Posted on September 21, 2004 at 11:35 a.m.

BIRMINGHAM, AL — Researchers with the University of Alabama, UAB (the University of Alabama at Birmingham), and the Howard Hughes Medical Institute (HHMI) have found a way to mimic epileptic seizures in the tiny roundworm C. elegans, which could make the worm a powerful model for unraveling the molecular regulation of epilepsy, a condition that affects 2 percent of the population.

The researchers studied worms with a mutation in the LIS1 gene. In its human form, the gene has been linked to a rare birth defect called lissencephaly, which affects one out of every 30,000 children born. In children with lissencephaly, the normally wrinkled surface of the brain's cortex is smooth. They also have mental retardation and severe epilepsy, the causes of which are not well understood.

Guy A. Caldwell, Ph.D., assistant professor of biological sciences at UA, adjunct professor in the department of neurology at the University of Alabama School of Medicine at UAB and coordinator of the HHMI’s Undergraduate Research Intern Program, led a research team that included Kim A. Caldwell, Ph.D., assistant professor of biological sciences, UAB adjunct professor and director of UA’s HHMI-sponsored Rural Science Scholars Program; graduate student Shelli N. Williams, and two HHMI undergraduate research interns, Cody J. Locke and Andrea L. Braden.

The team traced the mutation’s effect on specific neurons in the simple nervous system of the 1-millimeter roundworm and published their findings in September in the journal Human Molecular Genetics.

“The human brain has 100 billion neurons, whereas the worm has only 302. We know each type of neuron and how they connect to each other,” Caldwell explained.

“We knew that LIS1 is highly expressed in the nervous system, so we wanted to see if there was a way to use C. elegans to understand and simplify the complexities of brain disease,” he added.

The team identified a mutation in the LIS1 gene that causes the encoded protein to be only one-fourth the length of the normal protein. The mutation was lethal to 70 percent of the mutant worms. The team tested the survivors for nervous system defects. Although their nervous systems seemed to be organized correctly, the mutant worms were more susceptible to epilepsy-like convulsions than normal worms.

Caldwell hopes that the C. elegans convulsion model may help decode the mysteries of epilepsy and perhaps lead to better treatments for seizures. Researchers can knock out genes rapidly in worms, treat them with a variety of chemicals, and use other genetic techniques that are not possible with human patients.

“Epilepsy — one of the worst parts of lissencephaly — is still a black box on a genetic level,” Caldwell added. “This work shows that we can dissect out that part of the disease. It is one of those classic situations where a rare disorder is going to provide insights into a more common one, epilepsy.”

Additional support for this research came from The March of Dimes.