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Drug-induced Stress Granule Formation Protects Sensory Hair Cells in Mouse Cochlear Explants During Ototoxicity
Stress granules regulate RNA translation during cellular stress, a mechanism that is generally presumed to be protective, since stress granule dysregulation caused by mutation or ageing is associated with neurodegenerative disease. Here, we investigate whether pharmacological manipulation of the str...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715625/ https://www.ncbi.nlm.nih.gov/pubmed/31467369 http://dx.doi.org/10.1038/s41598-019-48393-w |
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author | Gonçalves, Ana Cláudia Towers, Emily R. Haq, Naila Porco, John A. Pelletier, Jerry Dawson, Sally J. Gale, Jonathan E. |
author_facet | Gonçalves, Ana Cláudia Towers, Emily R. Haq, Naila Porco, John A. Pelletier, Jerry Dawson, Sally J. Gale, Jonathan E. |
author_sort | Gonçalves, Ana Cláudia |
collection | PubMed |
description | Stress granules regulate RNA translation during cellular stress, a mechanism that is generally presumed to be protective, since stress granule dysregulation caused by mutation or ageing is associated with neurodegenerative disease. Here, we investigate whether pharmacological manipulation of the stress granule pathway in the auditory organ, the cochlea, affects the survival of sensory hair cells during aminoglycoside ototoxicity, a common cause of acquired hearing loss. We show that hydroxamate (-)-9, a silvestrol analogue that inhibits eIF4A, induces stress granule formation in both an auditory cell line and ex-vivo cochlear cultures and that it prevents ototoxin-induced hair-cell death. In contrast, preventing stress granule formation using the small molecule inhibitor ISRIB increases hair-cell death. Furthermore, we provide the first evidence of stress granule formation in mammalian hair cells in-vivo triggered by aminoglycoside treatment. Our results demonstrate that pharmacological induction of stress granules enhances cell survival in native-tissue, in a clinically-relevant context. This establishes stress granules as a viable therapeutic target not only for hearing loss but also other neurodegenerative diseases. |
format | Online Article Text |
id | pubmed-6715625 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-67156252019-09-13 Drug-induced Stress Granule Formation Protects Sensory Hair Cells in Mouse Cochlear Explants During Ototoxicity Gonçalves, Ana Cláudia Towers, Emily R. Haq, Naila Porco, John A. Pelletier, Jerry Dawson, Sally J. Gale, Jonathan E. Sci Rep Article Stress granules regulate RNA translation during cellular stress, a mechanism that is generally presumed to be protective, since stress granule dysregulation caused by mutation or ageing is associated with neurodegenerative disease. Here, we investigate whether pharmacological manipulation of the stress granule pathway in the auditory organ, the cochlea, affects the survival of sensory hair cells during aminoglycoside ototoxicity, a common cause of acquired hearing loss. We show that hydroxamate (-)-9, a silvestrol analogue that inhibits eIF4A, induces stress granule formation in both an auditory cell line and ex-vivo cochlear cultures and that it prevents ototoxin-induced hair-cell death. In contrast, preventing stress granule formation using the small molecule inhibitor ISRIB increases hair-cell death. Furthermore, we provide the first evidence of stress granule formation in mammalian hair cells in-vivo triggered by aminoglycoside treatment. Our results demonstrate that pharmacological induction of stress granules enhances cell survival in native-tissue, in a clinically-relevant context. This establishes stress granules as a viable therapeutic target not only for hearing loss but also other neurodegenerative diseases. Nature Publishing Group UK 2019-08-29 /pmc/articles/PMC6715625/ /pubmed/31467369 http://dx.doi.org/10.1038/s41598-019-48393-w Text en © The Author(s) 2019 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 Gonçalves, Ana Cláudia Towers, Emily R. Haq, Naila Porco, John A. Pelletier, Jerry Dawson, Sally J. Gale, Jonathan E. Drug-induced Stress Granule Formation Protects Sensory Hair Cells in Mouse Cochlear Explants During Ototoxicity |
title | Drug-induced Stress Granule Formation Protects Sensory Hair Cells in Mouse Cochlear Explants During Ototoxicity |
title_full | Drug-induced Stress Granule Formation Protects Sensory Hair Cells in Mouse Cochlear Explants During Ototoxicity |
title_fullStr | Drug-induced Stress Granule Formation Protects Sensory Hair Cells in Mouse Cochlear Explants During Ototoxicity |
title_full_unstemmed | Drug-induced Stress Granule Formation Protects Sensory Hair Cells in Mouse Cochlear Explants During Ototoxicity |
title_short | Drug-induced Stress Granule Formation Protects Sensory Hair Cells in Mouse Cochlear Explants During Ototoxicity |
title_sort | drug-induced stress granule formation protects sensory hair cells in mouse cochlear explants during ototoxicity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715625/ https://www.ncbi.nlm.nih.gov/pubmed/31467369 http://dx.doi.org/10.1038/s41598-019-48393-w |
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