ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load

• Published in: Nature communications Vol. 11; no. 1; pp. 5594 - 14
• Main Authors: Kasetti, Ramesh B., Patel, Pinkal D., Maddineni, Prabhavathi, Patil, Shruti, Kiehlbauch, Charles, Millar, J. Cameron, Searby, Charles C., Raghunathan, VijayKrishna, Sheffield, Val C., Zode, Gulab S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-11-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/2; 13/51; 14/19; 14/63; 42; 42/44; 631/378; 631/80; 631/80/304; 631/80/470; 631/80/82; 82/29; 82/51; Activating Transcription Factor 4 - antagonists & inhibitors; Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Animal models; Animals; Apoptosis; Aqueous Humor - metabolism; Blindness; Cell Death; Cells, Cultured; Depletion; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - genetics; GADD34 protein; Glaucoma; Glaucoma, Open-Angle - drug therapy; Glaucoma, Open-Angle - metabolism; Glaucoma, Open-Angle - pathology; Humanities and Social Sciences; Humans; Intraocular pressure; Mice; multidisciplinary; Neurodegeneration; Ocular Hypertension - drug therapy; Ocular Hypertension - metabolism; Ocular Hypertension - pathology; Optic Nerve - metabolism; Optic Nerve - pathology; Protein biosynthesis; Protein Biosynthesis - drug effects; Protein Phosphatase 1 - genetics; Protein Phosphatase 1 - metabolism; Protein synthesis; Proteins; Retinal Ganglion Cells - metabolism; Retinal Ganglion Cells - pathology; Science; Science (multidisciplinary); Signal Transduction; Trabecular Meshwork - drug effects; Trabecular Meshwork - metabolism; Trabecular Meshwork - pathology; Transcription Factor CHOP - genetics; Transcription Factor CHOP - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19352-1

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.
Glaucoma is the leading cause of irreversible blindness affecting over 70 million people worldwide. Here, the authors show that inhibition of chronic ER stress-induced ATF4-CHOP-GADD34 signaling pathway rescues pathology in mouse models of glaucoma, thus suggesting a possible treatment strategy.