Last month important findings from research we have been funding at UCL’s Ear Institute were announced, that we hope will pave the way for new medicines able to block the side-effects of aminoglycoside antibiotics.
Stress granules play an important role
Aminoglycoside antibiotics cause hearing loss by getting inside the tiny hair cells in the cochlea, causing them to degenerate and die. These hair cells are vital for detecting sound and our ears aren’t able to replace them once they have been lost, which is why hearing loss is permanent. Dr Cláudia Gonçalves, whose PhD we funded, discovered that shortly after being exposed to aminoglycosides, small granules appear inside the hair cells. These granules have been observed in other types of cell when put under strain and have been termed stress granules. They are formed by proteins and mRNA molecules clumping together. mRNA are the molecules that carry instructions for making proteins from the DNA to the structures where the proteins are made. It is thought that when a cell is under stress the formation of these granules may help the cell to sort mRNA molecules, so that the production of proteins able to protect the cell from the damage is prioritised and the production of those that might play a role in the cell’s demise are limited.
Could the formation of stress granules in hair cells exposed to aminoglycoside antibiotics actually be a natural cell survival response? To test this, Dr Gonçalves treated cells taken from the cochlea and grown in the laboratory with a drug that is known to boost the formation of stress granules, and then exposed them to aminoglycoside antibiotics. The result was a four-fold increase in the number of surviving hair cells compared to the preparations that weren’t treated with the stress granule-boosting drug.
In a separate experiment, she treated the cells with a different drug - one that prevents the formation of stress granules. This time she saw no increase in the number of surviving hair cells after being exposed to aminoglycosides.
Hair cells before and after aminoglycoside antibiotic treatment. On the left are healthy hair cells – three rows of outer hair cells (left) and one row of inner hair cells (right). The right image shows hair cells which have been treated with an aminoglycoside, kanamycin – many of the outer hair cells show signs of damage. Stress granules may be the cell’s way of trying to cope with this damage. With thanks to Professor David Furness (Keele University) for providing this image.
Boosting stress granules might be a way to protect hearingThe research findings suggest that drugs able to boost the production of stress granules might prime hair cells in the cochlea so that they are more resistant to the toxic side effects of aminoglycosides. They could be given to people just before they receive their antibiotic treatment to protect their hearing. The work so far has only been carried out in tissue taken from the cochlea and grown in the laboratory. It will be fascinating to learn whether the approach to protect hearing will work in an intact ear. What’s more, the approach might even help prevent other types of hearing loss that result from cellular stress such as other ear-toxic medicines used to treat cancer, exposure to loud noise and, perhaps, even age-related hearing loss.
Find out more
The research was funded by Action on Hearing Loss and the MRC. Dr Cláudia Gonçalves was funded by Action on Hearing Loss to do her PhD work in the laboratories of Dr Sally Dawson and Professor Jonathan Gale. You can read the original paper on the journal website: https://www.nature.com/articles/s41598-019-48393-w
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