线粒体未折叠蛋白反应在腓骨肌萎缩症1B型发病机制中的作用研究

Charcot-Marie-Tooth disease (CMT) is the most common form of hereditary peripheral neuropathy, and CMT1B is the second most common subtype of CMT1. Endoplasmic reticulum stress (ERS) participates in the pathogenesis of CMT1B caused by S63del MPZ mutation. Studies have shown that mitochondrial dysfunction can be detected under the condition of ERS. However, there are no reports of mitochondrial dysfunction in CMT1B. Mitochondrial unfolded protein response (mtUPR) is a newly discovered cellular stress response, which refers to the up-regulated expression of mitochondrial chaperone proteins and proteases under stress conditions, in which chaperones help restore normal conformation of misfolded proteins and promote correct folding of new synthetic proteins and proteases help degrade useless proteins. MtUPR is a mitochondrial protective response and plays an important role in neurodegenerative diseases. Previous studies of the applicant found up-regulated expression of heat shock protein 60 (HSP60) expression in CMT1B, suggesting that mtUPR might play an important role in CMT1B. The purpose of this study is to explore the molecular regulatory mechanism and signal transduction mechanism of mtUPR in CMT1B. It is important to clarify the role of mtUPR in CMT1B, to find new therapeutic targets and to develop effective therapeutic drugs.

腓骨肌萎缩症（Charcot-Marie-Tooth disease，CMT）是遗传性周围神经病中最常见的类型，CMT1B是CMT1中第二常见亚型。在S63del MPZ突变CMT1B中，产生内质网应激（endoplasmic reticulum stress, ERS）。研究表明，在ERS条件下出现线粒体功能障碍。线粒体未折叠蛋白反应（mitochondrial unfolded protein response, mtUPR）是新发现的细胞应激反应，是指线粒体伴侣蛋白、蛋白酶表达上调，帮助错误折叠蛋白恢复正常构象、降解无用蛋白，是早期线粒体保护反应。mtUPR在多种疾病中发挥作用。目前尚无在CMT1B中mtUPR的研究。申请者前期研究发现，在CMT1B中，热休克蛋白60表达上调，提示mtUPR在CMT1B中发挥作用。本研究旨在探讨mtUPR在CMT1B发病机制中的作用。

腓骨肌萎缩症（Charcot-Marie-Tooth disease，CMT）是遗传性周围神经病中最常见的类型，CMT1B是CMT1中第二常见亚型。在S63del MPZ突变CMT1B中，产生内质网应激（endoplasmic reticulum stress, ERS）。研究表明，在ERS条件下出现线粒体功能障碍。线粒体未折叠蛋白反应（mitochondrial unfolded protein response, mtUPR）是新发现的细胞应激反应，是指线粒体伴侣蛋白、蛋白酶表达上调，帮助错误折叠蛋白恢复正常构象、降解无用蛋白，是早期线粒体保护反应。mtUPR在多种疾病中发挥作用。目前尚无在CMT1B中mtUPR的研究。本课题研究成功构建了CMT1B细胞及动物模型，通过转录组学、RT-qPCR、Western blot、免疫荧光、mitotracker等实验，发现在CMT1B细胞及动物模型中，HSP10、HSP60、HSP70、CLPP、LONP1表达上调，提示CMT1B细胞及动物模型中发生了mtUPR。该课题发现，mtUPR在CMT1B发病机制中发挥重要作用。拟进一步探索mtUPR通过何种信号通路参与CMT1B发病机制。