Scientists at the Scripps Research Institute (TSRI) in San Diego, California, have discovered a gene essential to hearing, revealing one of the causes of deafness. This discovery may open the door to new strategies for developing therapies to address this condition.
The study shows how mutations in a gene called Tmie can cause deafness from birth. Underlining the critical nature of their findings, the researchers were able to reintroduce the gene in mice and restore the process for hearing.
“This raises hopes that we could, in principle, use gene-therapy approaches to restore function in hair cells and thus develop new treatment options for hearing loss,” said Professor Ulrich Müller, senior author of the new study, chair of the Department of Molecular and Cellular Neuroscience and director of the Dorris Neuroscience Center at TSRI.
The ear is a complex machine that converts mechanical sound waves into electrical signals that the brain processes. When a sound wave enters the ear, the uneven ends (stereocilia) of the inner ear’s hair cells are pushed back, as if they were grass that bends for a heavy wind. The movement causes tension in the strings of proteins (tip links) connecting the stereocilia, which sends a signal to the brain through ion channels that run through the tips of the hair cell bundles.
This process of converting mechanical force into electrical activity, called mechanotransduction, still poses several mysteries. In this case, the researchers did not know how signals were passed along the tip links to the ion channels, mechanism responsible for shaping the electrical signals.
To track this unknown component, the scientists built a library of thousands of genes with the potentiality of affecting mechanotransduction.
The team spent six months screening those genes to see if they produce proteins that interact with tip link proteins. Eventually, the team found the gene Tmie, which protein TMIE interacts with tip link proteins, connecting the tip links to a piece machinery near the ion channel.
The discovery answers a long-standing question in neuroscience. Scientists have long known that mutations in the Tmie gene could cause deafness, but were not sure how.
Once found that TMIE creates a bridge between the tip links and ion channels, the researchers bread a population of mice lacking the gene. Then, they examined their hair cells with electrophysiological techniques and found that without TMIE no electrical signals were produced in hair cells after stimulation.
“The mechanotransduction current is gone; the mouse is totally deaf,” explained Bo Zhao, a research associate in the Müller lab and first author of the new paper.
In a second experiment, the researchers reintroduced Tmie to mice that had been deaf since birth and found the electrical signals were restored.
Müller said the next challenge is to find out how the individual components of the complex mechanotransduction system form in hair cells. “We would also like to understand the biophysical principles by which these proteins convert mechanical signals into electrical signals,” he said.
The study was published November 20 in the journal Neuron.
Vía: Scripps Research Institute
