Regulation of lysosome positioning and function by the unfolded protein response

项目概要/摘要 这项研究计划的主要目标是了解细胞如何减轻聚集 神经退行性疾病的蛋白质基础，以及这些机制如何受到 压力途径和细胞器贩运。亨廷顿氏症、帕金森氏症和 阿尔茨海默病，因此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。本提案的第一个目标是了解如何 细胞降解致病形式的亨廷顿蛋白，特别是当它错误折叠时， 它形成了在病人大脑中发现的大的聚集体。这些中间体，低聚物 亨廷顿蛋白的一种形式被认为是毒性最大的，但我们不知道其机制 通过这些细胞最有效地降解它们。在初步数据的指导下，我们将探讨如何 细胞在这种降解中采用晚期内体介导的微自噬。微自噬并不好- 在机械水平上理解，特别是在哺乳动物细胞中，并且该提议还旨在 为研究这一基本的细胞过程提供了更普遍的见解和工具。第二顺 该提案的目标是了解蛋白质聚集、应激和蛋白质降解之间的关系。 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，但内质网应激反应途径之间的复杂相互作用， 神经退行性变还不足以提供一个明确的途径来操纵这些压力 治疗路径这个建议试图理解ER应力的一个特定方面是如何 反应，涉及一个特定的mRNA的降解和随后的定位晚 内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了解细胞如何在体内维持稳态。 ER，它在包括癌症和糖尿病在内的许多人类疾病中很重要。

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.