Journal
JOURNAL OF NEUROSCIENCE
Volume 33, Issue 7, Pages 3079-3093Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3430-12.2013
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Funding
- National Institute for Deafness and Communication Disorders [K99/R00 DC009412]
- National Science Foundation [MCB 1101859]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1101859] Funding Source: National Science Foundation
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Ototoxicity is a main dose-limiting factor in the clinical application of aminoglycoside antibiotics. Despite longstanding research efforts, our understanding of the mechanisms underlying aminoglycoside ototoxicity remains limited. Here we report the discovery of a novel stress pathway that contributes to aminoglycoside-induced hair cell degeneration. Modifying the previously developed bioorthogonal noncanonical amino acid tagging method, we used click chemistry to study the role of protein synthesis activity in aminoglycoside-induced hair cell stress. We demonstrate that aminoglycosides inhibit protein synthesis in hair cells and activate a signaling pathway similar to ribotoxic stress response, contributing to hair cell degeneration. The ability of a particular aminoglycoside to inhibit protein synthesis and to activate the c-Jun N-terminal kinase (JNK) pathway correlated well with its ototoxic potential. Finally, we report that a Food and Drug Administration-approved drug known to inhibit ribotoxic stress response also prevents JNK activation and improves hair cell survival, opening up novel strategies to prevent and treat aminoglycoside ototoxicity.
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