Evidence for the Unfolded Protein Response to be Involved in Age-Related Deafness
Researchers have found that deafness-associated gene TMTC4 causes pathology via an excessive increase in the unfolded protein response in sensory hair cells of the inner ear, and loud noise does much the same. This suggests that inhibition of the unfolded protein response in these cells might be a way to slow loss of hearing capacity, or protect against the effects of loud noise and drugs that can harm hair cells. Still, this isn't a path to restoration of hearing capacity. That would require some way to replace lost hair cells and their connections to the brain.
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.
"As mice with TMTC4 mutations grew, we saw that they didn't startle in response to loud noise. They had gone deaf after they had matured." Researchers investigated 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.
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. 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.