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质以及降解未组装和错误折叠蛋白质的能力对细胞器稳态很重要，并受到特定应激信号激活的未折叠蛋白质反应的调节。线粒体蛋白折叠缺陷在痉挛性截瘫和帕金森病等重要神经系统疾病中发挥作用。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。我将通过系统的、顺序的、全基因组的调查来确定线虫基因所需要的线粒体未折叠蛋白反应信号，这些基因被RNAi失活后会损害线粒体未折叠蛋白反应。我将根据测量活体秀丽隐杆线虫线粒体蛋白质折叠能力、降解能力和进口能力的生化分析，优先考虑并验证在本次调查中鉴定出的基因。最后，我将试图确定基因的作用模式，信号线粒体未折叠蛋白反应。通过了解从线粒体到细胞核的信号传导的基本原理，我希望对神经变性的病理生理过程提供深入的了解。

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.