For decades, neurologists have known that a diet high in fat and extremely low in carbohydrates can reduce epileptic seizures that resist drug therapy. But how the diet worked, and why, was a mystery — so much so that in 2010, The New York Times Magazine called it “Epilepsy’s Big, Fat Miracle.”
Now, researchers at Dana-Farber Cancer Institute (DFCI) and Harvard Medical School (HMS) have proposed an answer, linking resistance to seizures to a protein that modifies cellular metabolism in the brain. The research, to be published in the May 24 issue of the journal Neuron, may lead to the development of new treatments for epilepsy.
The research was led jointly by Nika Danial, HMS assistant professor of cell biology at Dana-Farber Cancer Institute, and Gary Yellen, professor of neurobiology at Harvard Medical School. The first author was Alfredo Giménez-Cassina, a research fellow in Danial’s lab.
Epilepsy is a neurological disorder characterized by an electrical storm in the brain that can manifest as convulsions, loss of motor control, or loss of consciousness. Some epilepsy cases can be improved by a diet that drastically reduces sugar intake. Such a diet causes neurons to switch from their customary fuel of sugar to fat byproducts called ketone bodies. The diet, which mimics the effects of starvation, was described more than 80 years ago and received renewed interest in the 1990s. Recent studies corroborate that it works, but shed little light on how.
Yellen was introduced to the ketogenic diet by his wife, Elizabeth Thiele, professor of neurology at HMS and director of the Pediatric Epilepsy Program at MassGeneral Hospital for Children, who was not involved in the study.
“The connection between metabolism and epilepsy has been such a puzzle,” said Yellen. “I’ve met a lot of kids whose lives are completely changed by this diet. It’s amazingly effective, and it works for many kids for whom drugs don’t work.”
The discovery involves a protein with the tongue-twisting name of “BCL-2-associated agonist of cell death,” or BAD, which has a role in the normal process of cell death. Danial had previously discovered a second function for the protein: It also regulates glucose metabolism.
Giménez-Cassina further discovered that certain modifications in BAD switched metabolism in brain cells from glucose to ketone bodies.
“It was then that we realized we had come upon a metabolic switch to do what the ketogenic diet does to the brain without any actual dietary therapy,” said Gimenez-Cassina. He went on to show that these same BAD modifications protect against seizures in experimental models of epilepsy. Still, it wasn’t clear exactly how.
Yellen suspected the answer involved potassium ion channels. Ion channels are pathways through cell membranes that allow the passage of certain kinds of charged molecules that, among other things, help carry nerve signals. Potassium channels tend to suppress cell electrical activity.
Yellen’s lab had previously linked ketone bodies like those from the high-fat epilepsy diet to the activation of a type of potassium channel in neurons. Yellen hypothesized that the diet worked because ketone bodies from fat provide enough neurons to fuel normal function, but when a seizure threatens, the associated potassium channel can shut the storm down. Dietary effects, however, are broad and complex, so it was impossible to say for sure.
The effects that Danial’s lab had discovered — BAD’s ability to alter metabolism and seizures — offered a new avenue for studying the therapeutic effects of altered metabolism. Together, the researchers decided to investigate whether Danial’s protein switch governed Yellen’s potassium pathway, and whether they could reverse engineer the seizure protection of a ketogenic diet.
They could. Working in genetically altered mice, the researchers modified the BAD protein to reduce glucose metabolism and increase ketone body metabolism in the brain. Seizures decreased, but the benefit was erased when they knocked out the associated potassium channel — strong evidence that the protein-channelpathway conferred resistance to epileptic seizures. Further experiments suggested that it was indeed BAD’s role in metabolism, not cell death, that mattered. The findings make the BAD protein a promising target for new epilepsy drugs.
“Diet sounds like this wholesome way to treat seizures, but it’s very hard. I mean, diets in general are hard, and this diet is really hard,” said Yellen. “So finding a pharmacological substitute for this would make lots of people really happy.”