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The Mouse Round-window Approach for Ototoxic Agent Delivery: A Rapid and Reliable Technique for Inducing Cochlear Cell Degeneration
Published on: November 26, 2015
Drug-induced Stress Granule Formation Protects Sensory Hair Cells in Mouse Cochlear Explants During Ototoxicity
Ana Cláudia Gonçalves1, Emily R Towers1, Naila Haq1
1UCL Ear Institute, University College London, 332 Gray's Inn Road, WC1X 8EE, London, UK.
Abstract:
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.
Insights
Pharmacological induction of stress granules protects sensory hair cells from damage, offering a potential therapeutic strategy for hearing loss and neurodegenerative diseases.
Area of Science:
- Cell Biology
- Neuroscience
- Otolaryngology
Background:
- Stress granules regulate RNA translation during cellular stress and are linked to neurodegenerative diseases.
- Aminoglycoside ototoxicity is a common cause of acquired hearing loss due to sensory hair cell death.
Purpose of the Study:
- To investigate if manipulating stress granule formation affects sensory hair cell survival in the cochlea during aminoglycoside ototoxicity.
- To explore stress granules as a potential therapeutic target for hearing loss.
Main Methods:
- Utilized a silvestrol analogue ((-)-9) to induce stress granule formation by inhibiting eIF4A.
- Employed the small molecule inhibitor ISRIB to prevent stress granule formation.
- Tested effects on an auditory cell line, ex-vivo cochlear cultures, and in-vivo mammalian hair cells.
Main Results:
- (-)-9 induced stress granules and prevented aminoglycoside-induced hair cell death.
- Inhibiting stress granule formation with ISRIB increased hair cell death.
- Demonstrated in-vivo stress granule formation in mammalian hair cells following aminoglycoside treatment.
Conclusions:
- Pharmacological induction of stress granules enhances sensory hair cell survival in a clinically relevant context.
- Stress granules represent a viable therapeutic target for acquired hearing loss and other neurodegenerative conditions.
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