Translational regulation downstream of nutrient sensing in a model of Alzheimer's-related proteotoxicity

阿尔茨海默病相关蛋白毒性模型中营养传感下游的翻译调控

• 批准号: 10282045
• 负责人: ARIC N ROGERS
• 金额: $ 41.5万
• 依托单位: MOUNT DESERT ISLAND BIOLOGICAL LAB
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10282045
• 关键词: 3' Untranslated Regions; Address; Administrative Supplement; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Model; Applications Grants; Area; Caenorhabditis elegans; Computer Analysis; Consumption; Data; Disease; Disease Outcome; Failure; Frontotemporal Dementia; Future; GRN gene; Gene Expression Regulation; Genes; Genetic Determinism; Genetic Transcription; Goals; Impairment; Incidence; Intervention; Investigation; Maintenance; Mammals; Mediating; Messenger RNA; Metabolism; Methods; MicroRNAs; Modeling; Muscle; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuropeptides; Neurotransmitters; Nutrient; PGRN gene; Pathologic; Pathology; Physiology; Proteins; RNA-Binding Proteins; Research; Risk; Role; Signal Transduction; System; Testing; Therapeutic; Time; Tissues; Transcript; Translating; Translational Regulation; Translations; biological adaptation to stress; deep sequencing; detection of nutrient; dietary restriction; genetic signature; improved; innovation; insight; neuroprotection; neurotrophic factor; novel strategies; parent grant; prevent; protein TDP-43; protein aggregation; protein misfolding; proteostasis; proteotoxicity; public health relevance; response; tool

Project Summary/Abstract of Supplement The risk of protein misfolding diseases increases with age as mechanisms regulating proteostasis begin to fail. Age-associated neurodegenerative disorders are frequently characterized by unfolded proteins and aggregation, as observed in Alzheimer’s disease (AD) and related dementias (ADRD). Failure to maintain proper protein processing during aging is a major factor in pathology associated with these diseases. In the case of frontotemporal dementia (FTD), disease incidence increases in the presence of mutations in the progranulin gene GRN. All pathological GRN mutations result from reduced expression or function. Thus, methods of increasing GRN expression have the potential to help prevent or delay disease. Dietary restriction (DR) has been shown to improve maintenance of proteostasis and ameliorate disease outcomes in animal models. In preliminary data, we found that DR increases the translational efficiency of the neurotrophic factor GRN/pgrn-1. Higher levels of this factor are known to reverse proteotoxicity induced by TDP-43 and amyloid beta aggregates. Similar increases in translational efficiency are observed for FRamide neuropeptides, which are known in mammals to have roles in metabolism and stress response, but for which there is a lack of understanding about how they are regulated. Thus, while the associated parent grant is focused on the effects of DR and DR-associated low translation on body muscle and organismal physiology, this FTD/Alzheimer’s- focused administrative supplement (NOT-AG-20-008) specifically addresses how progranulin and these neurotransmitters are post-transcriptionally regulated under DR and DR-related low translation conditions. As part of our investigation into this form of gene regulation, we will also create new tools to investigate neuroprotection and the contribution of DR-related translational responses. Translation is an understudied area of gene regulation with the potential to yield new insights into neurodegeneration research. These studies will inform more time-consuming studies in mammalian systems and may yield new approaches with therapeutic potential. In addition, this research will lead to new avenues of exploration and will be used to develop future grant applications involving FTD and ADRD studies.

项目摘要/补充摘要 随着调节蛋白质量的机制开始失败，蛋白质错误折叠疾病的风险随着年龄而增加。 与年龄相关的神经退行性疾病经常以展开的蛋白质和 正如阿尔茨海默氏病（AD）和相关痴呆症（ADRD）所观察到的，聚集。无法维护 衰老期间的适当蛋白质加工是与这些疾病相关的病理学的主要因素。在 额颞痴呆（FTD）的病例，疾病发生率在存在突变的情况下增加 程序努力蛋白基因GRN。所有病理GRN突变都是由表达或功能降低引起的。那， 增加GRN表达的方法有可能帮助预防或延迟疾病。饮食限制 （DR）已被证明可以改善动物中蛋白质的维持和改善疾病结果 型号。在初步数据中，我们发现DR提高了神经营养因子的翻译效率 GRN/PGRN-1。已知该因素的较高水平会反向TDP-43和淀粉样蛋白诱导的蛋白质毒性 beta聚合。观察到转化效率的类似提高，对于火好 在哺乳动物中已知在代谢和压力反应中扮演角色，但缺乏 了解如何调节它们。那虽然相关的父母赠款专注于效果 DR和DR相关的人体肌肉和有机生理学的低翻译，该FTD/阿尔茨海默氏症 集中的行政补充（非AG-20-008）专门解决了编程和这些方式如何 神经递质在DR和DR相关的低翻译条件下进行转录后调节。作为 我们对这种基因调节形式的一部分投资，我们还将创建新工具来调查 神经保护和DR相关的翻译反应的贡献。翻译是一个知识的区域 基因调节的潜力，有可能对神经退行性研究产生新的见解。这些研究会 在哺乳动物系统中告知更多耗时的研究，并可能通过治疗产生新的方法 潜在的。此外，这项研究将导致新的探索途径，并将用于发展未来 涉及FTD和ADRD研究的赠款申请。