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

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

doi:10.1172/jci58183

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

Journal article

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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, 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, …

The Journal of clinical investigation, Vol.121(9), pp.3542-3553

09/2011

DOI: 10.1172/jci58183

PMCID: PMC3163970

PMID: 21821918

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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-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.

Phenylbutyrates - therapeutic use

Cytoskeletal Proteins - genetics

Glaucoma, Open-Angle - genetics

Humans

Stress, Physiological

Endoplasmic Reticulum - metabolism

Glaucoma, Open-Angle - pathology

Endoplasmic Reticulum - pathology

Endoplasmic Reticulum - drug effects

Phenylbutyrates - pharmacology

Eye Proteins - genetics

Transgenes

Trabecular Meshwork - cytology

Glycoproteins - genetics

Trabecular Meshwork - pathology

Intraocular Pressure

Cells, Cultured

Glaucoma, Open-Angle - physiopathology

Mice, Transgenic

Unfolded Protein Response

Glaucoma, Open-Angle - drug therapy

Phenotype

Animals

Trabecular Meshwork - metabolism

Mice

Apoptosis - physiology

Mutation

Details

Title: Subtitle: Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma
Creators: Gulab S Zode - Howard Hughes Medical Institute, Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
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
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.121(9), pp.3542-3553
DOI: 10.1172/jci58183
PMID: 21821918
PMCID: PMC3163970
NLM abbreviation: J Clin Invest
ISSN: 0021-9738
eISSN: 1558-8238
Publisher: American Society for Clinical Investigation
Grant note: R01 EY019485 / NEI NIH HHS\nR01 EY018825 / NEI NIH HHS\nHoward Hughes Medical Institute\nR01 EY010564 / NEI NIH HHS\nR01 EY10564 / NEI NIH HHS\nR01 EY017673 / NEI NIH HHS\nR01 EY022044 / NEI NIH HHS
Language: English
Date published: 09/2011
Academic Unit: Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
Record Identifier: 9983979993002771

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