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Isoform-selective Hsp90 inhibition rescues model of hereditary open-angle glaucoma
The heat shock protein 90 (Hsp90) family of molecular chaperones regulates protein homeostasis, folding, and degradation. The ER-resident Hsp90 isoform, glucose-regulated protein 94 (Grp94), promotes the aggregation of mutant forms of myocilin, a protein associated with primary open-angle glaucoma....
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738387/ https://www.ncbi.nlm.nih.gov/pubmed/29263415 http://dx.doi.org/10.1038/s41598-017-18344-4 |
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author | Stothert, Andrew R. Suntharalingam, Amirthaa Tang, Xiaolan Crowley, Vincent M. Mishra, Sanket J. Webster, Jack M. Nordhues, Bryce A. Huard, Dustin J. E. Passaglia, Christopher L. Lieberman, Raquel L. Blagg, Brian S. J. Blair, Laura J. Koren, John Dickey, Chad A. |
author_facet | Stothert, Andrew R. Suntharalingam, Amirthaa Tang, Xiaolan Crowley, Vincent M. Mishra, Sanket J. Webster, Jack M. Nordhues, Bryce A. Huard, Dustin J. E. Passaglia, Christopher L. Lieberman, Raquel L. Blagg, Brian S. J. Blair, Laura J. Koren, John Dickey, Chad A. |
author_sort | Stothert, Andrew R. |
collection | PubMed |
description | The heat shock protein 90 (Hsp90) family of molecular chaperones regulates protein homeostasis, folding, and degradation. The ER-resident Hsp90 isoform, glucose-regulated protein 94 (Grp94), promotes the aggregation of mutant forms of myocilin, a protein associated with primary open-angle glaucoma. While inhibition of Grp94 promotes the degradation of mutant myocilin in vitro, to date no Grp94-selective inhibitors have been investigated in vivo. Here, a Grp94-selective inhibitor facilitated mutant myocilin degradation and rescued phenotypes in a transgenic mouse model of hereditary primary open-angle glaucoma. Ocular toxicities previously associated with pan-Hsp90 inhibitors were not evident with our Grp94-selective inhibitor, 4-Br-BnIm. Our study suggests that selective inhibition of a distinct Hsp90 family member holds translational promise for ocular and other diseases associated with cell stress and protein misfolding. |
format | Online Article Text |
id | pubmed-5738387 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-57383872017-12-22 Isoform-selective Hsp90 inhibition rescues model of hereditary open-angle glaucoma Stothert, Andrew R. Suntharalingam, Amirthaa Tang, Xiaolan Crowley, Vincent M. Mishra, Sanket J. Webster, Jack M. Nordhues, Bryce A. Huard, Dustin J. E. Passaglia, Christopher L. Lieberman, Raquel L. Blagg, Brian S. J. Blair, Laura J. Koren, John Dickey, Chad A. Sci Rep Article The heat shock protein 90 (Hsp90) family of molecular chaperones regulates protein homeostasis, folding, and degradation. The ER-resident Hsp90 isoform, glucose-regulated protein 94 (Grp94), promotes the aggregation of mutant forms of myocilin, a protein associated with primary open-angle glaucoma. While inhibition of Grp94 promotes the degradation of mutant myocilin in vitro, to date no Grp94-selective inhibitors have been investigated in vivo. Here, a Grp94-selective inhibitor facilitated mutant myocilin degradation and rescued phenotypes in a transgenic mouse model of hereditary primary open-angle glaucoma. Ocular toxicities previously associated with pan-Hsp90 inhibitors were not evident with our Grp94-selective inhibitor, 4-Br-BnIm. Our study suggests that selective inhibition of a distinct Hsp90 family member holds translational promise for ocular and other diseases associated with cell stress and protein misfolding. Nature Publishing Group UK 2017-12-20 /pmc/articles/PMC5738387/ /pubmed/29263415 http://dx.doi.org/10.1038/s41598-017-18344-4 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Stothert, Andrew R. Suntharalingam, Amirthaa Tang, Xiaolan Crowley, Vincent M. Mishra, Sanket J. Webster, Jack M. Nordhues, Bryce A. Huard, Dustin J. E. Passaglia, Christopher L. Lieberman, Raquel L. Blagg, Brian S. J. Blair, Laura J. Koren, John Dickey, Chad A. Isoform-selective Hsp90 inhibition rescues model of hereditary open-angle glaucoma |
title | Isoform-selective Hsp90 inhibition rescues model of hereditary open-angle glaucoma |
title_full | Isoform-selective Hsp90 inhibition rescues model of hereditary open-angle glaucoma |
title_fullStr | Isoform-selective Hsp90 inhibition rescues model of hereditary open-angle glaucoma |
title_full_unstemmed | Isoform-selective Hsp90 inhibition rescues model of hereditary open-angle glaucoma |
title_short | Isoform-selective Hsp90 inhibition rescues model of hereditary open-angle glaucoma |
title_sort | isoform-selective hsp90 inhibition rescues model of hereditary open-angle glaucoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738387/ https://www.ncbi.nlm.nih.gov/pubmed/29263415 http://dx.doi.org/10.1038/s41598-017-18344-4 |
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