A person’s hearing can be damaged by loud noise, aging and even certain medications, with little recourse beyond a hearing aid or cochlear implant.
But now, UCSF scientists have achieved a breakthrough in understanding what is happening in the inner ear during hearing loss, laying the groundwork for preventing deafness.

The research, published on Dec. 22, 2023, in the Journal of Clinical Investigation Insight, links animal studies on hearing loss with a rare type of inherited deafness in humans. In both cases, mutations to the TMTC4 gene trigger a molecular domino effect known as the unfolded protein response (UPR), leading to the death of hair cells in the inner ear.

Intriguingly, hearing loss from loud noise exposure or drugs such as cisplatin, a common form of chemotherapy, also stems from activation of the UPR in hair cells, suggesting that the UPR may underly several different forms of deafness.

There are several drugs that block the UPR – and stop hearing loss – in laboratory animals. The new findings make a stronger case for testing these drugs in people who are at risk of losing their hearing, according to the researchers.

How hair cells in the ear self-destruct

Sherr partnered with Chan, an expert on the inner ear, to look into what was happening to the mice, which looked like an accelerated version of age-related hearing loss in humans. They showed that mutations to TMTC4 primed hair cells in the ear to self-destruct, and loud noise did the same thing. In both cases, hair cells were flooded with excess calcium, throwing off the balance of other cellular signals, including the UPR.

But they found there was a way to stop this. ISRIB, a drug developed at UCSF to block the UPR’s self-destruct mechanism in traumatic brain injury, prevented animals who were exposed to noise from going deaf.

Translating a discovery to prevent deafness

Understanding TMTC4 mutations gives researchers a new way of studying progressive deafness, since it is critical for maintaining the health of the adult inner ear. The mutations mimic damage from noise, aging or drugs like cisplatin.

The researchers envision a future where people who must take Cisplatin, or who have to be exposed to loud noises for their jobs, take a drug that dampens the UPR and keeps hair cells from withering away, preserving their hearing.

The science also suggests that the UPR could be targeted in other contexts where nerve cells become overwhelmed and die, including diseases long thought to be incurable, like Alzheimer’s or Lou Gehrig’s disease.

“If there’s any way that we can get in the way of the hair cells dying, that’s how we’re going to be able to prevent hearing loss,” Chan said.

Source: https://www.ucsf.edu/news