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

项目摘要/增刊摘要 随着调节蛋白质平衡的机制开始失效，蛋白质错误折叠疾病的风险随着年龄的增长而增加。 与年龄相关的神经退行性疾病通常以未折叠的蛋白质和 聚集，如在阿尔茨海默病(AD)和相关痴呆(ADRD)中观察到的。未能维持 衰老过程中适当的蛋白质处理是与这些疾病相关的病理的一个主要因素。在 额颞叶痴呆(FTD)的病例，疾病发病率在存在突变的情况下增加 原颗粒蛋白基因grn。所有病理性GRN突变都是由于表达或功能降低所致。因此， 增加GRN表达的方法有可能有助于预防或延缓疾病。饮食限制 (DR)已被证明可以改善动物蛋白质平衡的维持和改善疾病结局 模特们。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。已知较高水平的该因子可逆转TDP-43和淀粉样蛋白诱导的蛋白毒性 贝塔聚合体。FRamide神经肽的翻译效率也有类似的提高， 已知在哺乳动物中在新陈代谢和应激反应中起作用，但对此缺乏 了解它们是如何被监管的。因此，当相关的父母赠款集中在效果上时 由于DR和DR相关的身体肌肉和机体生理学的低翻译，这种FTD/阿尔茨海默氏症- 有重点的行政补充(非-AG-20-008)专门针对前列腺素和这些 神经递质是在DR和DR相关的低翻译条件下转录后调节的。AS 作为我们对这种形式的基因调控的研究的一部分，我们还将创造新的工具来研究 神经保护和DR相关翻译反应的贡献。翻译是一个研究不足的领域。 基因调控，有可能为神经退化研究带来新的见解。这些研究将 为哺乳动物系统中更多耗时的研究提供信息，并可能产生新的治疗方法 潜力。此外，这项研究还将带来新的探索途径，并将用于未来的发展 资助涉及FTD和ADRD研究的申请。

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.