Scientists at the Institut Pasteur, Inserm, the Collège de France and Pierre & Marie Curie University, working closely with scientists at the University of Auvergne, have recently discovered the function of pejvakin, a molecule that plays a vital role in the hearing system. The absence of this molecule appears to be responsible for noise-induced hearing loss, one of the most common causes of deafness. The scientists’ discovery, which was published on November 5 in the journal Cell, offers new prospects for the treatment of this condition.
In 2006, the team led by Christine Petit in the Institut Pasteur’s Genetics & Physiology of Hearing Unit, especially Sedigheh Delmaghani, working in cooperation with Paul Avan’s team at the University of Auvergne’s Laboratory of Sensory Biophysics, identified a new gene that was responsible for early-onset sensorineural hearing loss. This gene codes for a protein which was given the name “pejvakin” (which means “echo” in Persan). Audiometric tests performed on individuals with mutations in this gene subsequently revealed an unusually high level of diversity in hearing impairments, in terms of both severity and characteristics. This latest study, carried out by scientists from the Institut Pasteur, Inserm, the Collège de France, Pierre & Marie Curie University and the University of Auvergne, aimed to clarify the reasons for this heterogeneity.
The scientists, particularly Sedigheh Delmaghani, studied young mice whose pejvakin gene had been inactivated. Their observations revealed an astonishing variation in hearing impairments from one mouse to the next, ranging from mild to profound hearing loss. Young mice are highly vocal for the first three weeks after they are born, particularly when feeding. The more mice there are in the cage, the noisier their acoustic environment. The scientists observed that as the number of mice in the cage increased, so did their hearing threshold – the minimum sound level at which they are able to hear sounds. Using direct, controlled acoustic stimulation, the scientists were able to prove that the auditory system of mice lacking in pejvakin is affected by their acoustic environment.
The scientists then set about investigating the physiological causes of this phenomenon. They observed that in mice without pejvakin, the auditory sensory cells are damaged as soon as they are exposed to even seemingly harmless sounds – the equivalent of a minute spent in a nightclub for humans. These cells need two weeks of silence to become functional again. With prolonged or repeated exposure, the cells eventually die. The scientists also identified the noise-sensitive element in the cell as being the peroxisome, a small organelle involved in detoxification.
“To put it simply, we discovered that a genetic disorder could be responsible for noise-induced hearing loss triggered by even very low noise levels,” explained Christine Petit.
The auditory sensory cells in people with impaired pejvakin were observed to be extremely vulnerable to noise. When a standard hearing test was performed on these hearing-impaired individuals, the responses of their auditory sensory cells and neurons, although normal to begin with, gradually worsened as the test went on as a result of the sounds used.
Noise-induced hearing loss is becoming increasingly prevalent. Urban crowding means that large cities are getting noisier, particularly in developing countries. WHO predicts that by 2030, one billion people will be at risk of noise-induced hearing loss. “Some of us have less effective natural defenses against the impact of overexposure to sound than others,” explained Profs. Avan and Petit. “Five million people in France end up suffering from hearing loss, which has a negative impact on their social life.
Hearing aids are one solution, but they work by exposing the wearer to amplified sounds. However, we don’t yet know what percentage of the population is either lacking in pejvakin or has a less effective form of the protein. Our findings indicate that in these people, hearing aids are most probably not only ineffective but also harmful.”
The scientists will now look into possible techniques to restore the function of pejvakin, particularly using gene therapy, which has already proved successful in conserving hearing in mice lacking in pejvakin, even when they are overexposed to noise.
Funding: This study received funding from the Louis-Jeantet Foundation, the Bettencourt Schueller Foundation, Humanis, AG2R La Mondiale, the BNP Paribas Foundation and Agir pour l’Audition Foundation.
Source: Marion Doucet – Institut Pasteur
Image Source: The image is credited to Institut Pasteur
Original Research: Abstract for “Hypervulnerability to sound-exposure through impaired adaptive proliferation of peroxisomes” by Sedigheh Delmaghani, Jean Defourny, Asadollah Aghaie, Maryline Beurg, Didier Dulon, Nicolas Thelen, Isabelle Perfettini, Tibor Zelles, Mate Aller, Anaïs Meyer, Alice Emptoz, Fabrice Giraudet, Michel Leibovici, Sylvie Dartevelle, Guillaume Soubigou, Marc Thiry, E. Sylvester Vizi, Saaid Safieddine, Jean-Pierre Hardelin, Paul Avan, and Christine Petit in Cell. Published online November 5 2015 doi:10.1016/j.cell.2015.10.023
Hypervulnerability to sound-exposure through impaired adaptive proliferation of peroxisomes
•Pejvakin-deficient mice and humans are hypervulnerable to sound exposure
•Oxidative stress induces a pejvakin-dependent proliferation of peroxisomes
•Peroxisome proliferation contributes to the physiological response to sound exposure
•Pjvk gene transfer can rescue auditory dysfunction in Pjvk−/− mice
A deficiency in pejvakin, a protein of unknown function, causes a strikingly heterogeneous form of human deafness. Pejvakin-deficient (Pjvk−/−) mice also exhibit variable auditory phenotypes. Correlation between their hearing thresholds and the number of pups per cage suggest a possible harmful effect of pup vocalizations. Direct sound or electrical stimulation show that the cochlear sensory hair cells and auditory pathway neurons of Pjvk−/− mice and patients are exceptionally vulnerable to sound. Subcellular analysis revealed that pejvakin is associated with peroxisomes and required for their oxidative-stress-induced proliferation. Pjvk−/− cochleas display features of marked oxidative stress and impaired antioxidant defenses, and peroxisomes in Pjvk−/− hair cells show structural abnormalities after the onset of hearing. Noise exposure rapidly upregulates Pjvk cochlear transcription in wild-type mice and triggers peroxisome proliferation in hair cells and primary auditory neurons. Our results reveal that the antioxidant activity of peroxisomes protects the auditory system against noise-induced damage.
“Hypervulnerability to sound-exposure through impaired adaptive proliferation of peroxisomes” by Sedigheh Delmaghani, Jean Defourny, Asadollah Aghaie, Maryline Beurg, Didier Dulon, Nicolas Thelen, Isabelle Perfettini, Tibor Zelles, Mate Aller, Anaïs Meyer, Alice Emptoz, Fabrice Giraudet, Michel Leibovici, Sylvie Dartevelle, Guillaume Soubigou, Marc Thiry, E. Sylvester Vizi, Saaid Safieddine, Jean-Pierre Hardelin, Paul Avan, and Christine Petit in Cell. Published online November 5 2015 doi:10.1016/j.cell.2015.10.023