线粒体-内质网结构偶联在2A型腓骨肌萎缩症（CMT2A）神经退行中的作用及机制

Charcot-Marie-Tooth disease type 2A (CMT2A) caused by mutations in MFN2, is one of the most common hereditary motor sensory neuropathies, whereas no effective treatment options are currently available. Neural degeneration of CMT2A closely related to the dysfunction of mitochondria. However, how mitochondrial dysfunction induces neural degeneration of CMT2A is unclear. Our previous study demonstrated that ER physically contact with mitochondria and formed mitochondria-ER complex during degeneration, which mediated the transfer of calcium from ER to mitochondria, and led to mitochondrial calcium overload (CNS Neurosci Ther, 2016; Cell Death Dis, 2018). Mitochondria-ER complex was also found in CMT2A neurons. Thus, we hypothesize that the mitochondria-ER complex caused by MFN2 mutation plays an important role in the pathogenesis of CMT2A. In this project, we will use the motor neurons differentiated from CMT2A iPSCs as a model to study: (1) the process and effect of the formation of mitochondrial-ER physical contact in CMT2A neurons, (2) the formation mechanism of mitochondria-ER complex in CMT2A neurons, (3) the effect of interruption of mitochondria-ER contact on the neural degeneration of CMT2A. This program will reveal the effect of mitochondria-ER contact in the pathogenesis of CMT2A, and shed light on the underlying mechanism of CMT2A disease.

2A型腓骨肌萎缩症（CMT2A）是MFN2突变引起的一种遗传性运动神经疾病，目前缺乏有效治疗。CMT2A神经退行与线粒体异常紧密相关，但线粒体异常如何诱发退行的机理尚不清晰。我们前期系列工作表明，体外诱导神经退行中，突起内质网与线粒体偶联形成复合体，介导线粒体钙过载（CNS Neurosci Ther，2016；Cell Death Dis，2018）；在CMT2A神经元中也发现线粒体-内质网复合体的存在，因此推测MFN2突变引发线粒体-内质网偶联在CMT2A病理中发挥重要作用。本项目拟基于我们前期建立的CMT2A诱导多能干-运动神经元疾病模型，研究（1）CMT2A神经中线粒体-内质网偶联过程及影响，（2）MFN2突变引发线粒体-内质网偶联的机制，（3）干预线粒体-内质网偶联对CMT2A神经退行的影响。阐明线粒体-内质网偶联对CMT2A病理过程的影响，为CMT2A发病机制研究提供新视角。

2A型腓骨肌萎缩症（CMT2A）是MFN2突变引起的一种遗传性运动神经疾病，目前缺乏有效治疗。CMT2A神经退行与线粒体异常紧密相关，但线粒体异常如何诱发退行的机理尚不清晰。我们发现CMT2A病人来源的神经元中线粒体-内质网偶联增强伴随线粒体总量下降和mtDNA减少。清除mtDNA导致神经元对退行更加敏感，发现mtDNA总量下降影响内质网-线粒体偶联。干预内质网-线粒体间的钙传递可以改善神经退行的表型。同时我们发现了一种新型的线粒体质量控制方式-mitolysosome介导的外排，这一过程可能参与了遗传性运动功能疾病如帕金森综合征的病理过程。