In future studies, the proteins discovered in this work could be used as drug targets to prevent aminoglycoside-induced hearing loss.
Researchers identify possible treatment targets to prevent antibiotic-induced hearing loss.
Researchers at Indiana University School of Medicine are exploring new methods to investigate why an antibiotic causes hair cell death and permanent hearing loss in humans.
In a study that was published in the journal Developmental Cell, the researchers described how they identified the autophagy pathway in hair cells that is connected to the permanent hearing loss caused by the antibiotic class aminoglycosides. The researchers also created one of the first model systems that is insusceptible to hearing loss caused by aminoglycosides.
“This work identifies multiple potential therapeutic targets for preventing hearing loss caused by aminoglycosides,” said Bo Zhao, Ph.D., assistant professor of otolaryngology—head and neck surgery.
One of the primary causes of hearing loss in people is ototoxicity, or hearing loss brought on by medication. In the United States alone, hearing loss affects more than 48 million individuals.
For over a century, serious infections have been treated using aminoglycosides. Although the drug is a first-line treatment for life-threatening infections because of its cheap cost and low incidence of antibiotic resistance, it has been shown to cause hair cell death and subsequent permanent hearing loss in 20-47% of patients, although the underlying processes remain unknown. Hair cells are responsible for sound reception in the inner ear.
Zhao, whose lab investigates the molecular mechanisms underlying hearing loss, used biochemical screening to identify proteins found in hair cells. They first discovered that aminoglycosides are bound to the protein RIPOR2, which is required 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 lab that has normal hearing but significantly decreased RIPOR2 expression. Through these experiments, Zhao said the model had neither significant hair cell death nor hearing loss after treatment of aminoglycosides.
“We then discovered 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 exhibit hair cell death or hearing loss when treated with the antibiotic,” said Jinan Li, Ph.D., a postdoctoral fellow in the Zhao lab and first author of the paper.
The study authors say the proteins identified in this study could potentially be used as drug targets to prevent aminoglycoside-induced hearing loss in future studies.
Reference: “RIPOR2-mediated autophagy dysfunction is critical for aminoglycoside-induced hearing loss” by Jinan Li, Chang Liu, Ulrich Müller and Bo Zhao, 15 September 2022, Developmental Cell.
DOI: 10.1016/j.devcel.2022.08.011
The study was funded by the National Institutes of Health and the IU School of Medicine.
