Researchers Identify Potential Way to Treat Genetic Epilepsy by Replacing ‘Lost’ Enzyme

CDD causes seizures and impaired development in children, and medications are limited to managing symptoms rather than tackling the root cause of the disease.

The disorder involves losing the function of a gene producing the CDKL5 enzyme, which phosphorylates proteins, meaning it adds an extra phosphate molecule to alter their function.

Following recent research from the same lab showing that a calcium channel could be a target for therapy for CDD, the team has now identified a new way to potentially treat CDD by boosting another enzyme’s activity to compensate for the loss of CDKL5.

These mice show similar symptoms to people with CDD like impaired learning or social interaction.

The researchers first identified that CDKL5 is active in nerve cells in mice but not in another type of brain cell called an astrocyte.

In the nerve cells, they measured the level of phosphorylation of EB2, a molecule known to be targeted by CDKL5, to understand what happens when CDKL5 isn’t produced.

Interestingly, even in mice that don’t produce CDKL5, there was still some EB2 phosphorylation taking place, which suggested that another similar enzyme must also be able to phosphorylate it.

By looking at enzymes similar to CDKL5, the researchers identified that one called CDKL2 also targets EB2 and is present in human neurons.

In mice without both CDKL5 and CDKL2, the remaining EB2 phosphorylation almost fully dropped off.

The researchers concluded that, although most activity comes from CDKL5, about 15% is from CDKL2, and the remaining <5% from another enzyme yet to be identified.

Their research suggests that increasing the level of CDKL2 in people who are deficient in CDKL5 could potentially treat some of the effects on the brain in early development.

Sila Ultanir, Group Leader of the Kinases and Brain Development Laboratory at the Crick, said, “CDD is a devastating condition that impacts young children from birth, and we don’t know a huge amount about why losing this one enzyme is so disastrous for the developing brain. Through this research, we’ve identified a potential way to compensate for the loss of CDKL5. If we can increase levels of CDKL2, we might one day be able to stop symptoms from developing or getting worse.”

The researchers are now investigating if mice without CDKL5 can be treated by stimulating their brain cells to produce more CDKL2.

The lab is also working with biotechnology companies to identify molecules that increase CDKL2 for potential new medicines for CDD.

Sources:

Margaux Silvestre, Kelvin Dempster, Simeon R. Mihaylov, Suzanne Claxton, Sila K. Ultanir. Cell type-specific expression, regulation and compensation of CDKL5 activity in mouse brain. Molecular Psychiatry, 2024; DOI: 10.1038/s41380-024-02434-7

The Francis Crick Institute. “Researchers identify potential way to treat genetic epilepsy by replacing ‘lost’ enzyme.” ScienceDaily. ScienceDaily, 8 February 2024. <www.sciencedaily.com/releases/2024/02/240208122034.htm>.

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