段干扰PQBP1与N-WASP的相互作用会导致神经元生长异常。在海马成熟神经元中敲除Pqbp1，会导致海马依赖的认知功能显著下降，并证实其认知能力下降是由于代谢型谷氨酸受体依赖的突触长时程抑制（mGluR-LTD）受损所引起的。该研究揭示了PQBP1在细胞质中参与调控神经元生长和神经元功能的作用机制，为揭示PQBP1突变导致的智力障碍提供新的视角，对今后的药物设计有非常重要的意义。