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

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32 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number108
JournalCell Death and Disease
Volume6
Issue number5
DOIs
Publication statusPublished - 2015 May 1

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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    Oishi, N., Duscha, S., Boukari, H., Meyer, M., Xie, J., Wei, G., Schrepfer, T., Roschitzki, B., Boettger, E. C., & Schacht, J. (2015). XBP1 mitigates aminoglycoside-induced endoplasmic reticulum stress and neuronal cell death. Cell Death and Disease, 6(5), [108]. https://doi.org/10.1038/cddis.2015.108