Stress Granules in Yeast and Mammals

描述（由申请人提供）：该基金的目标是了解压力颗粒在基因表达控制中的组装、动力学和功能，以及异常压力颗粒形成如何导致神经退行性疾病。应激颗粒是mRNA和蛋白质的细胞质颗粒，当翻译起始受到限制时形成，并部分通过RNA结合蛋白上朊病毒样结构域之间的相互作用组装。应力颗粒的重要性有两个原因。首先，它们隔离mRNA和mRNA结合蛋白，并在应激反应期间调节基因表达和细胞信号传导中发挥重要作用。第二，异常的应激颗粒积累似乎是诸如肌萎缩侧索硬化症（ALS）或额颞叶变性（FTLD）等疾病的致病事件。这些疾病可以由RNA结合蛋白（如hnRNPA 1）的突变引起，其增加了应激颗粒组装并促进了毒性淀粉样蛋白的形成，或者由AAA-ATP酶VCP的突变引起，其通过自噬减少了应激颗粒的清除。鉴于这种重要性，在正常的应激反应和病理条件下，正常和病理应激颗粒动力学的理解是至关重要的。我们将利用酵母细胞中强大的方法来了解应力颗粒动力学和功能的基本方面。我们还将应用我们从酵母中获得的知识来了解致病突变如何影响哺乳动物细胞中的应激颗粒。在这个建议中解决的具体问题是：I）在正常和致病条件下，应激颗粒的组成、动力学和影响是什么？II）连接应激颗粒组装与毒性淀粉样蛋白形成的分子机制是什么？III）应激颗粒靶向自噬的机制是什么？这些目标的完成将揭示应激颗粒动力学的基本原理，以及异常应激颗粒如何形成并导致退行性疾病，这可能有助于开发新的治疗方法。

DESCRIPTION (provided by applicant): The goals of this grant are to understand the assembly, dynamics, and functions of stress granules in the control of gene expression and how aberrant stress granule formation contributes to neurodegenerative diseases. Stress granules are cytoplasmic granules of mRNAs and proteins that form when translation initiation is limiting and assemble in part by interactions between prion-like domains on RNA binding proteins. Stress granules are of importance for two reasons. First, they sequester mRNAs and mRNA binding proteins and play important roles in modulating gene expression and cellular signaling during stress responses. Second, aberrant stress granule accumulation appears to be a causative event in diseases such as Amyotrophic Lateral Sclerosis (ALS), or Frontotemporal lobar degeneration (FTLD). These diseases can be caused by mutations in RNA binding proteins, such as hnRNPA1, which increase stress granule assembly and promote toxic amyloid formation, or by mutations in the AAA-ATPase VCP, which decrease stress granule clearance by autophagy. Given this importance in both normal stress responses and in pathological conditions, an understanding of both normal and pathological stress granule dynamics is critical. We will take advantage of the powerful approaches in yeast cells to understand fundamental aspects of stress granule dynamics and function. We will also apply our knowledge from yeast to understand how pathogenic mutations affect stress granules in mammalian cells. The specific questions addressed in this proposal are: I) What are the composition, dynamics and affects of stress granules in both normal and pathogenic conditions? II) What are molecular mechanisms connecting stress granule assembly with toxic amyloid formation? III) What are the mechanisms by which stress granules are targeted for autophagy? Completion of these aims will reveal fundamental principles of stress granule dynamics and how aberrant stress granules form and contribute to degenerative diseases, which could facilitate the development of new therapies.