Targeting protein synthesis dysregulation in Down syndrome-associated cognitive impairment with aging

项目摘要/摘要 唐氏综合征(DS)是与三体重复序列相关的最常见的智能障碍形式之一 21号染色体的。包括痴呆症在内的认知障碍是DS的一个标志，但潜在的 细胞/分子机制尚不清楚，阻碍了我们开发有效的认知疗法的能力 DS患者的缺陷。患有DS的人患阿尔茨海默病(AD)的风险要高得多， 毁灭性的神经退行性疾病和最常见的老年痴呆症。从中年开始， 大多数DS患者会出现类似AD的神经病理和痴呆症状。长时记忆 突触的可塑性需要从头合成蛋白质，最近的研究表明，mrna翻译 包括阿尔茨海默病在内的几种神经性疾病中，认知障碍与认知综合征有关，与大脑无关 淀粉样β病理。在之前的研究和我们的初步数据的推动下，这个项目的目标是 确定是否通过抑制eEF2K上调从头合成蛋白质的能力 和eEF2的磷酸化，将改善DS的多种与衰老相关的病理生理学，包括突触 失败和认知缺陷。已经设计了三个具体的目标来检验这一假设。目标1寻求 确定抑制eEF2K和eEF2磷酸化是否减轻突触可塑性损伤 唐氏综合征小鼠模型的建立。目的2是确定是否抑制eEF2K和eEF2 磷酸化可以改善DS相关的认知缺陷。目标3是阐明DS的潜在机制 与eEF2K/eEF2信号级联失调相关的病理生理学。该项目提出了深入的 使用神经科学中的多种方法进行分析，包括突触电生理学、药理学、 成像、小鼠遗传学和行为测试。我们将使用新的遗传模型和分析方法来评估 神经元中新蛋白的合成，包括生物正交非规范氨基酸标记(BONCAT) 邻近连接试验(PLA)(BONCAT-PLA)。结合质谱学/蛋白质组学的方法，我们 期待揭示DS大脑中因异常而合成失调的蛋白质的身份 EEF2K/eEF2信号转导。这个项目的发现将有助于我们对细胞/分子的理解 DS相关认知损害潜在的信号机制。这个项目的结果可能会让人们 最终为DS相关认知综合征开发新的治疗策略，但对这些综合征无效 治疗方法是存在的。

Project Summary/Abstract Down syndrome (DS) is one of the most common forms of intellectual disability associated with trisomic repeat of chromosome 21. Impaired cognition including dementia is a hallmark of DS, but the underlying cellular/molecular mechanisms remain unclear, hampering our ability to develop effective therapy for cognitive defects in people with DS. People with DS are at much higher risk for developing Alzheimer’s disease (AD), a devastating neurodegenerative disease and the most common of dementia in elderly. Starting at middle age, majority of DS patients develop neuropathology and dementia syndromes resembling AD. Long-term memory and synaptic plasticity require de novo protein synthesis, and recent studies indicate that mRNA translation impairments contribute to cognitive syndromes in several neuronal diseases including AD, independent of brain Amyloid beta pathology. Driven by previous studies and our preliminary data, the goal of this project is to determine whether upregulation of the capacity for de novo protein synthesis, via suppression of eEF2K and eEF2 phosphorylation, will improve multiple aging-related pathophysiology in DS including synaptic failure and cognitive deficits. Three specific aims have been designed to test this hypothesis. Aim 1 seeks to determine whether inhibition of eEF2K and eEF2 phosphorylation alleviates synaptic plasticity impairments in mouse models of Down syndrome. Aim 2 is to determine whether suppression of eEF2K and eEF2 phosphorylation can improve DS-associated cognitive deficits. Aim 3 is to elucidate mechanisms underlying DS pathophysiology associated with dysregulation of eEF2K/eEF2 signaling cascade. The project proposes in-depth analyses using multiple approaches in neuroscience, including synaptic electrophysiology, pharmacology, imaging, mouse genetics, and behavioral tests. We will employ novel genetic models and assays to assess de novo protein synthesis in neurons including bioorthogonal noncanonical amino acid tagging (BONCAT) with a proximity ligation assay (PLA) (BONCAT-PLA). Combined with mass spectrometry/proteomics approach, we expect to reveal identities of proteins in DS brains whose synthesis is dysregulated because of abnormal eEF2K/eEF2 signaling. Findings from this project will contribute to our understanding of the cellular/molecular signaling mechanisms underlying DS-associated cognitive impairments. Results from this project could inform eventual development of novel therapeutic strategies for DS-related cognitive syndromes, for which no effective treatments exist.