Calorie restriction has long been linked to reduced seizures in people with epilepsy. may open the door to new treatments that do not require
The results of this study were published in Cell Reports.
“This study is the first step in understanding how epilepsy diets work,” said lead author Christopher J., a neurologist at the Epilepsy Center and Epilepsy Genetics Program at Children’s Hospital Boston. Yuskaitis, M.D., said. “The mechanism has so far been completely unknown.”
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DEPDC5, mTOR, and fasting
To connect the dots between diet and seizures, researchers started with existing knowledge. They knew that the well-known mTOR cellular pathway is involved in many neurological disorders and had previously shown that hyperactivation of this pathway in neurons increases susceptibility to seizures. Studies by other researchers have shown that mTORC activity is inhibited by acute fasting, but these studies did not look at the brain.
Finally, Yuskaitis et al. knew that signaling by a protein called DEPDC5 acts as a brake on the mTOR pathway. This was interesting because mutations in the DEPDC5 gene have recently been found in many epilepsy patients. DEPDC5 mutations are associated with focal epilepsy, infantile convulsions, and sudden childhood death.
“Using an animal model that specifically knocked out DEPDC5 in the brain, we found that using mTOR inhibitors reduced seizures,” said Yuskaitis. “This gave us the idea to investigate the relationship between DEPDC5, mTOR, and fasting.”
amino acid sensing
In a new study, they showed that mTOR signaling decreased in the brain after fasting in a mouse model of seizures. Additional studies of rat neurons cultured in dishes suggest that this fasting effect is primarily caused by a deficiency of three amino acids (leucine, arginine, and glutamine).
The research team further demonstrated that the presence of these nutrients is sensed by the DEPDC5 protein. When they knocked out her DEPDC5 in the brain, mTOR activity did not decrease and fasting no longer protected mice from seizures.
“Amino acid sensing appears to be important for fasting to have beneficial effects on seizures,” says Juskaitis. However, patients without DEPDC5 mutations may benefit from targeted dietary strategies.”
This can take the form of a diet with low levels of the three amino acids, or drugs or supplements that block the absorption of these amino acids.
Next Step: The Ketogenic Diet
This research is just the first step. Yuskaitis and colleagues now want to test diets that eliminate specific amino acids in animal models and see their effects on seizures. They also want to explore how the ketogenic diet, a popular approach to epilepsy treatment, can help keep seizures at bay. I don’t even know.
“We hope that this will reveal additional diet-based treatments beyond the ketogenic diet.
Such studies may also provide a new lens on neurological disorders in general.
“We are beginning to use these rare genetic disorders to gain fundamental insight into the role of nutrients in brain function,” said Rosamund Stone Zander Center for Translational Neuroscience at Children’s Hospital Boston. said Mustafa Sahin, M.D., Senior Research Fellow, Managing Director of . “Findings from these rare diseases may open the door to better treatments for common epilepsy.”
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