A novel role of cytosolic protein synthesis inhibition in aminoglycoside ototoxicity.
A novel role of cytosolic protein synthesis inhibition in aminoglycoside ototoxicity.
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DOI：
10.1523/jneurosci.3430-12.2013
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发表时间：
2013-02-13
期刊：
影响因子：
--
通讯作者：
Shin JB
中科院分区：
文献类型：
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作者：
Francis SP;Katz J;Fanning KD;Harris KA;Nicholas BD;Lacy M;Pagana J;Agris PF;Shin JB
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 recently developed bioorthogonal noncanonical amino acid tagging (BONCAT) 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 FDA-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.
