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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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CCAAT-Enhancer-Binding Proteins / metabolism
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Cell Line
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Endoplasmic Reticulum / pathology
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Endoplasmic Reticulum Stress / drug effects*
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Female
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Gentamicins / pharmacology*
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HEK293 Cells
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Hair Cells, Auditory / pathology
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Hearing Loss, High-Frequency* / chemically induced
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Hearing Loss, High-Frequency* / genetics
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Hearing Loss, High-Frequency* / pathology
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Humans
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Male
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred CBA
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Neurons / pathology
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Protein Biosynthesis / drug effects
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Protein Folding
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Proteostasis Deficiencies
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RNA Splicing / genetics
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Regulatory Factor X Transcription Factors
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Spiral Ganglion / cytology
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Spiral Ganglion / drug effects
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Spiral Ganglion / pathology
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Taurochenodeoxycholic Acid / pharmacology*
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Unfolded Protein Response / genetics
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Unfolded Protein Response / physiology
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X-Box Binding Protein 1
Substances
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CCAAT-Enhancer-Binding Proteins
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CEBPA protein, human
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DNA-Binding Proteins
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Gentamicins
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Membrane Glycoproteins
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Regulatory Factor X Transcription Factors
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Transcription Factors
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X-Box Binding Protein 1
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XBP1 protein, human
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Xbp1 protein, mouse
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endoplasmin
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Taurochenodeoxycholic Acid
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ursodoxicoltaurine