本研究的总体目标是探索蛋白泛素化降解信号网络在神经发育相关疾病中对突触可塑性的调控机制。申请人最近的研究发现Cdh1-APC，一种脑内主要的泛素E3连接酶，可以特异性地调控fragile X综合症蛋白FMRP的泛素化降解，从而促进脑内海马代谢性谷氨酸依赖的长时程突触抑制(mGluR-LTD)的发生。为了进一步理解Cdh1-APC/FMRP蛋白泛素化信号网络对突触可塑性的调控机制，我们将通过结构－功能分析研究调控Cdh1-APC功能的上游分子机制；以及鉴定受Cdh1-APC/FMPR信号通路调节的目标蛋白，从而发现Cdh1-APC/FMRP调控mGluR-LTD的下游分子机制。本项目还将重点验证Cdh1-APC成为治疗fragile X综合症新的分子靶点的可行性，即是否可以通过抑制Cdh1-APC来恢复fragile X脑内FMRP的水平以及fragile X相关的认知行为障碍。

The goals of the proposed research are to elucidate the role of ubiquitin-signaling networks in the regulation of synaptic function in .neurodevelopmental disorders. We recently discovered that conditional knockout of Cdh1, the key coactivator of the major E3 ubiquitin ligase Cdh1-APC, profoundly impairs metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) in the hippocampus. In mechanistic studies, we have identified the fragile X syndrome protein FMRP as a novel substrate of Cdh1-APC in the regulation of mGluR-LTD in the hippocampus. These findings define the major E3 ubiquitin ligase Cdh1-APC and fragile X syndrome protein FMRP as components of a novel ubiquitin-signaling pathway that regulates mGluR-dependent synaptic plasticity. These findings also raise fundamental questions on the mechanisms of Cdh1-APC signaling in synaptic plasticity and potential biological implications of Cdh1-APC in the treatment of fragile X mental retardation. In the current proposal, we aim to elucidate mechanisms regulating Cdh1-APC in mGluR-LTD, define mechanisms by which Cdh1-APC drives mGluR-LTD, and determine implications of Cdh1-APC signaling in fragile X syndrome. Addressing these questions will advance our understanding of ubiquitin-signaling network in the regulation of synaptic function in neurodevelopmental disorders.