Cargando…
Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells
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 trabecula...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9124892/ https://www.ncbi.nlm.nih.gov/pubmed/35615698 http://dx.doi.org/10.3389/fcell.2022.900777 |
_version_ | 1784711826139774976 |
---|---|
author | Yan, Xuejing Wu, Shen Liu, Qian Cheng, Ying Zhang, Jingxue Wang, Ningli |
author_facet | Yan, Xuejing Wu, Shen Liu, Qian Cheng, Ying Zhang, Jingxue Wang, Ningli |
author_sort | Yan, Xuejing |
collection | PubMed |
description | 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-MYOC(N450Y)) and Tg-MYOC(N450Y) 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-MYOC(N450Y) mice, and aqueous humor dynamics are altered in Tg-MYOC(N450Y) mice. In summary, our studies demonstrate that activation of autophagy is correlated with pathogenesis of POAG. |
format | Online Article Text |
id | pubmed-9124892 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-91248922022-05-24 Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells Yan, Xuejing Wu, Shen Liu, Qian Cheng, Ying Zhang, Jingxue Wang, Ningli Front Cell Dev Biol Cell and Developmental Biology 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-MYOC(N450Y)) and Tg-MYOC(N450Y) 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-MYOC(N450Y) mice, and aqueous humor dynamics are altered in Tg-MYOC(N450Y) mice. In summary, our studies demonstrate that activation of autophagy is correlated with pathogenesis of POAG. Frontiers Media S.A. 2022-05-09 /pmc/articles/PMC9124892/ /pubmed/35615698 http://dx.doi.org/10.3389/fcell.2022.900777 Text en Copyright © 2022 Yan, Wu, Liu, Cheng, Zhang and Wang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cell and Developmental Biology Yan, Xuejing Wu, Shen Liu, Qian Cheng, Ying Zhang, Jingxue Wang, Ningli Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells |
title | Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells |
title_full | Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells |
title_fullStr | Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells |
title_full_unstemmed | Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells |
title_short | Myocilin Gene Mutation Induced Autophagy Activation Causes Dysfunction of Trabecular Meshwork Cells |
title_sort | myocilin gene mutation induced autophagy activation causes dysfunction of trabecular meshwork cells |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9124892/ https://www.ncbi.nlm.nih.gov/pubmed/35615698 http://dx.doi.org/10.3389/fcell.2022.900777 |
work_keys_str_mv | AT yanxuejing myocilingenemutationinducedautophagyactivationcausesdysfunctionoftrabecularmeshworkcells AT wushen myocilingenemutationinducedautophagyactivationcausesdysfunctionoftrabecularmeshworkcells AT liuqian myocilingenemutationinducedautophagyactivationcausesdysfunctionoftrabecularmeshworkcells AT chengying myocilingenemutationinducedautophagyactivationcausesdysfunctionoftrabecularmeshworkcells AT zhangjingxue myocilingenemutationinducedautophagyactivationcausesdysfunctionoftrabecularmeshworkcells AT wangningli myocilingenemutationinducedautophagyactivationcausesdysfunctionoftrabecularmeshworkcells |