ArticleHuman molecular genetics2014
Exploiting the interaction between Grp94 and aggregated myocilin to treat glaucoma.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
What it found
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The trial behind it
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Who cites it
37 citing papers in PubMed, 48 citations in OpenAlex.
- 4-phenylbutyric acid-loaded mesoporous silica nanoparticles alleviate endoplasmic reticulum stress and reduce intraocular pressure in glaucoma model.Biology direct · 2026Article
- Design, synthesis, and biological properties exhibited by 1,2,3-triazole based Grp94-selective inhibitors.European journal of medicinal chemistry · 2026Article
- Structural basis for anomalous cellular trafficking behavior of glaucoma-associated A427T mutant myocilin.bioRxiv : the preprint server for biology · 2025Article
- Article
- Protein misfolding and mitochondrial dysfunction in glaucoma.Frontiers in cell and developmental biology · 2025Review
- Endoplasmic reticulum stress: molecular mechanism and therapeutic targets.Signal transduction and targeted therapy · 2023Review
- Myocilin misfolding and glaucoma: A 20-year update.Progress in retinal and eye research · 2023Review
- Insight into the Nucleotide Based Modulation of the Grp94 Molecular Chaperone Using Multiscale Dynamics.The journal of physical chemistry. B · 2023Article
- The biology and inhibition of glucose-regulated protein 94/gp96.Medicinal research reviews · 2022Review
- Calcium dysregulation potentiates wild-type myocilin misfolding: implications for glaucoma pathogenesis.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2022Article
- Structure‒function‒pathogenicity analysis of C-terminal myocilin missense variants based on experiments and 3D models.Frontiers in genetics · 2022Article
- Common and rare myocilin variants: Predicting glaucoma pathogenicity based on genetics, clinical, and laboratory misfolding data.Human mutation · 2021Review
- Molecular Insights into Myocilin and Its Glaucoma-Causing Misfolded Olfactomedin Domain Variants.Accounts of chemical research · 2021Review
- Biological Evaluation of 5'-(ACS medicinal chemistry letters · 2021Article
- Fungal-Selective Resorcylate Aminopyrazole Hsp90 Inhibitors: Optimization of Whole-Cell Anticryptococcal Activity and Insights into the Structural Origins of Cryptococcal Selectivity.Journal of medicinal chemistry · 2021Article
- Myocilin-associated Glaucoma: A Historical Perspective and Recent Research Progress.Molecular vision · 2021Review
- Old and New Approaches to Target the Hsp90 Chaperone.Current cancer drug targets · 2020Review
- Different Grp94 components interact transiently with the myocilin olfactomedin domain in vitro to enhance or retard its amyloid aggregation.Scientific reports · 2019Article
- Stable calcium-free myocilin olfactomedin domain variants reveal challenges in differentiating between benign and glaucoma-causing mutations.The Journal of biological chemistry · 2019Article
- Physiological function of myocilin and its role in the pathogenesis of glaucoma in the trabecular meshwork (Review).International journal of molecular medicine · 2019Review
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Gain-of-function mutations in the olfactomedin domain of the MYOC gene facilitate the toxic accumulation of amyloid-containing myocilin aggregates, hastening the onset of the prevalent ocular disorder primary open-angle glaucoma. Aggregation of wild-type myocilin has been reported in other glaucoma subtypes, suggesting broader relevance of misfolded myocilin across the disease spectrum, but the absence of myocilin does not cause disease. Thus, strategies aimed at eliminating myocilin could be therapeutically relevant for glaucoma. Here, a novel and selective Grp94 inhibitor reduced the levels of several mutant myocilin proteins as well as wild-type myocilin when forced to misfold in cells. This inhibitor rescued mutant myocilin toxicity in primary human trabecular meshwork cells. Mechanistically, in vitro kinetics studies demonstrate that Grp94 recognizes on-pathway aggregates of the myocilin olfactomedin domain (myoc-OLF), accelerates rates of aggregation and co-precipitates with myoc-OLF. These results indicate that aberrant myocilin quaternary structure drives Grp94 recognition, rather than peptide motifs exposed by unfolded protein. Inhibition of Grp94 ameliorates the effects of Grp94-accelerated myoc-OLF aggregation, and Grp94 remains in solution. In cells, when wild-type myocilin is driven to misfold and aggregate, it becomes a client of Grp94 and sensitive to Grp94 inhibition. Taken together, the interaction of Grp94 with myocilin aggregates can be manipulated by cellular environment and genetics; this process can be exploited with Grp94 inhibitors to promote the clearance of toxic forms of myocilin.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.