ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load
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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.
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Activating Transcription Factor 4 /genetics
Activating Transcription Factor 4 /metabolism
Animals
Aqueous Humor / metabolism
Cell Death
Cells, Cultured
Endoplasmic Reticulum Stress / drug effects
Endoplasmic Reticulum Stress / genetics
Glaucoma, Open-Angle / drug therapy
Glaucoma, Open-Angle / metabolism
Glaucoma, Open-Angle / pathology
Humans
Mice
Ocular Hypertension / drug therapy
Ocular Hypertension / metabolism
Ocular Hypertension / pathology
Optic Nerve / metabolism
Optic Nerve / pathology
Protein Biosynthesis / drug effects
Protein Phosphatase 1 / genetics
Protein Phosphatase 1 / metabolism
Retinal Ganglion Cells / metabolism
Retinal Ganglion Cells / pathology
Signal Transduction
Trabecular Meshwork / drug effects
Trabecular Meshwork / metabolism
Trabecular Meshwork / pathology
Transcription Factor CHOP / genetics
Transcription Factor CHOP / metabolism