Regulation of lysosome positioning and function by the unfolded protein response

项目摘要/摘要 这项研究提案的主要目标是了解细胞如何缓解聚集 神经退行性疾病背后的蛋白质，以及这些机制如何受到 应激途径和细胞器运输。亨廷顿氏症、帕金森氏症和 阿尔茨海默病，所以探索细胞如何对蛋白质聚集做出反应的新机制是 对于提供新的治疗方法很重要。这项建议的第一个目标是了解如何 细胞降解亨廷顿蛋白的致病形式，特别是当它错误折叠时，但在 它形成了在患者大脑中发现的大聚集体。这些中间体、低聚物 亨廷顿蛋白的形式被认为是毒性最大的，但我们不知道其机制。 细胞通过这些细胞最有效地降解它们。在初步数据的指导下，我们将探索如何 在这种降解过程中，细胞采用晚期内噬体介导微自噬。微型自噬并不是很好- 在机械水平上理解，特别是在哺乳动物细胞中，这一提议也旨在 提供更一般的见解和工具来研究这一基本的细胞过程。第二个总体 这项建议的目标是了解蛋白质聚集、压力和压力之间的关系 内质网(ER)和细胞器运输/定位。许多神经退行性疾病 诱导内质网应激，但内质网应激反应通路和内质网应激反应通路之间复杂的相互作用 对神经退行性变的了解还不够充分，无法提供一条清晰的途径来操纵这些应激 治疗上的路径。这项建议试图理解ER的一个特定方面是如何应激的 反应，涉及特定信使核糖核酸的降解和后来的重新定位 内质体和溶酶体，影响亨廷顿蛋白的降解和聚集。 研究这种应激反应也将有助于我们理解细胞是如何维持体内平衡的。 呃，它在包括癌症和糖尿病在内的许多人类疾病中都是重要的。

Project Summary/Abstract The broad goals of this research proposal are to understand how cells mitigate the aggregation of proteins that underlie neurodegenerative diseases, and how these mechanisms are influenced by stress pathways and organelle trafficking. There are no cures for Huntington’s, Parkinson’s, and Alzheimer’s diseases, so exploring new mechanisms for how cells respond to protein aggregation is important for offering new therapeutic approaches. The first goal of this proposal is to understand how cells degrade the disease-causing form of the Huntington protein, in particular as it misfolds but before it forms the large aggregates that are found in the brains of patients. These intermediate, oligomeric forms of the Huntington protein are thought to be the most toxic, yet we do not know the mechanisms through which cells most effectively degrade them. Guided by preliminary data, we will explore how cells employ late endosome-mediated microautophagy in this degradation. Microautophagy is not well- understood at a mechanistic level, especially in mammalian cells, and this proposal is also designed to provide more general insights and tools to study this fundamental cellular process. The second overall goal of this proposal is to understand the relationships between protein aggregation, stress in the endoplasmic reticulum (ER), and organelle trafficking/positioning. Many neurodegenerative diseases induce ER stress, yet the complicated interplay between ER stress response pathways and neurodegeneration is not well-understood enough to provide a clear path for manipulating these stress pathways therapeutically. This proposal seeks to understand how a particular aspect of the ER stress response, involving the degradation of a specific mRNA and subsequent repositioning of late endosomes and lysosomes, affects the degradation and aggregation of the Huntington protein. Investigating this stress response will also help us to understand how cells maintain homeostasis in the ER, which is important in many human diseases including cancer and diabetes.