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Cell Death Dis. 2015 May 14;6:e1763. doi: 10.1038/cddis.2015.108.

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

Author information

1
Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI, USA.
2
Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
3
1] Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI, USA [2] Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
4
Functional Genomics Center Zurich, ETH Zürich, Universität Zürich, Zürich, Switzerland.

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, glucose-regulated 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.

PMID:
25973683
PMCID:
PMC4669688
DOI:
10.1038/cddis.2015.108
[Indexed for MEDLINE]
Free PMC Article

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