Abstract
The underlying pathological mechanisms of glaucomatous trabecular meshwork (TM) damage and elevation of intraocular pressure (IOP) are poorly understood. Here, we report that the chronic endoplasmic reticulum (ER) stress-induced ATF4-CHOP-GADD34 pathway is activated in TM of human and mouse glaucoma. Expression of ATF4 in TM promotes aberrant protein synthesis and ER client protein load, leading to TM dysfunction and cell death. These events lead to IOP elevation and glaucomatous neurodegeneration. ATF4 interacts with CHOP and this interaction is essential for IOP elevation. Notably, genetic depletion or pharmacological inhibition of ATF4-CHOP-GADD34 pathway prevents TM cell death and rescues mouse models of glaucoma by reducing protein synthesis and ER client protein load in TM cells. Importantly, glaucomatous TM cells exhibit significantly increased protein synthesis along with induction of ATF4-CHOP-GADD34 pathway. These studies indicate a pathological role of ATF4-CHOP-GADD34 pathway in glaucoma and provide a possible treatment for glaucoma by targeting this pathway.
Highlights
The underlying pathological mechanisms of glaucomatous trabecular meshwork (TM) damage and elevation of intraocular pressure (IOP) are poorly understood
Since Activating transcription factor 4 (ATF4) and C/ EBP homologous protein (CHOP) are known to play pathological roles in several diseases associated with endoplasmic reticulum (ER) stress, and our recent finding that ATF4 and CHOP are significantly induced in post-mortem TM tissues from primary open-angle glaucoma (POAG) donor eyes[36], we further explored the roles of ATF4 and CHOP in the glaucomatous TM damage and IOP elevation
We further examined whether ATF4–CHOP–GADD34 signaling axis is activated in TM cells and tissues of human and mouse glaucoma
Summary
The underlying pathological mechanisms of glaucomatous trabecular meshwork (TM) damage and elevation of intraocular pressure (IOP) are poorly understood. Expression of ATF4 in TM promotes aberrant protein synthesis and ER client protein load, leading to TM dysfunction and cell death These events lead to IOP elevation and glaucomatous neurodegeneration. Glaucomatous TM cells exhibit significantly increased protein synthesis along with induction of ATF4-CHOP-GADD34 pathway. Deletion of CHOP prevents ER stress-mediated cell death, recent studies have suggested an essential role for ATF4 in chronic ER stress-mediated cell death[51,52] It is not completely understood how chronic ER stress factors lead to cell death. Since ATF4 and CHOP are known to play pathological roles in several diseases associated with ER stress, and our recent finding that ATF4 and CHOP are significantly induced in post-mortem TM tissues from POAG donor eyes[36], we further explored the roles of ATF4 and CHOP in the glaucomatous TM damage and IOP elevation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
