Our sense of hearing depends on specialized sound-sensing cells in the inner ear, called hair cells. Hair cells are so-called because they have tiny hair-like protrusions at the top of each cell, which form structures called hair bundles. These structures are crucial for hearing – they are deflected when sound enters the inner ear, which causes channels in the hair cell surface membrane to open. This allows electrically-charged potassium ions in the fluid outside the cells to rush in to the cell, creating a change in voltage that triggers the hair cell to generate an electrical signal. This signal then passes along the auditory nerve to the brain, where it is perceived as sound. This process, known as mechanotransduction, is fundamental to hearing.
There are many genes (and their corresponding proteins) that are involved in the development and maintenance of the hair bundle and in mechanotransduction – mutations in these genes tend to cause hearing loss, often severe in nature.
What is Usher syndrome?
Usher syndrome is a genetic condition that causes deafblindness. There are three types, called type 1, 2 and 3, and although they all cause deafblindness, they decrease in severity from type 1 to type 3. They are all caused by mutations in genes that are involved in mechanotransduction or the formation and function of the hair bundle; these mutations cause the mechanotransduction process to fail, leading to hearing loss.
People with Usher syndrome type 3 are born with both hearing and vision. They begin to lose their hearing by early adolescence, and start to lose their vision soon afterwards. Usher syndrome type 3 is caused by mutations in a gene called CLRN-1 (the protein from this gene is called clarin-1).
How do mutations in CLRN-1 cause Usher syndrome type 3?
We don’t know exactly what role clarin-1 plays in the hair cell, but studies in animals have shown that it is found in the hair bundle. In its absence, the bundles form incorrectly and there is decreased mechanotransduction activity, leading to rapid profound hearing loss as the hair cells die. It’s likely, therefore, that clarin-1 is important for forming and maintaining the hair bundles.
A number of different mutations in CLRN-1 can cause Usher syndrome type 3, but one particular mutation is common – a single change in the gene’s DNA sequence, which changes one amino acid in the clarin-1 protein. This change causes the protein to get stuck in a structure within the hair cell called the endoplasmic reticulum (ER). This contains the machinery to build new proteins and transport them to wherever they’re needed in the cell.
To move a protein to another part of the cell (such as the hair bundle, where clarin-1 needs to go), they have to be ‘tagged’, marked by a chemical modification that tells the ER machinery where to send them. For clarin-1, this modification occurs on the amino acid that is changed by the mutation. The new amino acid in the mutated protein can’t be modified, so the protein remains in the ER and is eventually degraded. Without clarin-1, the hair bundles don’t form properly and hearing loss is the result.
Studying the mutated clarin-1 protein in more detail
Animal studies in which the mouse or zebrafish gene for clarin-1 was replaced with the mutated version of the human gene (normal human clarin-1 can replace both mouse and zebrafish clarin-1, as they are all very similar proteins) showed that a tiny fraction of the mutated protein was still getting to the hair bundles – and it appeared to be working normally.
Researchers from Case Western Reserve University in the US investigated this in more detail. They had two questions:
1) How did mutated clarin-1 get to the hair bundle?
2) Could they increase the amount of mutated clarin-1 in the hair bundle and prevent the ensuing hearing loss?
To do this, they studied the mutated protein in zebrafish. Zebrafish are very useful for studying hearing and genetic hearing loss, as they have hair cells on the outside of their bodies, which are similar to the hair cells in our ear. They use them to sense movements in the water as they swim, to find food and avoid danger. Their larvae are also translucent, meaning it’s very easy to look at the hair cells and visualize what’s going on, using fluorescently-labelled proteins.
It's also easy to genetically modify zebrafish – here, the researchers studied zebrafish in which their own clarin-1 gene had been replaced with the human version, either the normal version (these fish could hear normally, and moved normally as they could sense their environment) or the mutated version (these fish had diminished hearing, and moved less as they couldn’t sense their environment as well).
There are some processes by which proteins can be moved to other parts of the cell even if they lack the correct tag – these processes usually occur when the cell is under stress. They are called unconventional secretory pathways. The researchers were able to identify one such pathway, called GCUSP, which was responsible for moving a tiny amount of mutated clarin-1 to the hair bundle.
There are several drugs that can enhance the activity of this pathway, and the researchers found that one such drug, artemisinin, normally used to treat malaria, was able to increase the amount of mutated clarin-1 protein in the hair bundles of the hair cells. It also caused the fish to have improved hearing and movement, and their hair cells remained healthy – the drug was able to prevent the hearing loss usually seen with this mutation.
Could this work in people?
Assuming that similar processes occur in human hair cells, it might be possible to use artemisinin as a treatment for Usher syndrome type 3, or other genetic conditions caused by mutations that trap otherwise normal proteins in the ER. More research will be need to determine this before the drug can be tested in people with Usher syndrome type 3.
Artemisinin has a big advantage over a newly-developed drug – as it is already approved for use in people to treat malaria, it has already been through clinical trials to prove that it is safe and tolerated in people. So if the signs for it working in people like it does in zebrafish are good, its route to use in the clinic is shorter – it would still need to be tested to show it is an effective treatment for Usher syndrome type 3, but it’s already cleared some of the hurdles that face a new drug developed from scratch.
Find out more
This research was originally published in the journal Proceedings of the National Academy of Sciences USA
earlier this year – you can read the abstract on the journal website
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