April Flowers for redOrbit.com – Your Universe Online
Finding the exact genetic code that programs the ear´s machinery for responding to sound waves and converting them into electrical impulses in the inner ear has been something of a holy grail for the scientists who study the genetics of hearing and deafness.
A new study from The Scripps Research Institute (TSRI) has brought this search to fruition by identifying a critical component of the ear-to-brain conversation. This component is a protein called TMHS, a critical player in the ear´s so-called ℠mechanotransduction channels´. These channels convert the signals from mechanical sound waves into electrical impulses which are then transmitted to the nervous system.
The findings of this study were published recently in the journal Cell.
“Scientists have been trying for decades to identify the proteins that form mechanotransduction channels,” said Ulrich Mueller, a professor in the Department of Cell Biology and director of the Dorris Neuroscience Center at TSRI. The results suggest a promising new approach toward gene therapy.
The team was able to place functional TMHS into the sensory cells for sound perception in newborn deaf mice. This laboratory experiment allowed the researchers to restore the function of these cells.
“In some forms of human deafness, there may be a way to stick these genes back in and fix the cells after birth,” said Mueller.
Previous studies have found specific genetic forms of this protein in people with common inherited forms of deafness. This new discovery would also seem to suggest the first explanation for how these genetic variations affect hearing loss.
Receptor cells deep in the ear collect vibrations and convert them into electrical signals and are the physical basis for hearing and mechanotransduction. These signals run along nerve fibers to areas in the brain where they are interpreted as sound. This basic mechanism evolved early in the history of life on Earth, and structures nearly identical to the modern human inner ear have been found in the fossilized remains of dinosaurs that died out 120 million years ago. Almost all mammals today share the basic inner ear structure.
Mechanical vibration waves travel from a sound source to hit the outer ear, propagate down the ear canal into the middle ear and strike the eardrum. A delicate set of bones is moved by the vibrating eardrum, communicating the vibrations to a fluid-filled spiral in the inner ear known as the cochlea. The moving bones compress a membrane on one side of the cochlea, causing the fluid inside to move.
Specialized hair cells inside the cochlea have symmetric arrays of extensions known as stereocilia protruding out from their surface. The moving fluid inside the cochlea causes the stereocilia to move, which in turn causes proteins known as ion channels to open. Sensory neurons surrounding the hair cells monitor the opening of the channels. When those neurons sense some threshold level of stimulation, they fire off communicating electrical signals to the auditory cortex of the brain.
Hearing involves many structures and is such a complex process that there are hundreds and hundreds of underlying genes involved. There are many ways it can be disrupted as well.
Long before birth, hair cells form in the inner ear. Humans are born with a finite number of these hair cells, as they do not regenerate themselves throughout life. Many, if not most, forms of deafness are associated with defects and loss of these hair cells. Genetic forms of deafness emerge when those hair cells are unable to transduce sound waves into electrical signals.
Scientists have identified dozens of genes linked to hearing loss over the years. Some of these genes have been identified from genetic studies involving deaf people and some from studies with mice, which have inner ear structures remarkably similar to humans.
A clear picture of how these genes interact to form the biological basis of hearing has been missing, however. Though scientists have known that many of these genes are involved in deafness, they haven’t been able to account for the various forms of hearing loss. However, the picture is becoming clearer since the discovery of TMHS, which plays a role in a molecular complex called the ℠tip link´.
Several years ago, it was discovered that the tip link caps the stereocilia protruding out of hair cells. The tip links connect neighboring stereocilia at the top, bundling them together. When they are missing, the hair cells become splayed apart.
The tip links do more than maintain the structure of these bundles, however, they also house the machinery crucial for hearing — the proteins that physically receive the force of a sound wave and transduce it into electrical impulses by regulating the activity of ion channels. Mueller’s lab previously identified the molecules that form the tip links. But the ion channels and the molecules that connect the tip links to the channels remained elusive. Mueller says that scientists have been searching for the exact identity of the proteins responsible for this process for years.
The new study reveals that TMHS is one of the lynchpins of this process. TMHS is a subunit of the protein-based ion channel that directly binds it to the tip link. If the TMHS protein is missing, hair cells that are otherwise completely normal lose their ability to send electrical signals.
Mueller’s team demonstrated this using a lab technique that emulates hearing with cells in the test tube. Sounds are imitated by vibrations that are deflected off the cells, and the cells can be probed to see if they can transduce the vibrations into electrical signals. What these tests showed is that with TMHS, this ability to transduce disappears.
This, say the researchers, is a crucial puzzle piece in understanding the genetic basis of hearing and hearing loss.
“We can now start to understand how organisms convert mechanical signals to electrical signals, which are the language of the brain,” concluded Mueller.