内质网蛋白SIL1对NMDA受体运输的调节机制及其对突触可塑性的影响

项目名称： 内质网蛋白SIL1对NMDA受体运输的调节机制及其对突触可塑性的影响

项目编号： No.31460258

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 神经、认识与心理学

项目作者： 张筱敏

作者单位： 昆明医科大学

项目金额： 48万元

中文摘要： 依赖于内质网的树突局部合成可以为突触快速提供新生蛋白质，这一过程被称为非经典运输途径。然而，这一途径是否参与保障诸如长时程增强、长时程减弱等可塑性变化的顺利完成，也即其功能意义，目前并不清楚。内质网分子伴侣蛋白Bip的辅助因子SIL1的突变将会导致Marinesco-Sjogren综合症，该疾病经典症状之一为智力发育障碍。而我们的前期研究显示，NMDA受体的GluN2A亚基受可塑性刺激,在Bip介导下经由非经典途径运输表达。基于以上两点，我们认为SIL1的突变可能因为干扰了GluN2A的非经典运输而引起智力发育障碍。在本项目中，我们将重点研究SIL1的功能缺陷对于Bip的底物蛋白--NMDA受体GluN2A亚基的表达、运输及功能的影响，尤其是对神经元可塑性刺激调节含GluN2A的NMDA受体的突触表达的过程及NMDA受体参与的学习记忆功能的影响，从而揭示非经典运输在中枢神经系统的功能意义。

中文关键词： SIL1；NMDA受体；运输；突触可塑性；学习记忆

英文摘要： Endoplasmic Reticulum (ER) is an important organelle that responsible for the synthesis, folding and assembly of transmembrane proteins and secretory proteins. Recent years, it is found that the proper function of ER is of required for the plasticity of central nervous system. The non-canonical trafficking is a newly discovered trafficking pathway for dendritic localized proteins, in which the nascent proteins were synthesized in dendrite but not soma, and thus the nascent protein could quickly be transported into synapse. Several important dendritic localized neuronal receptors, including the NMDA receptor, have been proved to be transported non-canonically. However, it is not clear whether or not the non-canonical trafficking is required for the neuronal plasticity, for example long-term potentiation (LTP) and long-term depression (LTD). In other words, the physiological function of neuronal non-canonical pathway is unknown yet. Recent works on the genetics of disease has found a single gene SIL1, the mutation of which resulted in Marinesco-Sj?gren Syndrome (MSS). The MSS is an autosomal recessively inherited neurodegenerative disorder characterized by cerebellar ataxia, cataracts and mental retardation. SIL is the nucleotide exchange factor of Bip, which is a multi-functional ER chaperone. It is interesting that a single mutation of an ER localized protein causes disorders of central nervous system. It is possible that the mutation of SIL1 disrupted the local synthesis in ER and thus leading to the mental retardation. In this project, we set out a serious of experiments to explore this hypothesis and thus to make clear the physiological function of local synthesis in neuron. Since we have found in our earlier study that the GluN2A subunit of NMDA receptor was the substrate of Bip and thus whose synthesis and assembly with GluN1 may be regulated by SIL1. It is well-known that the NMDA receptor plays key roles in multiple high level functions of the central nervous system, including LTP and LTD, both of which are considered as the molecular basis of learning and memory. Thus in this project we will focus on studying the deficits in the synthesis, trafficking and function of NMDA receptor, especially the GluN2A-containing NMDA receptor resulted from SIL1 mutation. Through this project, we hope to uncover the molecular mechanism underling the mental retardation of MSS, and to proved evidence for the physiological importance of dendritic ER-involved local synthesis of neuron.

英文关键词： SIL1;NMDA receptor;trafficking;synaptic plasticity;learning and memory