Molecular Genetic Analysis of TORC1 and TORC2 Signaling in Neuronal Maintenance

本附录回应NOT-AG-20-034：特别关注通知：关注阿尔茨海默氏症的行政管理 美国国立卫生研究院不专注于阿尔茨海默病的补助金补充。阿尔茨海默病(AD)仍然是一种 公共卫生危机迫在眉睫，尽管进行了密集的研究和制药努力。没有有效的治疗方法 目前有一种选择可以停止疾病的进程。最近几家备受瞩目的临床诊所的失败 针对淀粉样斑块和神经原纤维缠结的试验，AD的病理特征由 一个多世纪前，Alois阿尔茨海默氏症博士提出了新的想法和新的方向来描绘 在开发有效的治疗方法之前，应探索AD的致病机制。 在父母的资助中，我们建议阐明神经元维持的基本机制。 通过雷帕霉素(MTOR)信号的机械性靶点。我们确定了联合翻译的质量控制 线粒体外膜相关翻译作为应激状态下线粒体保护的关键事件， 并表明它受与帕金森病有关的保守的PINK1-mTOR信号通路的调节 疾病(PD)。在这个过程中，我们发现这条质量控制途径还涉及到其他 神经退行性疾病环境，包括阿尔茨海默病。在这个补充项目中，我们将检验假设 APP的生物发生需要足够的共翻译质量控制活动，而供应不足 由于衰老或新陈代谢应激可导致蛋白平衡紊乱，从而导致或启动AD。至 增强本项目的疾病相关性，我们建议使用AD小鼠模型和患者来源的细胞 用模型来检验这一假设。提出了两个具体目标：目标1：使用AD患者的成纤维细胞和 诱导多能干细胞(IPSC)来源的神经元测试共翻译质量控制在 蛋白质平衡。目的2：用5xFAD小鼠模型检验共翻译基因的遗传操作效果 淀粉样斑块形成和行为的质量控制活性。 预计在本补编项目结束时，我们将获得具体证据 共翻译质量控制在APP生物发生中的参与，建立有缺陷的共翻译 翻译质量控制可能是AD最早的致病事件之一。这可能会深刻地影响到 影响我们对AD发病机制的认识，激发出新的合理的治疗策略 治疗和预防AD以及其他破坏性的神经退行性疾病，在这些疾病中， 翻译质量控制已牵涉其中。

This supplement responds to NOT-AG-20-034: Notice of Special Interest: Alzheimer's-focused administrative supplements for NIH grants that are not focused on Alzheimer's disease. Alzheimer's disease (AD) remains a looming public health crisis, despite intensive research and pharmaceutical efforts. No effective treatment option is currently available that can halt the disease process. The recent failures of several high-profile clinical trials targeting the amyloid plaques and neurofibrillary tangles, the pathological hallmarks of AD identified by Dr. Alois Alzheimer more than a century ago, suggest that new ideas and new directions in delineating the pathogenic mechanisms of AD should be pursued before effective treatment of the disease can be developed. In the parent grant, we propose to elucidate fundamental mechanisms governing neuronal maintenance by mechanistic target of rapamycin (mTOR) signaling. We identified co-translational quality control of mitochondrial outer membrane-associated translation as a key event in mitochondrial protection under stress, and showed that it is regulated by the conserved PINK1-mTOR signaling pathway implicated in Parkinson's disease (PD). In the process, we found that this quality control pathway is also involved in other neurodegenerative disease settings, including AD. In this Supplement Project, we will test the hypothesis that the biogenesis of APP requires adequate co-translational quality control activity, the insufficient supply of which due to aging or metabolic stress can result in perturbed proteostasis that contributes to or initiates AD. To enhance the disease relevance of this project, we propose to use AD mouse model and patient-derived cellular models to test this hypothesis. Two Specific Aims are proposed: Aim 1: Using AD patient fibroblasts and induced pluripotent stem cell (iPSC)-derived neurons to test the roles of co-translational quality control in proteostasis. Aim 2: Using the 5xFAD mouse model to test the effect of genetic manipulation of co-translational quality control activity on amyloid plaque formation and behavior. It is anticipated that at the end of this Supplement Project, we will have obtained concrete evidence of the involvement of co-translational quality control in the biogenesis of APP, establishing defective co- translational quality control as potentially one of the earliest pathogenic events of AD. This may profoundly impact our understanding of AD pathogenesis and stimulate novel and rational therapeutic strategies for the treatment and prevention of AD as well as other devastating neurodegenerative diseases in which impaired co- translational quality control has been implicated.