According to a recent report in an October issue of The Journal of Clinical Investigation, a team of UC San Francisco researchers have discovered a gene that plays an essential role in noise-induced deafness.
By administering an experimental chemical — identified in a separate UCSF lab in 2013 — that acts on the pathway linking this gene to hearing loss, the researchers found they could prevent noise-induced deafness in mice. Further, the researchers surmise a similar drug to the one used in their study might one day be used as a hearing-protection regimen (oto-protective agent) before working in a noisy environment, using loud tools or attending a raucous concert.
The research team is also examining whether the otoprotective agent could be taken shortly after exposure to loud noise to protect hearing.
Preventing Hearing Loss
Lead researcher Elliott Sherr, professor of neurology and of pediatrics at UCSF and colleagues were interested in a gene called Tmtc4 for its potential role in brain development. When the team deleted the gene in mouse embryos, they were surprised to discover that the mice became almost completely deaf by one month after birth.
The Tmtc4 protein normally plays a role in the endoplasmic reticulum (ER), a structure inside the cell that helps regulate much of protein production. Sherr’s group found that the loss of Tmtc4 in cochlear hair cells distorted the delicate balance of calcium that ordinarily exists between the ER and the rest of the cell and triggered the unfolded protein response (UPR) — a quality control system that causes a cell to self-destruct if it’s producing faulty (and perhaps dangerous) proteins. The UPR triggered hair-cell suicide, ultimately leading to total deafness.
Because the mice could hear normally after they were born, the researchers realized that they weren’t dealing with some form of congenital deafness. Instead, they suspected that the rapid hearing loss observed in Tmtc4-deficient mice was due to a heightened sensitivity to normal sounds. To test this hypothesis, the researchers exposed normal mice to loud noises and found that this triggered hair-cell death triggered by the UPR, just as was seen in the mice lacking Tmtc4.
To prevent noise-induced hearing loss in the mice, the scientists needed to somehow block the UPR and prevent hair cells from self-destructing. Fortunately, they were right down the hall from Peter Walter, Ph.D., a professor of biochemistry and biophysics at UCSF whose lab identified a drug in 2013 that does precisely that. The compound, known as ISRIB (for Integrated Stress Response Inhibitor) inhibits part of the UPR. It has been shown to reverse memory failure caused by traumatic brain injury in mice and to kill aggressive prostate cancer cells. Giving the mice ISRIB before they were exposed to loud noises prevented hair cell damage and noise-induced hearing loss.
Sherr and his team are investigating if this treatment would be useful to prevent other types of hearing loss, including age-related hearing loss.
The entire study can be accessed here: https://www.jci.org/articles/view/97498