Calorie restriction has long been related to reduced seizures in epilepsy. Latest research from Boston Kid’s Hospital helps explain how fasting affects neurons within the brain and could lead on the technique to recent approaches that will avoid the necessity for fasting or restrictive diets. The findings were published August 30 within the journal Cell Reports.

This study is step one in understanding how dietary therapies for epilepsy work. The mechanisms have until now been completely unknown.”

Christopher J. Yuskaitis, MD, PhD, first writer, neurologist, Epilepsy Center and Epilepsy Genetics Program at Boston Kid’s Hospital

DEPDC5, mTOR, and fasting

To attach the dots between weight-reduction plan and seizures, the researchers began with existing knowledge. They knew that the well-known mTOR cellular pathway is involved in lots of neurological disorders and had shown previously that over-activation of this pathway in neurons increases susceptibility to seizures. Studies by others had shown that mTORC activity is inhibited by acute fasting, though these studies didn’t have a look at the brain.

Finally, Yuskaitis and colleagues knew that signaling by a protein called DEPDC5 acts as a brake on the mTOR pathway. That was intriguing, since mutations within the DEPDC5 gene have recently been present in many individuals with epilepsy. DEPDC5 mutations have been linked to focal epilepsy, infantile spasms, and sudden death in children.

“After we used an animal model that knocks out DEPDC5 specifically within the brain, we found that we could reduce seizures by utilizing an mTOR inhibitor,” says Yuskaitis. “That gave us the concept to explore the connection between DEPDC5, mTOR, and fasting.”

Amino acid sensing

In the brand new study, they showed in a mouse seizure model that mTOR signaling was reduced within the brain after fasting. Additional studies of cultured rat neurons in a dish suggest that this fasting effect is primarily driven by the shortage of three amino acids (leucine, arginine, and glutamine).

Going further, the team demonstrated that the presence of those nutrients is sensed by the DEPDC5 protein. Once they knocked out DEPDC5 within the brain, mTOR activity was not reduced and fasting now not protected the mice against seizures.

“Amino acid sensing appears to be critical for the useful effects of fasting on seizures,” says Yuskaitis. “This means that patients with DEPDC5 mutations cannot sense the lack of amino acids and should not profit from dietary manipulation. But patients who haven’t got DEPDC5 mutations may profit from a targeted dietary strategy.”

This might take the shape of diets with lower levels of the three amino acids, or medications or supplements that block absorption of those amino acids, he adds.

Next step: Ketogenic weight-reduction plan

This study is barely a primary step. Yuskaitis and colleagues now wish to try diets in animal models that eliminate specific amino acids and observe the results on seizures. Additionally they wish to explore how the ketogenic weight-reduction plan, a preferred approach to treating epilepsy, helps curb seizures. Nobody currently knows why this low-carbohydrate, high-fat weight-reduction plan works.

“We’re hoping this can hope us uncover additional dietary-based therapies aside from ketogenic weight-reduction plan, which is typically difficult to follow long run attributable to uncomfortable side effects,” says Yuskaitis.

Such work may provide a recent lens on neurologic disorders overall.

“Using these rare genetic disorders, we’re starting to achieve fundamental insights into the role of nutrients in brain function,” says senior investigator Mustafa Sahin, MD, PhD, managing director of the Rosamund Stone Zander Translational Neuroscience Center at Boston Kid’s. “Findings from these rare disorders may open doors for higher treatments of epilepsy generally.”

The study was supported by the National Institutes of Health (1K08NS107637), the Hearst Foundation, the Boston Kid’s Hospital Translational Research Program, the Boston Kid’s Office of Faculty Development Profession Development Fellowship, the Mental and Developmental Disabilities Research Center (NIH P50HD105351), and Boston Kid’s Rosamund Stone Zander Translational Neuroscience Center.

Mustafa Sahin receives grant support from Novartis, Biogen, Astellas, Aeovian, Bridgebio, and Aucta, and has served on the scientific advisor boards of Novartis, Roche, Regenxbio, SpringWorks Therapeutics, Jaguar Therapeutics and Alkermes. Not one of the other authors has any conflict of interest to reveal.

Source:

Boston Kid’s Hospital

Journal reference:

Yuskaitis, C.J., et al. (2022) DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting. Cell Reports. doi.org/10.1016/j.celrep.2022.111278.