Shahin Saba, Lu Bin, Zhou Yueqin, Xu Hui, Chetsawang Jason, Baloh Robert H, Wang Shaomei
Board of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
iScience. 2023 Feb 25;26(3):106270. doi: 10.1016/j.isci.2023.106270. eCollection 2023 Mar 17.
Charcot-Marie-Tooth disease type 2A (CMT2A), the most common inherited peripheral axonal neuropathy, is associated with more than 100 dominant mutations, including R94Q as the most abundant mutation in the Mitofusin2 (MFN2) gene. CMT2A is characterized by progressive motor and sensory loss, color-vision defects, and progressive loss of visual acuity. We used a well-established transgenic mouse model of CMT2A with R94Q mutation on MFN2 gene ( ) to investigate the functional and morphological changes in retina. We documented extensive vision loss due to photoreceptor degeneration, retinal ganglion cell and their axonal loss, retinal secondary neuronal and synaptic alternation, and Müller cell gliosis in the retina of mice. Imbalanced MFN1/MFN2 ratio and dysregulated mitochondrial fusion/fission result in retinal degeneration via P62/LC3B-mediated mitophagy/autophagy in mice. Finally, transgenic MFN1 augmentation ( :) rescued vision and retinal morphology to wild-type level via restoring homeostasis in mitochondrial MFN1/MFN2 ratio, fusion/fission cycle, and PINK1-dependent, Parkin-independent mitophagy.
2A型夏科-马里-图斯病（CMT2A）是最常见的遗传性周围轴索性神经病，与100多种显性突变相关，其中R94Q是线粒体融合蛋白2（MFN2）基因中最常见的突变。CMT2A的特征是进行性运动和感觉丧失、色觉缺陷以及视力逐渐丧失。我们使用一种成熟的CMT2A转基因小鼠模型，该模型的MFN2基因存在R94Q突变，以研究视网膜的功能和形态变化。我们记录了该转基因小鼠视网膜中由于光感受器退化、视网膜神经节细胞及其轴突丧失、视网膜继发性神经元和突触改变以及穆勒细胞胶质增生导致的广泛视力丧失。MFN1/MFN2比例失衡以及线粒体融合/分裂失调通过P62/LC3B介导的线粒体自噬/自噬作用导致转基因小鼠视网膜退化。最后，转基因增强MFN1（MFN1过表达）通过恢复线粒体MFN1/MFN2比例、融合/分裂循环以及PINK1依赖性、Parkin非依赖性线粒体自噬的稳态，将视力和视网膜形态恢复到野生型水平。
