Many genes (over 100) are linked to hearing loss. In many cases, we don’t know exactly why mutations in these genes cause hearing loss, which makes it difficult to develop effective treatments. Studying these genes can also tell us more about how hearing works, and how the inner ear develops, all of which is important information to help develop medicines to prevent hearing loss and restore hearing.
Mutations in a gene called PCDH-15 cause Type I Usher syndrome (a form of deaf-blindness), as well as non-syndromic hearing loss (hearing loss with no other health issues). The PCDH-15 gene produces a protein, called protocadherin-15, which is found in the sound-sensing hair cells of the inner ear. Hair cells are so-called as they have three rows of projections on the top of the cell, which look like hairs. The ‘hairs’ in each row are of increasing height, like a staircase. Each hair is connected to the one behind it by a structure known as a tip link – protocadherin-15 protein is one of the main components of these tip links. Sound waves enter the inner ear and deflect these hairs, causing a tugging force on the tip links – this leads the hair cell to transmit electrical information about the sound to the brain via the auditory nerve. We still don’t know exactly how this happens.
The researchers have previously found that protocadherin-15 is found in a modified form in hair cells. This modification changes how protocadherin-15 connects to other proteins. In this project, the researchers will study this alteration in more detail, and investigate whether it also changes how the hair cells respond to sound. This could help to explain exactly how hair cells turn sound vibration information into electrical signals that the brain can process, and suggest ways in which protocadherin-15 can be targeted to develop treatments for hearing loss.
The researchers will use a mix of cell lines and animal studies to investigate protocadherin-15. They already know that, in its modified form, protocadherin-15 interacts with another specific protein. They will use this knowledge to identify exactly where on the protocadherin-15 protein it is modified. This will allow them to design chemical probes to find out where within the hair cell the modified form of protocadherin-15 is found.
They will also investigate how important the modified form of protocadherin-15 is to the normal function of a hair cell in detecting and passing on information about sound. They will do this by studying mice that have been genetically engineered so that their protocadherin-15 protein cannot be modified. They will also study these mice to identify other proteins that bind to the modified protocadherin-15 and what they do.
Protocadherin-15 is crucial in allowing the inner ear to detect sound and balance information and pass it on to the brain, and mutations in protocadherin-15 cause hearing loss. This research will provide more insight into how protocadherin-15 is important for hearing, and how it could be targeted with drugs to repair its function and restore hearing.