Mechanism of Gp1 mGluR-dependent translation and plasticity

项目摘要/摘要 生物体对不断变化的环境的适应取决于生物体的可塑性 神经系统。神经元的可塑性通常需要依赖活动的翻译来快速供应选定的 蛋白质，例如，通过激活第1组代谢性谷氨酸受体(Gp1 MGluRs)。GP1 MGluR，包括mGluR1和mGluR5，介导翻译依赖的突触可塑性，包括长期 突触抑制(LTD)。Gp1 mGluR信号异常在多种神经和精神疾病中被观察到 疾病，包括脆性X综合征(FXS)和自闭症谱系障碍(ASDS)。虽然 Gp1 mGluR活性的药物校正可逆转这些动物模型的许多表型 疾病，Gp1 mGluR介导的突触可塑性的分子和细胞机制 难以捉摸。我们已发表的和初步的数据介绍泛素E3连接酶小鼠双分钟-2(MDM2)为 一种新的翻译抑制物和允许Gp1 mGluR诱导的蛋白质翻译的开关(Liu等人， Hum Mol Genet，2017)。在我们提出的研究中，我们的目标是表征MDM2在Gp1 mGluR- 依赖突触可塑性(目标1)并确定MDM2介导活动依赖的机制 蛋白质翻译(目标2)。我们的新数据还表明，MDM2是分子上的改变，对Gp1没有反应 Fmr1基因敲除(KO)小鼠mGluR活化是研究FXS(TSAI)的常用动物模型 等人，Hum Mol Genet，2017)。在目标3中，我们将描述Fmr1与Gp1互连的机制 MGluR信号允许通过去抑制MDM2来进行翻译激活。成功完成这项工作 建议将极大地促进理解Gp1 mGluR通过一种新的 翻译控制机制。在癌症生物学中对MDM2的深入了解基础上，我们的研究 也将为研究与Gp1 mGluR异常相关的神经疾病开辟一条新的途径 发信号。

PROJECT SUMMARY/ABSTRACT Adaptation of living organisms to constantly changing environments depends on the plasticity of the nervous system. Neuronal plasticity often requires activity-dependent translation to rapidly supply selected proteins, for example, through activation of Group 1 metabotropic glutamate receptors (Gp1 mGluRs). Gp1 mGluRs, including mGluR1 and mGluR5, mediate translation-dependent synaptic plasticity, including long-term synaptic depression (LTD). Dysregulated Gp1 mGluR signaling is observed with various neurological and mental disorders, including Fragile X Syndrome (FXS) and autism spectrum disorders (ASDs). Although pharmacological correction of Gp1 mGluR activity reverses many of the phenotypes in animal models of those diseases, the molecular and cellular mechanisms underlying Gp1 mGluR-mediated synaptic plasticity have been elusive. Our published and preliminary data introduce the ubiquitin E3 ligase Murine double minute-2 (Mdm2) as a novel translational repressor and a “switch” that permits Gp1 mGluR-induced protein translation (Liu et al., Hum Mol Genet., 2017). In our proposed research, we aim to characterize the role of Mdm2 in Gp1 mGluR- dependent synaptic plasticity (Aim 1) and determine the mechanism by which Mdm2 mediates activity-dependent protein translation (Aim 2). Our new data also show that Mdm2 is molecularly altered and unresponsive to Gp1 mGluR activation in the Fmr1 knockout (KO) mouse, the commonly used animal model for studying FXS (Tsai et al., Hum Mol Genet., 2017). In Aim 3 we will characterize the mechanism by which Fmr1 interconnects Gp1 mGluR signaling to permit translational activation through de-repressing Mdm2. Successful completion of this proposal will greatly facilitate the understanding of Gp1 mGluR-mediated synaptic plasticity through a novel mechanism of translational control. Building on the deep knowledge of Mdm2 in cancer biology, our research will also open a new avenue for the study of neurological disorders associated with abnormal Gp1 mGluR signaling.