Abstract #90872 Published in IGR 21-4

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

Kasetti RB; Patel PD; Maddineni P; Patil S; Kiehlbauch C; Millar JC; Searby CC; Raghunathan V; Sheffield VC; Zode GS
Nature communications 2020; 11: 5594

See also comment(s) by Katie Bollinger & Barbara Mysona

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.

Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, TX, 76107, Fort Worth, USA.

Full article


3.8 Pharmacology (Part of: 3 Laboratory methods)
3.6 Cellular biology (Part of: 3 Laboratory methods)
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)
11.8 Neuroprotection (Part of: 11 Medical treatment)

Issue 21-4

Change Issue