Mechanisms of Novel Regulators of Proteotoxicity and Quality Control Associated with ALS/FTD

项目摘要 神经退行性变是一个日益严重的公共卫生挑战，仍然是一个悬而未决的问题 生物医学问题。蛋白质错误折叠和聚集是 神经退行性疾病，包括肌萎缩侧索硬化症(ALS)和额颞部 痴呆症(FTD)。神经退行性变的复杂性要求进行大规模的无偏见筛查 学习。在过去的几年里，我们取得了突破性的观察，具有重要的意义 理解细胞防御系统对潜在的蛋白毒性的影响 ALS/FTD的发病机制。利用遗传、生物化学和细胞生物学的独特结合 方法，我们发现了新的途径，使蛋白质质量重新编程 控制以对抗蛋白毒性。这个项目中新提出的工作旨在阐明 蛋白质质量中新发现的调节器和主开关的机制 控制力。对之前未被承认的更高级别调节器的研究可能会扩大我们的 了解细胞中蛋白质毒性-应激反应质量控制系统，超越 良好的热休克反应或未折叠的蛋白质反应。我们独特的能力 对这一领域的贡献是在概念和技术层面上的：除了小说 途径，我们开发了独特的线虫/哺乳动物报告系统来研究 蛋白毒性相关的神经退行性变，我们最近的成功预示着未来的良好前景 计划。此外，我们不断扩展的工具库将使我们能够将调查结果扩展到 不同的模型和患者细胞。具体目的是通过以下方式阐明这些机制 这是一条新的保守途径，涉及一个以前未知的转录主开关， 在蛋白质质量控制的调控中，勾勒出一条新的 靶点及其信号通路调节蛋白毒性，并开发更多的新工具 对蛋白质毒性和质量控制关键调控因子的高级搜索。调查结果将不会 仅为了解ALS/FTD关键蛋白的毒性提供了新的切入点，例如 SOD1、TDP-43和C9orf72 dprs，但也揭示了利用细胞的分子靶点。 防御系统，预防和治疗相关的神经退行性疾病。我们预测 通过我们的研究努力获得的进步最终将导致新的治疗方法 在世界迅速老龄化的人口中解决这些疾病的干预措施。

Project Summary Neurodegeneration is an increasing public health challenge and remains an unsolved biomedical problem. Protein misfolding and aggregation are a central feature of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The complexity of neurodegeneration calls for large-scale unbiased screening studies. Over the past few years, we have made breakthrough observations with significant implications for understanding the cellular defense systems against proteotoxicity underlying pathogenesis in ALS/FTD. Using a unique blend of genetic, biochemical, and cell biological approaches, we have uncovered novel pathways that enable reprogramming of protein quality control to counter proteotoxicity. The newly proposed work in this project is aimed at elucidating mechanisms underlying newly identified regulators and master switches in protein quality control. The studies on the previously unrecognized higher-order regulators could expand our understanding of proteotoxic-stress-responsive quality control systems in the cell, beyond the well-established heat shock response or unfolded protein response. Our unique abilities to contribute to this field are at both conceptual and technical levels: In additional to novel pathways, we have developed unique C. elegans/mammalian reporter systems to study proteotoxicity-associated neurodegeneration, and our recent success bodes well for future plans. Furthermore, our expanding repertoire of tools will allow us to extend the findings to diverse models and patient cells. The specific aims are to elucidate the mechanisms through which a novel conserved pathway, involving a previously unknown transcriptional master switch, in the regulation of protein quality control, to delineate the pathways through which a novel target and its signaling pathway regulate proteotoxicity, and to develop new tools for more advanced search for key regulators of proteotoxicity and quality control. The findings will not only provide novel entry points for understanding the toxicities of key ALS/FTD proteins, such as SOD1, TDP-43, and C9orf72 DPRs, but also reveal molecular targets for harnessing the cellular defense system to prevent and treat the relevant neurodegenerative diseases. We predict that the advances gained through our research efforts will eventually lead to new therapeutic interventions to address these diseases in the world’s rapidly aging population.