Translational control in neurons

描述(申请人提供)：非蛋白质编码(NPC)RNA是控制真核基因表达的关键媒介。在大脑中，npcRNAs与适应性变化有关，这是神经元对外部刺激做出长期可塑性反应的基础。据认为，这种能力至少部分是由突触基因表达的翻译调控支持的。然而，虽然为突触蛋白质谱的输入特异性管理提供了一个分子框架，但突触翻译的概念取决于确保严格控制翻译机制的分子工具。实施这种控制的功能机制是什么，它们在神经元中是如何调节的？在这里提出的研究中，提出了小的npcRNA在神经元翻译控制的协调中发挥作用。具体地说，推测突触-树突状BC RNAs通过抑制起始机制参与神经元翻译。这个猜想将按如下方式进行实验研究。首先，通过解剖Bc1 RNA与其翻译途径中的靶标真核细胞起始因子4A(EIF4A)之间的功能相互作用，阐明BC介导的抑制的分子机制。这项分析还将探索eIF4A辅助因子eIF4B作为bc1-eIF4A相互作用的效应者的作用。下一步将建立人类BC200 RNA在翻译控制中的作用模式。这一努力是由BC200 RNA的概念推动的，BC200 RNA是一种发挥翻译抑制因子功能的灵长类npcRNA，可能与神经系统疾病有关。BC介导的抑制的神经元靶点将使用候选和无偏见的方法来识别。由于BC抑制的功能结果似乎与脆性X智力低下蛋白(FMRP)的功能结果相交，因此有必要确定这两条抑制途径的作用模式和潜在的趋同。在最后的目标中，这一假设将被仔细研究，即BC抑制可能操作于MEK/ERK信号通路，有助于通过代谢性谷氨酸受体激活而导致突触力量相对于翻译刺激的平衡。建立npcRNAs在神经元翻译控制通路中的分子机制和功能意义是本研究的总体目标。预计这项工作的结果将阐明这些通路在突触可塑性维持和功能障碍中的作用。与公共健康相关：在神经元中，突触-树突状BC RNA的翻译控制与突触局部刺激-抑制动态平衡的维持有关。Bc1控制的失调导致突触的高兴奋性和致痫反应，这些反应似乎与由于缺乏脆性X智力低下蛋白而导致的后遗症交叉。因此，失调的BC控制的功能后果与神经和精神障碍的生物学直接相关。

DESCRIPTION (provided by applicant): Non-protein-coding (npc) RNAs are key mediators in the control of eukaryotic gene expression. In brain, npcRNAs have been implicated in adaptive changes that underlie a neuron's capacity for long-term plastic responses to external stimuli. Such capacity, it is suggested, is supported at least in part by the translational regulation of gene expression at the synapse. However, while providing a molecular framework for the input-specific management of synaptic protein repertoires, the concept of synaptic translation is contingent upon molecular tools to ensure stringent control of the translational machinery. What are the functional mechanisms to implement such control, and how are they regulated in neurons? In the research proposed here, it is submitted that small npcRNAs are instrumental in the orchestration of neuronal translational control. Specifically, it is conjectured that synapto-dendritic BC RNAs engage neuronal translation by repressing the initiation mechanism. This conjecture will be experimentally investigated as follows. First, the molecular mechanism of BC-mediated repression will be elucidated by dissecting the functional interplay between BC1 RNA and its target in the translation pathway, eukaryotic initiation factor 4A (eIF4A). This analysis will also probe the role of eIF4B, an eIF4A co-factor, as an effector of BC1-eIF4A interactions. The subsequent step will establish the mode of action of human BC200 RNA in translational control. This effort is prompted by the notion that BC200 RNA, a primate npcRNA that functions as a translational repressor, may be implicated in neurological disease. Neuronal targets of BC-mediated repression will be identified using candidate and unbiased approaches. Because the functional consequences of BC repression appear to intersect with those of the fragile X mental retardation protein (FMRP), it will be necessary to ascertain mode of action and potential convergence of the two repression pathways. In the final objective, the hypothesis will be scrutinized that BC repression, conceivably operating in the MEK/ERK signaling pathway, contributes to a synaptic balance of power vis-¿-vis translational stimulation resulting from metabotropic glutamate receptor activation. It is the overall goal of the proposed research to establish molecular mechanisms and functional significance of npcRNAs in neuronal translational control pathways. It is anticipated that results from this work will shed light on the role of such pathways in synaptic plasticity maintenance and dysfunction. PUBLIC HEALTH RELEVANCE: In neurons, translational control by synapto-dendritic BC RNAs has been implicated in the maintenance of local stimulation-repression homeostasis at the synapse. Dysregulation of BC1 control precipitates synaptic hyperexcitability and epileptogenic responses that appear to intersect with sequelae resulting from lack of fragile X mental retardation protein. The functional consequences of dysregulated BC control are therefore of direct relevance to the biology of neurological and mental disorders.