Ohio State researchers ear discoveries that may help deafness and balance disorders

High-resolution images of structures in the inner ear, produced by X-ray crystallography, were used by Ohio State University researchers to simulate for the first time in detail the actions of tip link filaments.

The researchers used three supercomputers working in tandem for months to produce movie simulations depicting how sound and motion vibrations are converted into hearing and balance.

Hearing and balance perception are the result of the minute, intricate machinery of the inner ear. It was already known that the inner ear filaments, called tip links, are composed of two large proteins, cadherin-23 and protocadherin-15.

Each tip link sits on top of microscopic hairs, which are grouped in bundles. The bundles resemble tiers of pipes in a pipe organ. Some of the hair bundles process high-pitched sound waves, others process lower pitches.

The bending of the hair bundles causes the tip links to stretch, which triggers the opening of ion channels, resulting in electrical signals reaching the brain. The brain then processes these signals into sound. 

All this happens within millionths of a second.

A decade ago, the project's lead researcher, Marcos Sotomayor, discovered that the two proteins, cadherin-23 and protocadherin-15, join in what he called a molecular "handshake" to strengthen the tip line. The molecular images available at that time were low resolution.

In the latest work using X-ray crystallography, Sotomayor and his Ohio State team observed in high resolution that the proteins use two "handshakes" to strengthen the tip line.

The new X-ray crystallography produced images of the tip links and proteins at a resolution of 2.9 angstroms. (One angstrom is one ten-billionth of a meter.)

At this very high resolution, the researchers were able to see the type of tip link motion and whether it was stiff or soft. This enabled them to create multiple model simulations of tip link actions and failures.

Tip link protein complexes are also present on the hair cells that respond to head motions. These are responsible for balance sensing.

Sotomayor, an associate professor of chemistry and biochemistry at Ohio State, told the university press office that the models his team created will be useful in understanding and perhaps preventing deafness and balance disorders.

"The structures also reveal tip link sites that are mutated in inherited deafness," Sotomayor said. "So we can try to understand what is happening with the tip links when you have these sites modified by mutations, not only by looking at the static structures but also at the simulated trajectories of tip links responding to sound.”

“These are the most complete and advanced molecular models and simulations of the tip link to date and required the use of massive computational resources,” Sotomayor said.

The research work was published in the Proceedings of the National Academy of Sciences, Sept. 22.