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

针对与唐氏综合症相关的衰老认知障碍中的蛋白质合成失调

• 批准号: 10295206
• 负责人: Tao Ma
• 金额: $ 114.27万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295206
• 关键词: Age; Aging; Alzheimer' s Disease; Amino Acids; Award; Basic Science; Biological Assay; Brain; Chromosome 21; Cognition Disorders; Cognitive deficits; Data; Dementia; Dendritic Spines; Development; Disease; Down Syndrome; Elderly; Electrophysiology (science); Failure; Functional disorder; Future; Genetic Models; Genetic Suppression; Genetic Translation; Goals; Image; Impaired cognition; Impairment; Individual; Intellectual functioning disability; Life Expectancy; Ligation; Link; Long-Term Potentiation; Maintenance; Mass Spectrum Analysis; Mediating; Memory; Messenger RNA; Methods; Molecular; Morphology; Mus; Neurodegenerative Disorders; Neurons; Neurosciences; Patients; Peptide Elongation Factor 2; Pharmacology; Phase; Phosphorylation; Phosphotransferases; Protein Biosynthesis; Proteins; Proteomics; Reporting; Repression; Research; Ribosomes; Role; Signal Transduction; Site; Structure; Synapses; Synaptic plasticity; Syndrome; Testing; Tissue Model; United States National Institutes of Health; Up-Regulation; Vertebral column; Work; amyloid pathology; behavior test; beta amyloid pathology; density; design; effective therapy; genetic approach; genetic testing; high reward; high risk; human tissue; improved; inhibitor/antagonist; long term memory; middle age; mouse Ts65Dn; mouse genetics; mouse model; neuropathology; new therapeutic target; novel; novel strategies; novel therapeutic intervention; peptidyl-tRNA; prevent; small molecule inhibitor; synaptic failure

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.

项目摘要/摘要 唐氏综合症（DS）是与trisomic重复相关的最常见智障形式之一 21号染色体。包括痴呆在内的认知受损是DS的标志，但基础是 细胞/分子机制尚不清楚，这阻碍了我们开发有效治疗认知能力的能力 DS患者的缺陷。患有DS的人患阿尔茨海默氏病（AD）的风险要高得多 毁灭性神经退行性疾病和最常见的痴呆症。从中年开始， 大多数DS患者患有类似AD的神经病理学和痴呆综合症。长期记忆 突触可塑性需要从头蛋白质的合成，最近的研究表明mRNA翻译 损伤导致多种神经元疾病的认知综合征，包括AD，独立于大脑 淀粉样β病理学。在以前的研究和我们的初步数据的驱动下，该项目的目标是 确定通过抑制EEF2K的从头蛋白质合成的能力上调是否上调 和EEF2磷酸化，将改善包括突触的DS中多种与衰老相关的病理生理学 失败和认知缺陷。已经设计了三个特定目标来检验这一假设。目标1寻求 确定抑制EEF2K和EEF2磷酸化是否减轻了突触可塑性障碍 唐氏综合症的小鼠模型。 AIM 2是确定抑制EEF2K和EEF2是否抑制 磷酸化可以改善与DS相关的认知缺陷。目标3是阐明DS的基础机制 与EEF2K/EEF2信号级联反应失调相关的病理生理学。该项目的建议深入 使用神经科学中多种方法的分析，包括突触电生理学，药理学， 成像，小鼠遗传学和行为测试。我们将采用新颖的遗传模型和测定来评估DE 神经元中的Novo蛋白质合成，包括生物正交非规范氨基酸标记（Boncat） 接近连接测定（PLA）（Boncat-Pla）。结合质谱/蛋白质组学方法，我们 期望揭示DS大脑中蛋白质的身份，其合成因异常而失调 EEF2K/EEF2信号传导。该项目的发现将有助于我们对细胞/分子的理解 信号机制与DS相关的认知障碍。该项目的结果可以告知 最终开发针对DS相关认知综合征的新型治疗策略，没有有效 存在治疗。