A team at the Royal College of Surgeons is tracking down a gene that may provide useful new treatments for epilepsy, writes DICK AHLSTROM.
RESEARCHERS at the Royal College of Surgeons in Ireland are on the search for what goes wrong inside brain-cells to trigger epilepsy. It is extremely detailed work but a hoped- for result might be a new drug therapy to help those suffering from the disorder.
About 1 per cent of the Irish population, 35,000 people, suffer from epileptic seizures, says Dr David Henshall of the department of physiology and medical physics at the Royal College of Surgeons in Ireland.
Importantly, about one in three of those who have epileptic seizures do not respond to the main treatments “even though they are on the best drugs available”, says Henshall.
He recently received Science Foundation Ireland funding worth €1 million in support of a four-year study of what goes wrong inside brain cells to cause seizures. “Our group is interested in the cell and the molecular processes that cause epilepsy,” he says.
“One of the most common triggers for epilepsy is brain injury. It can occur very quickly or after a period of 10 or 20 years when suddenly out of the blue you have a seizure.”
One consequence of these seizures is downstream damage caused to certain parts of the brain such as the hippocampus. Cells die causing a shrinkage seen in one of the two hippocampi found at the base of the brain. One treatment option for patients who do not respond to drug therapy is the surgical removal of the affected hippocampus.
His lab is studying what various genes are doing inside the cell, looking for changes that might be linked to epilepsy.
Genes make proteins, the chemicals that allow cells to do things. The normal protein mix in the cell will change if a disease process is under way and this provides a focus for Henshall and his research group of two post-doctoral researchers, a PhD student and a research assistant.
The work included studies of brain tissue recovered from epileptic patients after surgical treatment, and also in mouse models of epilepsy. “We were interested in cell death and survival mechanisms in the brain cells,” explains Henshall.
Each seizure causes some cell loss, he says. “This could lead over time to the progressive damage seen in the hippocampus.”
They reasoned that if cell death was taking place in the brain after seizures, then perhaps they could track this process or find a way to block it. Cells die in a highly regulated way in a process known as apoptosis, so they assumed that at least some of the genes being switched on and off during a seizure might be linked to apoptosis.
Cells are monstrously complex however and they had to deal with 35,000 different proteins in their search for any connections to epilepsy.
“What we saw was an increase in the level of activity [after seizures] in some of the genes associated with apoptosis. There was a bit of a battle going on within the brain cells,” he explains, with proteins that aid survival being produced along side of proteins associated with cell death.
Their studies showed that if a cell was challenged it would protect itself by forcing protein production to slow down. They discovered that a full 75 per cent of genes were down-regulated in this way, and this included genes that would otherwise encourage cell death through apoptosis.
“The question is how is this down-regulation being controlled,” says Henshall. If they can find what controls it then perhaps it might be possible to use it to block cell death.
“We had a short list of what could be doing this,” he adds and the focus is now on something called microRNAs. These very small components are only 20 to 40 steps long, yet they have a powerful effect and are able to block off protein production.
He is collaborating with Prof Ray Stallings who heads cancer genetics research at the college and also at Our Lady’s Hospital for Sick Children in Crumlin, Dublin. Stallings has particular expertise in the study of microRNAs The microRNAs are produced by something called the “dicer gene”. It produces a dicer enzyme which chops up a longer piece of RNA into the microRNAs.
Henshall and his group are now studying dicer in order to see how its regulation might effect cell death during seizures. It may be possible to develop a drug that could block or enhance the activity of dicer.