Indiana University School of Medicine researchers are developing new ways to study why an antibiotic causes hair cell death and permanent hearing loss in people.
In a study recently published in Developmental Cellthe researchers explained how they identified the autophagy pathway in hair cells that is linked to permanent hearing loss caused by aminoglycosides, a class of antibiotics. The researchers also developed one of the first insensitive laboratory models of aminoglycoside-induced hearing loss.
This work identifies several potential therapeutic targets to prevent hearing loss caused by aminoglycosides. »
Bo Zhao, PhD, Assistant Professor of Otolaryngology – Head and Neck Surgery
Ototoxicity – hearing loss caused by drugs – is one of the main causes of hearing loss in humans. More than 48 million people in the United States have hearing problems.
Aminoglycosides have been used for almost a century to treat serious infections. Although this drug is a first-line treatment for life-threatening infections – especially in developing countries – due to its low cost and low incidence of antibiotic resistance, it has been reported to cause hair cell death and permanent hearing loss in 20-47% of patients, but the underlying mechanisms are unclear. Hair cells are responsible for receiving sounds in the inner ear.
Zhao, whose lab studies the molecular mechanisms behind hearing loss, used biochemical screening to identify proteins found in hair cells. They first discovered that aminoglycosides bind to the protein RIPOR2, which is necessary for auditory perception.
“As aminoglycosides specifically trigger a rapid localization change of RIPOR2 in hair cells, we hypothesize that RIPOR2 is essential for aminoglycoside-induced hair cell death,” Zhao said.
The researchers developed a model in the laboratory that has normal hearing but significantly reduced RIPOR2 expression. Through these experiments, Zhao said the model showed no significant hair cell death or hearing loss after aminoglycoside treatment.
“We then discovered that RIPOR2 regulates the autophagy pathway in hair cells. Knowing this, we developed other laboratory models without the expression of several key autophagy proteins that did not show hair cell death or hearing loss when treated with the antibiotic,” said Jinan Li, PhD, a postdoctoral fellow in Zhao’s lab and the paper’s first author.
The study authors say that the proteins identified in this study could potentially be used as drug targets to prevent aminoglycoside-induced hearing loss in future studies.
In addition to Zhao and Li, the paper’s authors include Chang Liu, PhD, postdoctoral fellow in Zhao’s lab, and Ulrich Mueller, PhD, Bloomberg Distinguished Professor of Neuroscience and Biology at Johns Hopkins University. Funding for the research was provided by the National Institutes of Health and the IU School of Medicine.
Source :
Indiana University School of Medicine
Journal reference:
Li, J., et al. (2022) RIPOR2-mediated autophagy dysfunction is critical for aminoglycoside-induced hearing loss. Development Cell. doi.org/10.1016/j.devcel.2022.08.011.