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.

项目总结/摘要 广泛的研究表明，细胞应激和随后的应激反应，如 在淀粉样蛋白β（Aβ）相关的阿尔茨海默病中被夸大， 它们促进神经退化。减轻应激反应已被证明可以改善神经元和 Aβ病理学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有限。此外，还不清楚是否有任何 这些机制背后的性别特异性调节。为了解决这些问题，我们收集了初步的 这些数据揭示了Aβ诱导的脆性X智力低下蛋白（FMRP）和FMRP- 真核翻译延伸因子2（eEF 2）的依赖性磷酸化和随后的翻译 镇压值得注意的是，我们的数据还表明，这些机制可能只发生在女性，而不是男性。 在Aβ病理学小鼠模型的雄性小鼠中。因此，我们假设Aβ诱导的FMRP升高可能与Aβ诱导的FMRP升高有关。 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eEF 2磷酸化，以改善其翻译， 抑制体外原代神经元。在目标2中，我们提出研究FMRP的性别特异性调节， 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- 在小鼠体内诱导神经变性。这项补充研究属于《公约》目标3的范围。 父母奖，其中FMRP依赖的全球翻译抑制和突触可塑性的调节 正在通过磷酸化信号进行研究。通过对FMRP在阿尔茨海默病中的研究， 预期我们的结果将（1）阐明一种新的机制，通过这种机制，Aβ的积累导致翻译 抑制，（2）揭示了Aβ病理学中翻译抑制的性别特异性调节，（3）提示 用于改善神经退行性疾病中过度的细胞应激反应和神经变性的新的治疗靶点 老年痴呆症基于现有的工具和FMRP的大量知识，我们的研究具有 有可能为阿尔茨海默病相关认知能力下降的未来研究快速开辟新的途径 和记忆障碍