Summary: Researchers have identified an autophagy pathway in hair cells in the ear thats linked to permanent hearing loss that occurs as a result of exposure to aminoglycosides antibiotics in some patients.

Source: Indiana University

Researchers at Indiana University School of Medicine are developing new ways to study why an antibiotic causes hair cell death and permanent hearing loss in people.

In astudy recently published inDevelopmental Cell, the researchers explained how they identified the autophagy pathway in hair cells thats linked to permanent hearing loss brought about by aminoglycosidesa class of antibiotics.

The researchers also developed one of the first laboratory models thats insusceptible to aminoglycoside-induced hearing loss.

This work identifies multiple potential therapeutic targets for preventing hearing loss caused by aminoglycosides, saidBo Zhao, PhD, assistant professor of otolaryngologyhead and neck surgery.

Ototoxicityhearing loss caused by medicationis one of the main causes of hearing loss in humans. More than 48 million people in the United States experience trouble hearing.

Aminoglycosides for nearly a century have been used to treat severe infections. Although the drug is a first-line treatment for life-threatening infectionsparticularly in developing countriesdue to their low cost and low incidence of antibiotic resistance, it has been reported to cause hair cell death and subsequent permanent hearing loss among 20-47% of patients, but the underlying mechanisms are not clear. 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 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, saidJinan Li, PhD, 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.

In addition to Zhao and Li, authors of the article includeChang Liu, PhD, postdoctoral fellow in the Zhao lab, andUlrich 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 IU School of Medicine.

Author: Christina GriffithsSource: Indiana UniversityContact: Christina Griffiths Indiana UniversityImage: The image is in the public domain

Original Research: Closed access.RIPOR2-mediated autophagy dysfunction is critical for aminoglycoside-induced hearing loss by Bo Zhao et al. Developmental Cell

Abstract

RIPOR2-mediated autophagy dysfunction is critical for aminoglycoside-induced hearing loss

Aminoglycosides (AGs) are potent antibiotics that are capable of treating a wide variety of life-threatening infections; however, they are ototoxic and cause irreversible damage to cochlear hair cells.

Despite substantial progress, little is known about the molecular pathways critical for hair cell function and survival that are affected by AG exposure.

We demonstrate here that gentamicin, a representative AG antibiotic, binds to and within minutes triggers translocation of RIPOR2 in murine hair cells from stereocilia to the pericuticular area.

Then, by interacting with a central autophagy component, GABARAP, RIPOR2 affects autophagy activation. Reducing the expression of RIPOR2 or GABARAP completely prevents AG-induced hair cell death and subsequent hearing loss in mice.

Additionally, abolishing the expression of PINK1 or Parkin, two key mitochondrial autophagy proteins, prevents hair cell death and subsequent hearing loss caused by AG. In summary, our study demonstrates that RIPOR2-mediated autophagic dysfunction is essential for AG-induced hearing loss.

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Potential Therapeutic Targets to Prevent Hearing Loss Caused by Antibiotics - Neuroscience News