机构：[1]Beijing Tongren Eye Center, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing Tongren Hospital, Beijing Institute of Ophthalmology, Capital Medical University, Beijing, China,首都医科大学附属北京同仁医院研究所眼科研究所[2]Collaborative Innovation Center for Brain Disorders, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
Trabecular meshwork dysfunction is the main cause of primary open angle glaucoma (POAG) associated with elevated intraocular pressure (IOP). Mutant myocilin causes glaucoma mainly via elevating IOP. Previously we have found that accumulated Asn 450 Tyr (N450Y) mutant myocilin impairs human trabecular meshwork (TM) cells by inducing chronic endoplasmic reticulum (ER) stress response in vitro. However, it is unclear how ER stress leads to TM damage and whether N450Y myocilin mutation is associated with POAG in vivo. Here we found that N450Y mutant myocilin induces autophagy, which worsens cell viability, whereas inhibition of autophagy increases viability and decreases cell death in human TM cells. Furthermore, we construct a transgenic mouse model of N450Y myocilin mutation (Tg-MYOCN450Y) and Tg-MYOCN450Y mice exhibiting glaucoma phenotypes: IOP elevation, retinal ganglion cell loss and visual impairment. Consistent with our published in vitro studies, mutant myocilin fails to secrete into aqueous humor, causes ER stress and actives autophagy in Tg-MYOCN450Y mice, and aqueous humor dynamics are altered in Tg-MYOCN450Y mice. In summary, our studies demonstrate that activation of autophagy is correlated with pathogenesis of POAG.
基金：
This work was supported by National Natural Science
Foundation of China (81730027 and 82130029), Beijing
Natural Science Foundation (L212036), Beijing Municipal
Institute of Public Medical Research Development and Reform
Pilot Project (2018-2).
第一作者机构：[1]Beijing Tongren Eye Center, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing Tongren Hospital, Beijing Institute of Ophthalmology, Capital Medical University, Beijing, China,[2]Collaborative Innovation Center for Brain Disorders, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
通讯作者：
通讯机构：[1]Beijing Tongren Eye Center, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing Tongren Hospital, Beijing Institute of Ophthalmology, Capital Medical University, Beijing, China,[2]Collaborative Innovation Center for Brain Disorders, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
推荐引用方式(GB/T 7714)：
Yan Xuejing,Wu Shen,Liu Qian,et al.Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells[J].FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY.2022,10:doi:10.3389/fcell.2022.900777.
APA：
Yan, Xuejing,Wu, Shen,Liu, Qian,Cheng, Ying,Zhang, Jingxue&Wang, Ningli.(2022).Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells.FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY,10,
MLA：
Yan, Xuejing,et al."Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells".FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY 10.(2022)
