Researchers at the University of California, San Francisco (UCSF), have made a significant breakthrough in understanding the mechanisms behind hearing loss and have identified a gene that links deafness to cell death in the inner ear. This discovery paves the way for potential interventions to prevent hearing loss.
Hearing loss can be caused by various factors such as exposure to loud noise, aging, and certain medications. Currently, the primary solutions for individuals with hearing loss are hearing aids or cochlear implants. However, the UCSF scientists’ research sheds light on the processes occurring in the inner ear during hearing loss, potentially offering alternatives to traditional treatments.
The study, published in JCI Insight, draws connections between animal studies on hearing loss and a rare type of inherited deafness in humans. In both cases, mutations in the TMTC4 gene trigger a molecular response called the unfolded protein response (UPR), leading to the death of hair cells in the inner ear.
Interestingly, the UPR is also activated in hair cells during hearing loss caused by loud noise exposure or certain medications, such as cisplatin, a common chemotherapy drug. This suggests that the UPR may be a common factor underlying various forms of deafness.
Laboratory experiments on animals have shown that there are drugs that can block the UPR and prevent hearing loss. The researchers believe that these drugs should be tested on individuals at risk of hearing loss, such as those exposed to loud noise or taking medications that can affect hearing.
In the United States alone, millions of adults experience hearing loss due to noise exposure or age-related factors each year. Until now, the exact cause of this hearing loss has been a mystery. The identification of the TMTC4 gene as a human deafness gene and the UPR as a potential target for preventing deafness provide concrete evidence for new strategies in preserving hearing.
The initial observation linking TMTC4 mutations to deafness came in 2014 when Dr. Elliott Sherr, co-senior author of the study and director of the UCSF Brain Development Research Program, noticed that several of his young patients with brain malformations had mutations in the TMTC4 gene. However, it was perplexing that mice with similar TMTC4 mutations did not exhibit severe brain defects early on but rather experienced deafness as they matured.
Dr. Sherr collaborated with Dr. Dylan Chan, co-senior author of the study and director of the Children’s Communication Center in the UCSF Department of Otolaryngology, to investigate this phenomenon. They discovered that TMTC4 mutations sensitized hair cells in the ear to self-destruct, similar to the effects of loud noise exposure. In both cases, excessive calcium influx disrupted cellular signaling, including the UPR.
However, the researchers found a potential solution to prevent this self-destruction. They tested ISRIB, a drug developed at UCSF to inhibit the self-destruct mechanism of the UPR in traumatic brain injuries, and found that it prevented noise-induced hearing loss in animals.
In 2020, researchers from South Korea validated the findings of the 2018 study, identifying TMTC4 mutations in two siblings who were losing their hearing in their mid-20s. The mutations shared similarities with those seen in animals but were distinct from those observed in Dr. Sherr’s pediatric patients. This swift validation of the mouse studies in humans was made possible through the collaborative efforts of Dr. Bong Jik Kim and his team at the Chungnam National University College of Medicine in Korea.
Further experiments on cells from the Korean family confirmed that this specific TMTC4 mutation led to UPR activation and subsequent cell self-destruction. When the researchers mutated TMTC4 in hair cells of mice or cells from unaffected individuals and laboratory human cell lines, the UPR induced cell death. This finding emphasizes that TMTC4 is not only a deafness gene in mice but also in humans.
Understanding TMTC4 mutations provides a new avenue for studying progressive deafness, as the gene is critical for maintaining the health of the adult inner ear. The mutations mimic the damage caused by noise, aging, or medications such as cisplatin.
The researchers envision a future where individuals who must take medications like cisplatin or have occupational exposure to loud noise can take a drug that inhibits the UPR, thereby preserving their hearing by preventing hair cell degeneration.
Additionally, the discovery that the UPR plays a role in cell death could have implications beyond hearing loss. It may be applicable to other conditions where nerve cells undergo overwhelming stress and die, potentially offering insights into diseases such as Alzheimer’s and Amyotrophic Lateral Sclerosis (ALS).
Dr. Chan highlighted the significance of preventing hair cell death to preserve hearing: “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.”
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1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
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