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Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma
Gulab S. Zode, … , Edwin M. Stone, Val C. Sheffield
Gulab S. Zode, … , Edwin M. Stone, Val C. Sheffield
Published August 8, 2011
Citation Information: J Clin Invest. 2011;121(9):3542-3553. https://doi.org/10.1172/JCI58183.
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Research Article Article has an altmetric score of 5

Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma

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Abstract

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-MYOCY437H mice. Analysis of adult Tg-MYOCY437H 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-MYOCY437H mice. Furthermore, chronic and persistent ER stress was found to be associated with TM cell death and elevation of IOP in Tg-MYOCY437H mice. Reduction of ER stress with a chemical chaperone, phenylbutyric acid (PBA), prevented glaucoma phenotypes in Tg-MYOCY437H 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.

Authors

Gulab S. Zode, Markus H. Kuehn, Darryl Y. Nishimura, Charles C. Searby, Kabhilan Mohan, Sinisa D. Grozdanic, Kevin Bugge, Michael G. Anderson, Abbot F. Clark, Edwin M. Stone, Val C. Sheffield

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Figure 4

Mutant MYOC upregulates ER stress–induced apoptotic proteins, which is associated with loss of TM.

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Mutant MYOC upregulates ER stress–induced apoptotic proteins, which is a...
(A) Distention of rER in the TM of Tg-MYOCY437H mice. TEM of both genotypes demonstrated that rER (arrows) of 12-month-old Tg-MYOCY437H was dilated compared with that of WT littermates. Similar findings were observed in 6-month-old Tg-­MYOCY437H mice. Scale bars: 0.2 μm. (B) Induction of ER stress–initiated apoptotic proteins in 12-month-old Tg-MYOCY437H mice. Western blot analysis of anterior segment tissue lysate for ER stress–induced apoptotic proteins Chop and cleaved caspase 12 (n = 3). (C) Loss of TM cells in 12-month-old Tg-MYOCY437H mice examined by TEM analysis. Data are shown as an average number of TM cells/iridocorneal angle sections of WT (n = 5) and Tg-MYOCY437H mice (n = 6). Data are shown as mean ± SEM. *P < 0.02 versus WT. (D) Y437H MYOC leads to TM cell death in cultured TM cells. Percentage of DAPI-positive cells expressing either WT or Y437H MYOC represented over control cells expressing empty virus. Data are shown as mean ± SEM. n = 4. ***P < 0.0004.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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