The Journal of clinical investigationAug 9, 2011

Reducing cell stress with a chemical helper prevents glaucoma symptoms in mice

Updated Feb 16, 2026

Abstract

Tg-MYOC(Y437H) mice exhibit glaucoma phenotypes such as elevated intraocular pressure and retinal ganglion cell death.

Mutations in the myocilin gene are the leading genetic cause of primary open angle glaucoma.
Adult Tg-MYOC(Y437H) mice express the Y437H mutation and display glaucoma characteristics similar to those in affected humans.
Accumulation of mutant myocilin in the endoplasmic reticulum of the trabecular meshwork induces stress and cell death.
Chronic ER stress is linked to increased intraocular pressure and trabecular meshwork cell death in the Tg-MYOC(Y437H) model.
Using a chemical chaperone, phenylbutyric acid (PBA), alleviated ER stress and prevented glaucoma symptoms in these mice.

Simplified

Mutations in myocilin (MYOC) are the most common genetic cause of primary open angle glaucoma (POAG), but the mechanisms underlying MYOC-associated glaucoma are not fully understood. Here, we report the development of a transgenic mouse model of POAG caused by the Y437H MYOC mutation; the mice are referred to herein as Tg-MYOC(Y437H) mice. Analysis of adult Tg-MYOC(Y437H) mice, which we showed express human MYOC containing the Y437H mutation within relevant eye tissues, revealed that they display glaucoma phenotypes (i.e., elevated intraocular pressure [IOP], retinal ganglion cell death, and axonal degeneration) closely resembling those seen in patients with POAG caused by the Y437H MYOC mutation. Mutant myocilin was not secreted into the aqueous humor but accumulated in the ER of the trabecular meshwork (TM), thereby inducing ER stress in the TM of Tg-MYOC(Y437H) mice. Furthermore, chronic and persistent ER stress was found to be associated with TM cell death and elevation of IOP in Tg-MYOC(Y437H) mice. Reduction of ER stress with a chemical chaperone, phenylbutyric acid (PBA), prevented glaucoma phenotypes in Tg-MYOC(Y437H) mice by promoting the secretion of mutant myocilin in the aqueous humor and by decreasing intracellular accumulation of myocilin in the ER, thus preventing TM cell death. These results demonstrate that ER stress is linked to the pathogenesis of POAG and may be a target for treatment in human patients.

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