A possible new treatment target for refractory epilepsy

An image of a DNA double helix, in dark pink and dark purple, on a multi-coloured background. Ref: www.dreamstime.com

Every cell in our body has a protective scaffolding that is responsible for maintaining its shape. This scaffolding, known as a cytoskeleton, also enables the cell to move and plays an important role in cell division and intracellular transport (transport within the cell) of different molecules. In order for the cytoskeleton to function normally it needs to be stabilised, and in the brain a protein known as tau is largely responsible for ensuring this. Tau is encoded by a gene known as MAPT, and defects in this gene are linked to a range of neurodegenerative disorders including Alzheimer’s disease.

There is now evidence that normal tau plays an important role in regulating neuronal excitability (it prevents neurons from becoming hyperexcited and causing seizures). Indeed, researchers at the Mayo Clinic, in Jacksonville, have found that animals with an inherited condition that is very similar to Alzheimer’s disease (this will be referred to as rAD), often experience epileptic seizures in the memory centres of the brain. In collaboration with scientists at the University of California, this group have also shown that deletion of the tau gene in these animals leads to improved cognitive function and fewer seizures.  

These observations are significant because they suggest that defective tau function can not only lead to Alzheimer’s disease, but also to neuronal hyperexcitability and seizures. This in turn implies that Alzheimer’s disease and epilepsy may share similar deficits in signalling within memory circuits, and that the decline in memory and cognition seen in Alzheimer’s disease might be caused by too much activity in neurons rather than too little (as previously thought).

In a more recent investigation, the researchers at the Mayo Clinic wondered whether the reduction in seizures they saw following deletion of tau only occurred in animals with rAD, or if this was also the case in animals with severe epilepsy but no rAD.

For this study, the team obtained animal models that had been bred with a severe form of epilepsy that causes severe, spontaneous seizures and early/sudden death. In the first instance, they observed these animals over a short period of time and noted their seizure frequencies. The team then divided the models into three groups: those that were to have one copy of the tau-encoding gene MAPT deleted; those that were to have both copies of the gene deleted and those that were to have neither copy deleted (the controls). Having carried out the relevant procedures, they recorded the seizure frequencies of the groups to see if there was any difference compared to before. They were also interested in discovering whether or not deletion of MAPT (either one or both copies of the gene) affected the survival rates of the animals.

The researchers found that the animals with both copies of the MAPT gene removed (that produced no tau protein) showed a significant reduction in seizure frequency, and that they lived considerably longer than the controls. Interestingly, deletion of just one copy of the MAPT gene (i.e. halving as opposed to eliminating tau) was also highly effective in reducing seizure frequency and prolonging life.

These are very early findings and need to be replicated in humans; however they are extremely promising because they suggest that a reduction in tau could potentially help to reduce seizures, and even sudden death, in people with refractory epilepsy. In time, drugs that block the action of defective tau may become available as new, more effective, treatment options. We look forward to reading the developments in this research.

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