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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.<\/jats:p>","DOI":"10.1523\/jneurosci.3430-12.2013","type":"journal-article","created":{"date-parts":[[2013,2,13]],"date-time":"2013-02-13T12:38:14Z","timestamp":1360759094000},"page":"3079-3093","source":"Crossref","is-referenced-by-count":64,"title":["A Novel Role of Cytosolic Protein Synthesis Inhibition in Aminoglycoside Ototoxicity"],"prefix":"10.1523","volume":"33","author":[{"given":"Shimon P.","family":"Francis","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua","family":"Katz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn 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