Prague scientists have discovered the mechanism driving an ion channel that causes epilepsy. The findings were published this month in Scientific Reports.
This group of investigators, including Dr. Norbert Weiss and his team at the Institute of Organic Chemistry and Biochemistry in Prague, in collaboration with two Canadian teams led by Dr. Gerald W. Zamponi at the University of Calgary, and Dr. Terrance P. Snutch at the University of British Columbia, are working to unlock the secrets of ion channels and discover how these proteins contribute to neurological diseases.
Ion channels are a particular class of proteins that form gates to control the flow of ions across the membranes of nerve cells that ultimately drives the activity of the brain. Therefore, it is essential for nerve cells to have mechanisms to keep these channels in check in order to maintain normal brain activity.
“These mechanisms are usually not perfect and it often ends up being problematic,” says Weiss the lead author of the study.
Epilepsy is a neurological disorder in which the activity of nerve cells in the brain is disrupted. For example, childhood absence epilepsy (CAE) is one particular type of epilepsy that essentially begins in young children. Seizures of CAE are characterized by periods of loss of consciousness during which the child is not aware or responsive. Although seizures are usually brief, they can occur frequently, sometimes in the hundreds per day, which can have dramatic consequences on the development of the child. The cause is mostly genetic and mutations in CACNA1H – a gene that encodes for a calcium channel called the T-type channel, have been found in CAE patients.
“We have known for quite a long time that this channel is causally linked to CAE but we did not quite understand the detailed mechanisms by which it is implicated in the disease”, says Weiss. “What we found is that one mutation disrupts a mechanism that in normal conditions limits the number of channels expressed in the membrane of nerve cells”.
This causes brain cells to be more active which eventually ends up driving seizures.
When asked whether this mechanism can be exploited for therapeutic purpose, Weiss remains prudent.
“The mutation we have been working on is found in an animal model of absence epilepsy and at this stage we do not know whether it applies to the human disease”.
But scientists also discovered that brain cells naturally produce two types of the calcium channel, and one of them escapes this control mechanism similarly to what the animal mutation does on the channel.
“We do not quite understand yet why brain cells produce two variants of the channel and how they control the balance between the two, but now that we understand the minutiae we can start to think of the disease from a different angle and explore new avenues that have not been considered yet,” says Weiss, the lead author of the study and group leader at the Institute of Organic Chemistry and Biochemistry in Prague.