Mechanism of Gp1 mGluR-dependent translation and plasticity

项目摘要/摘要 广泛的研究表明，细胞应激和随后的应激反应，如 全球翻译抑制在淀粉样β蛋白(Aβ)相关的阿尔茨海默病中被夸大，而且 它们会促进神经退化。缓解应激反应已被证明可以改善神经元和 电路在β病理动物模型中的作用。然而，我们对分子机制的理解 潜在的β诱导的细胞应激反应是有限的。此外，也不清楚是否有任何 这些机制背后有针对性别的监管。为了解决这些问题，我们收集了初步的 数据显示Aβ诱导的脆性X智力低下蛋白上调和脆性X智力低下蛋白- 真核细胞翻译延伸因子2(EEF2)的依赖磷酸化及其随后的翻译 压制。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 在Aβ病理小鼠模型中的雄性小鼠中。因此，我们假设Aβ引起的FMRP升高 导致夸大的翻译抑制和神经变性，特别是在女性。在目标1中， 我们建议表征并减少β相关的eEF2磷酸化以改善翻译 体外培养的原代神经元抑制。在目标2中，我们建议研究FMRP和FMRP的性别特异性调控 体内β病理中的翻译抑制。我们还建议通过基因抑制FMRP来改善A-β- 在体内诱导小鼠神经变性。这项补充研究属于目标3的范围。 FMRP依赖的全球翻译抑制和突触可塑性调节的亲本奖 正在通过磷酸化信号转导进行研究。通过对阿尔茨海默病FMRP的研究，我们发现 预计我们的结果将(1)阐明一种新的机制，即Aβ的积累导致翻译 抑制，(2)揭示β病理中翻译抑制的性别特异性调节，以及(3)建议 新的治疗靶点，以改善夸大的细胞应激反应和神经变性 阿尔茨海默氏症。在现有工具和FMRP大量知识的基础上，我们的研究具有 有可能迅速为阿尔茨海默病相关认知障碍的未来研究开辟新的途径 以及记忆力减退。

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.