Related Experiment Video

Updated: Apr 12, 2026

Molecular Modulation by Lentivirus-Delivered Specific shRNAs in Endoplasmic Reticulum Stressed Neurons
10:50

Molecular Modulation by Lentivirus-Delivered Specific shRNAs in Endoplasmic Reticulum Stressed Neurons

Published on: April 24, 2021

1.4K

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

N Oishi1, S Duscha2, H Boukari2

  • 1Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI, USA.

Cell Death & Disease
|May 15, 2015
PubMed

Insights

Aminoglycoside antibiotics cause cellular stress, leading to potential nerve damage. Protecting the unfolded protein response pathway, particularly X-box binding protein-1, can prevent hearing loss and neurotoxicity.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Genetics

Background:

  • Aminoglycosides are known to cause mistranslation and protein misfolding.
  • Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are critical cellular pathways involved in protein homeostasis.
  • Neuropathy and ototoxicity are potential side effects of aminoglycoside treatment.

Purpose of the Study:

  • To investigate the link between aminoglycoside-induced mistranslation, protein misfolding, and neuropathy.
  • To assess the role of ER stress and UPR pathways in aminoglycoside toxicity.
  • To determine the protective effect of the X-box binding protein-1 (XBP1) pathway against aminoglycoside-induced ototoxicity.

Main Methods:

  • Mammalian cell cultures were used to study aminoglycoside-induced misreading.
  • Genome-wide transcriptome and proteome analyses were performed to identify affected genes.
  • Quantitative PCR was used to confirm the induction of UPR markers.
  • Haploinsufficient XBP1 (XBP1(+/-)) mice were treated with aminoglycosides to assess ototoxicity.
  • Tauroursodeoxycholic acid was used as a chemical chaperone to evaluate its protective effects.

Main Results:

  • Aminoglycosides were shown to induce misreading in mammalian cells.
  • UPR markers, including XBP1 mRNA splicing, were upregulated, indicating ER stress.
  • XBP1(+/-) mice exhibited significant high-frequency hearing loss and decreased spiral ganglion neuron density after aminoglycoside treatment, unlike wild-type littermates.
  • Sensory cells remained preserved in treated XBP1(+/-) mice.
  • Tauroursodeoxycholic acid attenuated the aminoglycoside-induced hearing loss.

Conclusions:

  • Aminoglycoside-induced ER stress and cell death in spiral ganglion neurons contribute to neuropathy and ototoxicity.
  • The XBP1 pathway plays a crucial protective role in mitigating aminoglycoside neurotoxicity.
  • XBP1-mediated UPR activation can mask aminoglycoside-induced toxicity at the organismal level, highlighting its therapeutic potential.

More Related Videos

Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons10:36

Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons

Published on: November 6, 2017

8.6K
Measurements of Physiological Stress Responses in C. Elegans10:36

Measurements of Physiological Stress Responses in C. Elegans

Published on: May 21, 2020

15.3K

Related Concept Videos

Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
3.2K
Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
5.7K
The Unfolded Protein Response01:37

The Unfolded Protein Response

The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
7.1K