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

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

doi:10.1172/jci58183

Cited by 245 publications

(268 citation statements)

References 41 publications

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“…45 Importantly, a second transgenic mouse generated in a different laboratory and carrying the human myocilin Y437H cDNA driven by a CMV promoter developed a more robust glaucomatous phenotype and induced ER stress. 46 This transgenic mouse showed elevated IOP plus retinal ganglion cells and axon degeneration at 3-4 months of age. 46 Moreover, topical administration 2 · daily with a 0.2% solution of sodium 4-phenylbutyrate (PBA) significantly reduced the elevated IOP in these mice.…”

Section: Focused Myocilin Mutant Studiesmentioning

confidence: 93%

“…46 This transgenic mouse showed elevated IOP plus retinal ganglion cells and axon degeneration at 3-4 months of age. 46 Moreover, topical administration 2 · daily with a 0.2% solution of sodium 4-phenylbutyrate (PBA) significantly reduced the elevated IOP in these mice. 47 PBA is a clinically approved chemical chaperone, which has been shown to reduce ER stress in several diseases.…”

Section: Focused Myocilin Mutant Studiesmentioning

confidence: 93%

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The Effects of Myocilin Expression on Functionally Relevant Trabecular Meshwork Genes: A Mini-Review

Borrás

2014

Journal of Ocular Pharmacology and Therapeutics

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Myocilin is a secreted glaucoma-associated protein, specifically induced by dexamethasone in human trabecular meshwork cells, where it was discovered. Myocilin is expressed in several tissues of the body, but it causes disease only in the eye. The protein contains two domains: an N-terminal region with significant homologies to nonmuscle myosin, and a C-terminal region, which is similar to the olfactomedin proteins. Forty percent of myocilin undergoes an intracellular endoproteolytic cleavage by calpain II, a calcium-dependent cysteine protease, which releases the 2 domains. The protein is known to interact with intracellular and extracellular matrix proteins, and some is released into the extracellular space associated with exosomes. Myocilin mutations are linked to glaucoma and induce elevated intraocular pressure. Most of the glaucoma-causative mutations map to the olfactomedin domain, which appears to be a critical domain for the function of the protein. Myocilin mutants are misfolded, aggregate in the endoplasmic reticulum, and are not secreted. Overexpression of myocilin and of its mutants in primary human trabecular meshwork cells triggers changes in the expression of numerous genes, many of which have been known to be involved in mechanisms important for the physiology and pathology of the tissue.Here we review recent studies from our laboratory and those of others that deal with trabecular meshwork genes, which are altered by the overexpression of wild-type and glaucoma-causative mutant myocilin genes.

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Section: Focused Myocilin Mutant Studiesmentioning

confidence: 93%

Section: Focused Myocilin Mutant Studiesmentioning

confidence: 93%

The Effects of Myocilin Expression on Functionally Relevant Trabecular Meshwork Genes: A Mini-Review

Borrás

2014

Journal of Ocular Pharmacology and Therapeutics

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“…Chemical chaperones can either act broadly and interact with numerous substrates, or stabilize specific proteins [31]. Interestingly, chemical chaperones are implicated in countering ER stress [32,33].…”

Section: Elevation Of O-glcnacylationmentioning

confidence: 99%

Hexosamine pathway and (ER) protein quality control

Denzel

Antebi

2015

Current Opinion in Cell Biology

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“…However, the presence or role of UPR in asthma has not been directly shown, nor has a clear functional role of ORMDL3 in UPR and asthma been defined (17,18). This is an important lacuna because it is possible to inhibit UPR using high concentrations of small molecules, called "chemical chaperones" without any major toxicity (19)(20)(21)(22)(23)(24).…”

mentioning

confidence: 99%

“…We hypothesized that airway injury in asthma relates to excessive maladaptive UPR and therefore administration of exogenous chemical chaperones could alleviate asthma by attenuating ER stress and UPR. Chemical chaperones, such as 4-PBA or tauroursodeoxycholic acid, were found to be extremely safe in preclinical studies and are now in clinical trials (21)(22)(23)(24)(42)(43)(44) for diseases like diabetes. In this study we investigated the possibility of inhaled chemical chaperone as treatment for allergic airway disease.…”

mentioning

confidence: 99%

Chemical Chaperones Mitigate Experimental Asthma by Attenuating Endoplasmic Reticulum Stress

Makhija¹,

Krishnan²,

Rehman³

et al. 2014

Am J Respir Cell Mol Biol

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Endoplasmic reticulum (ER) stress and consequent unfolded protein response (UPR) are important in inflammation but have been poorly explored in asthma. We used a mouse model of allergic airway inflammation (AAI) with features of asthma to understand the role of ER stress and to explore potential therapeutic effects of inhaled chemical chaperones, which are small molecules that can promote protein folding and diminish UPR. UPR markers were initially measured on alternate days during a 7-day daily allergen challenge model. UPR markers increased within 24 hours after the first allergen challenge and peaked by the third challenge, before AAI was fully established (from the fifth challenge onward). Three chemical chaperones-glycerol, trehalose, and trimethylamine-N-oxide (TMAO)-were initially administered during allergen challenge (preventive regimen). TMAO, the most effective of these chemical chaperones and 4-phenylbutyric acid, a chemical chaperone currently in clinical trials, were further tested for potential therapeutic activities after AAI was established (therapeutic regimen). Chemical chaperones showed a dose-dependent reduction in UPR markers, airway inflammation, and remodeling in both regimens. Our results indicate an early and important role of the ER stress pathway in asthma pathogenesis and show therapeutic potential for chemical chaperones.

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

Abstract: Mutations in myocilin (

Cited by 245 publications

References 41 publications

The Effects of Myocilin Expression on Functionally Relevant Trabecular Meshwork Genes: A Mini-Review

The Effects of Myocilin Expression on Functionally Relevant Trabecular Meshwork Genes: A Mini-Review

Hexosamine pathway and (ER) protein quality control

Chemical Chaperones Mitigate Experimental Asthma by Attenuating Endoplasmic Reticulum Stress

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