Mitochondrial Unfolded Proteins and Cell Degeneration

描述（由申请人提供）：折叠和组装新生未折叠蛋白以及降解未组装和错误折叠蛋白的能力对于细胞器稳态很重要，并且受到特定应激信号激活的未折叠蛋白反应的调节。线粒体蛋白质折叠缺陷在重要的神经系统疾病中发挥着重要作用，例如痉挛性截瘫和帕金森病。我的目标是了解线粒体如何调节其折叠和加工蛋白质的能力，以响应未折叠蛋白质负载的变化。我将通过对秀丽隐杆线虫基因进行系统性、连续性、全基因组调查来确定线粒体未折叠蛋白反应所需的基因，这些基因被 RNAi 失活会损害线粒体未折叠蛋白反应。我将根据测量线虫线粒体蛋白质折叠能力、降解能力和输入能力的生化测定，对本次调查中确定的基因进行优先排序和验证。最后，我将寻求确定发出线粒体未折叠蛋白反应信号的基因的作用模式。通过了解从线粒体到细胞核的信号传导的基本原理，我希望能够深入了解神经退行性病变所涉及的病理生理过程。

DESCRIPTION (provided by applicant): The capacity to fold and assemble nascent unfolded proteins and to degrade unassembled and misfolded proteins is important to organelle homeostasis and is regulated by unfolded protein responses activated by specific stress signals. Defects in mitochondrial protein folding play a role in important neurological diseases such as spastic paraplegia and Parkinson's disease. My goal is to understand how mitochondria regulate their ability to fold and process proteins in response to variations in unfolded protein load. I will identify genes required for signaling the mitochondrial unfolded protein response by a systematic, sequential, genome-wide survey for C. elegans genes whose inactivation by RNAi impairs the mitochondrial unfolded protein response. I will prioritize and validate the genes identified in this survey based on biochemical assays that measure mitochondrial protein folding capacity, degradation capacity and import capacity in living C. elegans. Finally I will seek to identify the mode of action of genes that signal the mitochondrial unfolded protein response. By understanding the basic principles of signaling from the mitochondria to the nucleus I expect to provide insight into pathophysiological processes involved in neurodegeneration.