XBP1 mitigates aminoglycoside-induced endoplasmic reticulum stress and neuronal cell death
| Autor: | Jochen Schacht, Naoki Oishi, G Wei, Heithem Boukari, E C Boettger, Stefan Duscha, B Roschitzki, Thomas Schrepfer, J. Xie, Martin Meyer |
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| Přispěvatelé: | University of Zurich, Schacht, Jochen |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Cancer Research XBP1 Immunology 2804 Cellular and Molecular Neuroscience Biology 1307 Cell Biology Taurochenodeoxycholic Acid 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Downregulation and upregulation medicine Animals Humans 1306 Cancer Research Hearing Loss High-Frequency Spiral ganglion 030304 developmental biology 2403 Immunology 0303 health sciences 10093 Institute of Psychology 10179 Institute of Medical Microbiology Endoplasmic reticulum Cell Biology Endoplasmic Reticulum Stress X-Box Binding Protein 1 Molecular biology 3. Good health DNA-Binding Proteins medicine.anatomical_structure Unfolded protein response biology.protein Original Article Female Binding immunoglobulin protein Chemical chaperone Gentamicins 150 Psychology 030217 neurology & neurosurgery Transcription Factors |
| Zdroj: | Cell Death & Disease, 6 Cell Death & Disease |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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