Mechanism of Gp1 mGluR-dependent translation and plasticity

Gp1 mGluR 依赖性翻译和可塑性机制

• 批准号: 10469161
• 负责人: Nien-Pei Tsai
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10469161
• 关键词: Address; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Award; Cellular Stress; Cellular Stress Response; Data; FMR1; Female; Future; GTPBP1 gene; Impaired cognition; In Vitro; Knowledge; Memory impairment; Molecular; Mus; Nerve Degeneration; Neurons; Parents; Pathology; Peptide Elongation Factor 2; Phosphorylation; Regulation; Research; Risk Factors; Sex Differences; Signal Pathway; Signal Transduction; Synaptic plasticity; Translations; Up-Regulation; abeta accumulation; biological adaptation to stress; improved; in vivo; male; mouse model; neuronal circuitry; neurotoxic; new therapeutic target; novel; sex; tool

PROJECT SUMMARY/ABSTRACT Extensive studies have demonstrated that cellular stress and the subsequent stress response, such as global translational suppression, are exaggerated in amyloid beta (Aβ)–associated Alzheimer’s disease and that they facilitate neurodegeneration. Alleviating the stress response has been shown to improve neuronal and circuit functions in animal models of Aβ pathology. However, our understanding of the molecular mechanisms underlying Aβ-induced cellular stress response is limited. Furthermore, it is also unclear whether there is any sex-specific regulation behind those mechanisms. To address these questions, we have gathered preliminary data that reveal an Aβ-induced up-regulation of fragile X mental retardation protein (FMRP) and the FMRP- dependent phosphorylation of eukaryotic translation elongation factor 2 (eEF2) and subsequent translational suppression. Remarkably, our data also suggest that these mechanisms potentially occur only in female but not in male mice in an Aβ-pathology mouse model. We therefore hypothesize that elevated FMRP induced by Aβ contributes to exaggerated translational suppression and neurodegeneration, particularly in females. In Aim 1, we propose to characterize, as well as reduce, Aβ-associated eEF2 phosphorylation to ameliorate translational suppression in primary neurons in vitro. In Aim 2, we propose to study sex-specific regulation of FMRP and translational suppression in Aβ pathology in vivo. We also propose to genetically inhibit FMRP to ameliorate Aβ- induced neurodegeneration in mice in vivo. This supplemental research is within the scope of the Aim 3 of the parent award in which the FMRP-dependent regulation of global translational suppression and synaptic plasticity are being studied through phosphorylation signaling. Through the research of FMRP in Alzheimer’s disease, we expect that our results will (1) elucidate a novel mechanism by which accumulation of Aβ leads to translational suppression, (2) uncover a sex-specific regulation in translational suppression in Aβ pathology, and (3) suggest novel therapeutic targets for ameliorating exaggerated cellular stress response and neurodegeneration in Alzheimer’s disease. Building on existing tools and substantial knowledge of FMRP, our research has the potential to quickly open new avenues for the future study of Alzheimer’s disease–associated cognitive decline and memory impairment.

项目摘要/摘要 广泛的研究表明，细胞应激和随后的应激应力反应，例如 在淀粉样β（Aβ） - 相关的阿尔茨海默氏病中被夸大了全球翻译抑制作用。 它们促进神经变性。 电路在Aβ病理学的动物模型中的功能。 另外，Aβ诱导的细胞应激反应受到限制。 这些机制的特定于性别的法规。 揭示Aβ引起的易碎X智力低下蛋白（FMRP）和FMRP-的上调的数据 真核翻译伸长因子2（EEF2）的依赖性磷酸化和随后的翻译 spectness。 在Aβ-Phatogy小鼠模型中，我们假设Aβ诱导的FMRP升高 在AIM 1中有助于夸张的翻译抑制和神经变性。 我们建议表征并减少与Aβ相关的EEF2磷酸化对氨基酯转化的磷酸化 在AIM 2中的原发性神经元中，我们建议研究FMRP的特定法规 在体内Aβ病理学中的转化。我们还建议遗传抑制FMRP 在体内诱导的小鼠神经变性。 FMRP依赖的全球翻译抑制和突触可塑性调节的父母奖 正在研究FMRP在阿尔茨海默氏病中的研究。 期望我们的结果将（1）阐明一种新的机制，通过该机制，Aβ的积累导致翻译 提倡，（2）在Aβ病理学中的转化抑制中发现了性别特定的调节，（3）表明 新型的治疗靶标，用于在夸张的细胞应激反应和神经退行性范围 阿尔茨海默氏病。 潜力迅速开放新的途径，以对阿尔茨海默氏病相关的认知能力下降的未来研究 和记忆力障碍。