Scientists have discovered that a genetic mutation that triggers a domino effect of hearing loss mirrors the mechanism of noise- and age-related hearing loss. They believe that inhibiting a key player in this mechanism could instead protect all ears from damage and even prevent deafness.

Researchers at the University of California, San Francisco (UCSF) have discovered that mutations in the Tmtc4 gene trigger a mechanism called the unfolded protein response (UPR), which kills hair cells in the inner ear.

Humans and all mammals have two types of cochlear hair cells - inner ear hair cells and outer ear hair cells - that play different but crucial roles in sensory communication. There are approximately 3,500 hair cells in the inner ear at birth. They convert sound vibrations in the cochlear fluid into electrical signals and transmit them to the brain. Once damaged, they cannot regenerate.

Hair cells are the sensory cells of the ear, so named because their hair-like structures bend in response to sound. Hair cells convert this movement into signals that are transmitted to the brain. When we make loud noises in our cars or cheer at football stadiums with tens of thousands of fans, the noise can cause hairs to bend and even break. Research from the University of California, San Francisco, shows that this activates the unfolded protein response (UPR) in hair cells, forcing them to self-destruct, leading to hearing loss. Picture taken by Henning Horn, Brian Burke and Colin Stewart from the Institute of Medical Biology, A*STAR.

The scientists found that targeting activation of the UPR in hair cells - which occurs both in genetic mutations and in lifestyle- and age-related hearing loss, as well as in chemotherapy drugs such as cisplatin - could protect these precious sensors from death.

"Millions of American adults lose their hearing every year due to exposure to noise or aging, but exactly what causes hearing loss has been a mystery," said co-first author Dylan Chan, MD, of UCSF's Department of Otolaryngology. "We now have conclusive evidence that Tmtc4 is a human deafness gene and that UPR is a real target for preventing deafness."

When exposed to stimuli such as loud music or a crowd at a stadium, the noise can cause hair cells to bend to the point of rupture. The researchers believe this activates the UPR, essentially causing the cells to self-destruct, causing permanent damage.

In this study, Dr. Chen collaborated with Elliott Sherr, who had earlier studied Tmtc4 gene mutations in young patients and mouse models. They found that genetic variants in both humans and mice trigger hair cells to self-destruct, causing hearing loss to rapidly worsen, as is typically seen with age-related injuries or noise exposure injuries. In all cases, the hair cells were flooded with excess calcium, causing signaling, including the UPR, to malfunction.

However, a drug developed at UCSF to reverse memory decline after traumatic brain injury was also shown to inhibit part of the UPR, protecting inner hair cells from damage, even when mice were exposed to loud, potentially harmful noise.

The research team hopes to develop a non-invasive drug that inhibits UPR activation and protects hair cells from damage, thereby avoiding hearing loss.

An earlier study conducted by the University of Iowa also highlighted the potential for targeting the chemical and electrical mechanisms of the inner ear to prevent hearing loss at the molecular level.

"If we had a way to stop hair cells from dying, we could prevent hearing loss," Chen said.

The study was published in the journal Clinical Investigation Insights.