ursodoxicoltaurine and Hearing-Loss--High-Frequency

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.

Topics: Animals; CCAAT-Enhancer-Binding Proteins; Cell Line; DNA-Binding Proteins; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Female; Gentamicins; Hair Cells, Auditory; Hearing Loss, High-Frequency; HEK293 Cells; Humans; Male; Membrane Glycoproteins; Mice; Mice, Inbred CBA; Neurons; Protein Biosynthesis; Protein Folding; Proteostasis Deficiencies; Regulatory Factor X Transcription Factors; RNA Splicing; Spiral Ganglion; Taurochenodeoxycholic Acid; Transcription Factors; Unfolded Protein Response; X-Box Binding Protein 1