Rare epilepsy shines new light on glucose and the brain

by Kayt Sukel

February 1, 2008

Researchers in Spain studying a rare form of epilepsy have discovered that the metabolic mechanisms that could give neurons energy may also play a role in neurodegenerative diseases.

Lafora disease is an extremely rare and lethal type of genetic epilepsy that affects adolescents. “It is quite devastating,” says Joan J. Guinovart, director of Barcelona’s Institute for Research in Biomedicine and a professor at the University of Barcelona. “Children are normal until they are about 10 years old and then they start having seizures. From there, the disease evolves very rapidly.” About 200 people currently have Lafora disease and most die from six to ten years after the first symptoms are observed.

The disease gets its name from Gonzalo Rodriguez Lafora, a neuropathologist who nearly a century ago noticed that people with the disease had unique "inclusion bodies," or clumps of material in their neurons and other cells in the muscle, skin, and organs.

“These bodies are absolutely the hallmark of the disease,” says Guinovart. It is now known that these “Lafora bodies” are accumulations of glycogen, but these clumps of energy-rich glucose are abnormally branched, and the body cannot metabolize them. The Lafora bodies remain in cells, interfering with cell function and eventually leading to apoptosis, or cell death.

Glucose as the “bad guy”

The discovery that nothing more than glycogen chains could cause such neural destruction was a surprise to researchers.

“Most of the cells in our body—in the liver, in muscle—store glucose as polymers” such as glycogen, Guinovart says. “They accumulate in this way so they can be used when those cells need energy. Glycogen storage is normally considered a good thing. It was never thought that glucose could be a bad guy.”

Healthy neurons rely on outside energy sources, and biologists had long believed that neurons did not have the machinery to make or store glucose polymers for later use. “The interpretation was that neurons are novel cells dedicated to the higher task of transmitting nerve signals,” Guinovart says. “Like high-class people, neurons don’t care about food. They rely on the servants—the blood or nearby cells like astrocytes—to put food on the table.”

To solve the mystery of how neurons were accumulating glycogen, leading to Lafora disease, scientists first turned to genetics.

“It was very clear from the beginning that Lafora was a genetic disease,” says Santiago Rodríguez de Córdoba, a researcher at the Council of Higher Scientific Research in Spain. “And this is how the disease was presented to us at the beginning of the 1990s, when genetics were starting to be applied to identify the genes response for clearly inherited diseases.”

Proteins as guardians

When they mapped the genes of people with Lafora disease, researchers in Canada and Spain discovered that in approximately half the families studied, there was a defect in a single gene, which the scientists called “laforin.” Another group of researchers found a second malfunctioning gene, which they named “malin,” in 40 percent of people in their study. No matter which one of these genes is faulty, the clinical symptoms are identical.

“This suggests that both of these proteins are important, that they interact in such a way that, regardless of which one is missing, this glycogen will accumulate in the neurons,” Guinovart says.

In the November 1, 2007, issue of Nature Neuroscience, Guinovart, Rodríguez de Córdoba and colleagues outlined how these genes allow neurons to create Lafora bodies in this genetic disease.

“Neurons in Lafora patients are able to produce polymers of glucose,” says Guinovart. “The only enzyme able to do that is one called glycogen synthase.” This enzyme is responsible for converting excess glucose into polymer chains for storage.

The group analyzed whether neurons in normal mice had glycogen synthase enzymes present in the cell. “To our surprise, we found that they do contain glycogen synthase,” says Guinovart. “But normally, they don’t use it. It is confined to the nucleus of the neuron in a very inactive way.”

Further analysis showed that the glycogen synthase was kept inactive by phosphorylation, or the addition of phosphate molecules to the enzyme. Phosphorylation is a common process involved in turning biochemical mechanisms in cells on and off.

“In neurons, this enzyme is fully phosphorylated,” Guinovart says. “So the neuron is able to keep it fully inactivated and contained.”

But in animals that had mutated laforin or malin genes, glycogen synthase was able to move out of the nucleus of the cell and start making the glycogen chains. “In vitro, under certain conditions, laforin and malin remove the phosphates from the glycogen synthase, activating it and putting it to work,” Guinovart says. “This interferes with the signal transmission of cells and eventually leads the cell to basically commit suicide.”

Guinovart argues that malin and laforin act as “guardians” of glycogen synthase, making sure that the enzyme remains in its inactive state and protecting the cell from these excess glycogen chains.

More potential applications

 This description of the genetic and cellular mechanisms underlying Lafora disease may help researchers find a potential pharmacological treatment for the disease. But this result also has implications for both cell physiology and other neurodegenerative diseases.

“Lafora disease was first described in 1911,” says Matthew Gentry, a postdoctoral fellow at the School of Medicine at the University of California, San Diego. “To be able to get to the molecular mechanism behind it is really exciting. But beyond that, a new phosphorylation step has been uncovered that’s been missed for almost 60 years.”

And this greater understanding of the cellular machinery of neurons may help further the understanding of other neurodegenerative disorders.

“The common bad guy in many neurodegenerative diseases is that the neurons accumulate junk,” says Guinovart, including prions in mad cow disease and amyloid-beta proteins in Alzheimer’s disease. “We show in our paper that glycogen can also be junk for neurons. These products are useless, take up space and disturb the normal structure of the neuron.”

Rodríguez de Córdoba believes that there is still more to learn about the role of laforin and malin in glucose metabolism that might be a boon to the study of all neurodegenerative diseases.

“These two proteins may have a much wider role in the proper functioning of the cell,” he says, perhaps involved in energy metabolism and dealing with cellular debris. “And if we can learn more about how that debris is accumulated, perhaps we can also learn how to get rid of it.”