Neurodegeneration and Proteotoxicity Dissected in C. elegans and Mammals

项目摘要 肌萎缩侧索硬化症是一种进行性神经退行性疾病 以运动神经元的退化为特征。蛋白质的错误折叠和聚集是一个 ALS和相关神经退行性疾病的中心特征。的复杂性 神经变性需要大规模无偏见的筛选研究。在过去的几年里， 我们已经取得了突破性的观察， 对蛋白毒性的细胞防御系统的理解。使用独特的混合， 通过生物化学、遗传学和细胞生物学方法，我们发现了一种新的途径， 重编程蛋白质质量控制，并与新的基因命中相关的这一途径在手。我们 现在提出的工作，以阐明一个以前未认识的p53网络蛋白质质量控制。 对这一网络的研究可以扩展我们对蛋白毒性应激反应的理解， 质量控制系统的细胞，超越了完善的热休克反应或展开 蛋白质反应我们在这一领域的独特潜力是技术和 概念：我们开发了一种独特的串联C。elegans/哺乳动物系统研究 神经退化，我们最近的成功预示着未来的计划。比如我们 扩大疾病模型库将使我们能够进行无偏见的筛选研究， 蛋白毒性相关的神经退行性变，并将研究结果扩展到哺乳动物 模型和患者细胞。这些发现不仅将为理解 关键ALS基因的分子原因，但也提出了新的策略，利用 细胞防御系统，以预防和治疗相关形式的ALS和其他相关 神经退行性疾病我们预测，通过我们的研究工作所取得的进展 最终将导致新的治疗干预措施，以解决这些疾病在世界上的 人口迅速老龄化。

Project Summary Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. Protein misfolding and aggregation are a central feature of ALS and related neurodegenerative diseases. The complexity of neurodegeneration calls for large-scale unbiased screening studies. Over the past few years, we have made breakthrough observations that have significant implications for the understanding of cellular defense systems against proteotoxicity. Using a unique blend of biochemical, genetic, and cell biological approaches, we discovered a novel pathway to reprogram protein quality control, and with new genetic hits related to this pathway in hand. We now propose work to elucidate a previously unrecognized p53 network in protein quality control. The studies on this network 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 potential to contribute to this field is both technical and conceptual: We have developed a unique tandem C. elegans/mammalian system to study neurodegeneration, and our recent success bodes well for future plans. For example, our expanding repertoire of diease models will allow us to conduct unbiased screening studies of proteotoxicity-associated neurodegeneration in vivo and extend the findings to mammalian models and patient cells. The findings will not only provide novel entry points for understanding the molecular causes of key ALS genes but also suggest new strategies for harnessing the cellular defense system to prevent and treat the relevant forms of ALS and other related 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.