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Holy Grail of Hearing: True Identity of Pivotal Hearing Structure Is Revealed

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Top: Scanning electron microscopy shows the stair-step pattern of stereocilia. Bottom: Fluorescence microscopy image shows the presence of CDH23 (green) at the point where each short stereocilium (red) meets the side of its taller neighbor.
Credit: B. Kachar, NIDCD

Our ability to hear is made possible by way of a Rube Goldberg-style process in which sound vibrations entering the ear shake and jostle a successive chain of structures until, lo and behold, they are converted into electrical signals that can be interpreted by the brain. Exactly how the electrical signal is generated has been the subject of ongoing research interest.

In a study published in the September 6 issue of the journal Nature, researchers have shed new light on the hearing process by identifying two key proteins that join together at the precise location where energy of motion is turned into electrical impulses. The discovery, described by some scientists as one of the holy grails of the field, was made by researchers at the National Institute on Deafness and Other Communication Disorders (NIDCD), one of the National Institutes of Health (NIH), and the Scripps Research Institute in La Jolla, CA.

This team has helped solve one of the lingering mysteries of the field, says James F. Battey, Jr., M.D., Ph.D., director of the NIDCD. The better we understand the pivotal point at which a person is able to discern sound, the closer we are to developing more precise therapies for treating people with hearing loss, a condition that affects roughly 32.5 million people in the United States alone.

When a noise occurs, such as a car honking or a person laughing, sound vibrations entering the ear first bounce against the eardrum, causing it to vibrate. This, in turn, causes three bones in the middle ear to vibrate, amplifying the sound. Vibrations from the middle ear set fluid in the inner ear, or cochlea, into motion and a traveling wave to form along a membrane running down its length. Sensory cells (called hair cells) sitting atop the membrane ride the wave and in doing so, bump up against an overlying membrane. When this happens, bristly structures protruding from their tops (called stereocilia) deflect, or tilt to one side. The tilting of the stereocilia cause pore-sized channels to open up, ions to rush in, and an electrical signal to be generated that travels to the brain, a process called mechanoelectrical transduction.

Most scientists believe that the channel gates are opened and closed by microscopic bridgescalled tip linksthat connect shorter stereocilia to taller ones positioned behind them. If scientists could determine what the tip links are made of, theyd be one step closer to understanding what causes the channel gates to open. This is no easy feat, however, because stereocilia are extremely small, scarce, and difficult to handle. Several proteins had been reported to occur at the tip link in earlier studies, but results have been conflicting to this point.

Cadherin 23 and Protocadherin 15 Unite to Form Tip Link

Using three lines of evidence, NIDCD scientists Hirofumi Sakaguchi, M.D., Ph.D., Joshua Tokita, and Bechara Kachar, M.D., together with Piotr Kazmierczak and Ulrich Mller, Ph.D., of Scripps Research Institute, and other collaborators have demonstrated that two proteins associated with hearing losscadherin 23 (CDH23) and protocadherin 15 (PCDH15)unite and adhere to one another to form the tip link. Mutations in CDH23 are known to cause one form of Usher syndrome as well as a nonsyndromic recessive form of deafness, and mutations in PCDH15 are responsible for another form of Usher syndrome. (A syndrome is a disease or disorder that has more than one feature or symptom, while the term nonsyndromic refers to a disease or disorder that is not associated with other inherited characteristics.) Usher syndrome is the most common cause of deaf-blindness in humans.

Cadherin 23 and protocadherin 15 have been implicated in a variety of forms of late- and early-onset deafness, and a whole range of mutations can produce different outcomes, says NIDCDs Kachar, a co-senior investigator on the study. Now that we know how these two proteins interact at the tip link, we can perhaps predict how different types of hearing loss can take place depending on where a mutation is located.

Three Lines of Evidence

The researchers first created antibodies that would bind to and label short segments on the CDH23 and PCDH15 proteins in the inner ears of rats and guinea pigs. (Both proteins were identified at the tip link, respectively, in earlier studies.) Using green fluorescence and electron microscopy studies, they showed that CDH23 was located on the side of the taller stereocilium and PCDH15 was present on the tip of the shorter one, with their loose ends overlapping in between. The researchers were able to identify both proteins, while earlier studies had not, because they removed an obstacle to the antibody-binding process: calcium. Under normal conditions, CDH23 and PCDH15 are studded with calcium ions, which prevent antibodies from binding to the targeted sites. When calcium was removed through the addition of a chemical known as BAPTA, both labels became visible.

Next, the researchers built a structure resembling a tip link by expressing the CDH23 and PCDH15 proteins in the laboratory and watching how they interacted. When conditions were right, the two proteins wound themselves tightly together from one end to the other in a configuration that mirrored a naturally occurring tip link. The results were surprising, since the scientific consensus had been that these proteins would not interact at all. As with normal tip links, the structure thrived in calcium concentrations that paralleled those found in fluid of the inner ear, while a drastic reduction in calcium disrupted the structure.

Lastly, the scientists found that one mutation of PCDH15 that causes one form of deafness inhibited the interaction of the two proteins, leading them to conclude that the mutation reduces the adhesive properties of the two proteins and prevents the formation of the tip link. In a second mutation of PCDH15, the tip link was not destroyed; the scientists suggested that the deafness is not likely caused by the breakup of the tip link but by interference with its mechanical properties.

Knowing precisely the composition and configuration of the tip link, scientists can now explore how these proteins interact with other components to form the rest of the transduction machinery. In addition, scientists can study how new treatments might be developed to address the breaking up of tip links through environmental factors, such as loud noise.

Now that we understand what the tip link is made of and what conditions are required to assemble it, says Kachar, we can study what it might take to rejoin tip links as a possible method for restoring hearing in people with some forms of hearing loss that may have resulted from disruption of the tip link.

Funding of the study was principally provided by the NIDCD. Other NIH institutes and centers that contributed funding were the National Institute of General Medical Sciences (NIGMS), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and the National Center for Research Resources (NCRR).

The National Institutes of Health (NIH)the Nation's Medical Research Agencyincludes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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