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.

项目概要/摘要 广泛的研究表明，细胞应激和随后的应激反应，例如 全局翻译抑制在与淀粉样蛋白β（Aβ）相关的阿尔茨海默氏病中被夸大，并且 它们促进神经退行性变。缓解压力反应已被证明可以改善神经元和 Aβ 病理动物模型中的电路功能。然而，我们对分子机制的理解 潜在的 Aβ 诱导的细胞应激反应是有限的。此外，目前还不清楚是否存在任何 这些机制背后的性别特异性调节。为了解答这些问题，我们初步收集了 数据揭示了 Aβ 诱导的脆性 X 智力迟钝蛋白 (FMRP) 和 FMRP- 的上调 真核翻译延伸因子 2 (eEF2) 的依赖性磷酸化和随后的翻译 抑制。值得注意的是，我们的数据还表明这些机制可能只发生在女性身上，而不是女性身上。 在 Aβ 病理小鼠模型中的雄性小鼠中。因此，我们假设 Aβ 诱导 FMRP 升高 导致过度的翻译抑制和神经变性，特别是在女性中。在目标 1 中， 我们建议表征并减少 Aβ 相关的 eEF2 磷酸化，以改善翻译 体外原代神经元的抑制。在目标 2 中，我们建议研究 FMRP 的性别特异性调节和 体内 Aβ 病理学中的翻译抑制。我们还建议通过基因抑制 FMRP 来改善 Aβ- 诱导小鼠体内神经变性。这项补充研究属于目标 3 的范围 家长奖，其中 FMRP 依赖性调节全局翻译抑制和突触可塑性 正在通过磷酸化信号进行研究。通过FMRP在阿尔茨海默病中的研究，我们 期望我们的结果将 (1) 阐明 Aβ 积累导致转化的新机制 抑制，(2) 揭示 Aβ 病理学中翻译抑制的性别特异性调节，(3) 表明 改善过度细胞应激反应和神经退行性变的新治疗靶点 阿尔茨海默病。我们的研究以现有工具和 FMRP 的丰富知识为基础， 有望为未来研究阿尔茨海默病相关认知能力下降迅速开辟新途径 和记忆障碍。