自噬基因Epg5 z-bo 2020-11-13 343

　　The Epg5 gene is a highly conserved autophagy gene unique to multicellular organisms that was previously discovered by Zhang Hong's research group at the Institute of Biophysics, Chinese Academy of Sciences using C. elegans for genetic screening. Previous studies have found that the Epg5 gene defect leads to reduced autophagy activity in mice, and the autophagy substrate SQSTM1 accumulates in the nervous system in large quantities. The mice have selective damage to the fifth layer of pyramidal neurons in the cerebral cortex and spinal cord motor neurons. It has been found in human disease research that recessive mutations in the EPG5 gene are an important cause of human Vici syndrome. Vici syndrome is a recessively inherited multi-system disorder. The main feature is dysplasia of the corpus callosum area of the brain, accompanied by cardiomyopathy, cataracts, comprehensive immune deficiency, and neurodegenerative diseases of the skin and retina.

　　The study found that, in addition to selective degeneration of pyramidal neurons in the fifth layer of the cerebral cortex and spinal motor neurons, Epg5 knockout mice also have the same retinas as patients with Vici syndrome. There are progressive retinal neurodegenerative changes. As the Epg5 knockout mice age, the outer nuclear layer and photoreceptor cell layer of the retina gradually degenerate, and their visual function is severely damaged. This is consistent with the clinical manifestations of retinitis pigmentosa. Further research found that compared with the wild-type control group, the apoptotic activity in the outer nuclear layer of the Epg5 gene knockout mice was significantly increased, and the number of apoptotic cells in the outer nuclear layer of the retina increased significantly. At the same time, the mRNA and protein levels of unfolded protein response (UPR) related genes have also increased significantly. Therefore, the researchers believe that the neurodegeneration of the retina of Epg5 knockout mice may be related to the apoptosis of the retinal photoreceptor cell layer activated by UPR. The Epg5 knockout mice used in this study provide a model animal for research on retinitis pigmentosa, and also provide a new perspective for revealing the pathogenesis of retinal neurodegenerative diseases and possible future treatments.

　　Zhang Hong, a researcher at the Institute of Biophysics, Chinese Academy of Sciences, and Chen Yingyu, a professor at the Department of Immunology, Peking University School of Medicine, are the co-corresponding authors of this article. Zhang Hong's research group and Peking University jointly trained Miao Guangyan as the first author of the article. Associate researcher Zhao Yan of Zhang Hong's group, postdoctoral fellow Zhao Hongyu, doctoral student Ji Cuicui, and technician Sun Huayu also participated in the research. This project was funded by the National Natural Science Foundation of China, the National Key Basic Research and Development Program ("973" Program) and the Howard Hughes Medical Institute Young Scientist Fund.