XBP1 mitigates aminoglycoside-induced endoplasmic reticulum stress and neuronal cell death

N. Oishi, S. Duscha, H. Boukari, M. Meyer, J. Xie, G. Wei, T. Schrepfer, B. Roschitzki, E. C. Boettger, J. Schacht

研究成果: Article査読

52 被引用数 (Scopus)


Here we study links between aminoglycoside-induced mistranslation, protein misfolding and neuropathy. We demonstrate that aminoglycosides induce misreading in mammalian cells and assess endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathways. Genome-wide transcriptome and proteome analyses revealed upregulation of genes related to protein folding and degradation. Quantitative PCR confirmed induction of UPR markers including C/EBP homologous protein, glucoseregulated protein 94, binding immunoglobulin protein and X-box binding protein-1 (XBP1) mRNA splicing, which is crucial for UPR activation. We studied the effect of a compromised UPR on aminoglycoside ototoxicity in haploinsufficient XBP1 (XBP1+/-) mice. Intra-tympanic aminoglycoside treatment caused high-frequency hearing loss in XBP1+/- mice but not in wild-type littermates. Densities of spiral ganglion cells and synaptic ribbons were decreased in gentamicin-treated XBP1+/- mice, while sensory cells were preserved. Co-injection of the chemical chaperone tauroursodeoxycholic acid attenuated hearing loss. These results suggest that aminoglycoside-induced ER stress and cell death in spiral ganglion neurons is mitigated by XBP1, masking aminoglycoside neurotoxicity at the organismal level.

ジャーナルCell Death and Disease
出版ステータスPublished - 2015 5月 1

ASJC Scopus subject areas

  • 免疫学
  • 細胞および分子神経科学
  • 細胞生物学
  • 癌研究


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