Mechanism of Gp1 mGluR-dependent translation and plasticity

项目总结/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。 神经系统神经元可塑性通常需要依赖于活动的翻译，以快速提供选择的 蛋白质，例如通过激活组1代谢型谷氨酸受体（Gp 1 mGluRs）。GP1 mGluR，包括mGluR 1和mGluR 5，介导突触可塑性，包括长时程突触可塑性。 突触抑制（LTD）。Gp 1 mGluR信号转导失调可在多种神经和精神疾病中观察到。 这些疾病包括脆性X综合征（FXS）和自闭症谱系障碍（ASD）。虽然 Gp 1 mGluR活性的药理学校正逆转了这些动物模型中的许多表型， 疾病，潜在的Gp 1 mGluR介导的突触可塑性的分子和细胞机制已被 难以捉摸我们已发表的和初步的数据介绍了泛素E3连接酶小鼠双分钟-2（Mdm 2）， 一种新的翻译阻遏物和一种允许Gp 1 mGluR诱导的蛋白翻译的“开关”（Liu等， Mol Genet.，2017年）。在我们提出的研究中，我们的目标是表征Mdm 2在Gp 1 mGluR中的作用。 依赖性突触可塑性（Aim 1），并确定Mdm 2介导活动依赖性突触可塑性的机制。 蛋白质翻译（Aim 2）。我们的新数据还表明，Mdm 2在分子上发生了改变，对Gp 1没有反应。 Fmr 1敲除（KO）小鼠中的mGluR激活，这是研究FXS的常用动物模型（Tsai 例如，Mol Genet.，2017年）。在目标3中，我们将描述Fmr 1与Gp 1相互连接的机制 mGluR信号传导以允许通过去阻遏Mdm 2的翻译激活。成功完成本 该提案将通过一种新的方法极大地促进对Gp 1 mGluR介导的突触可塑性的理解。 翻译控制机制。基于对Mdm 2在癌症生物学中的深入了解，我们的研究 也将为研究与异常Gp 1 mGluR相关的神经系统疾病开辟新的途径 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.