The case of the epileptic flies
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Since the 1930s, scientists have studied the prickle gene, noting that flies carrying mutated prickle genes exhibit physical malformations such as body bristles pointed in abnormal directions.
Until a Sunday morning two winters ago, no one had recognized that these flies were also epileptic.
John Manak, assistant professor of biology and pediatrics and faculty member in the Interdisciplinary Graduate Program in Geneticsat the University of Iowa, made the crucial connection, leading to his discovery that mutations of the prickle gene produce seizures in fruit flies. His finding was a key component in a research paper, published Feb. 11, 2011 in theAmerican Journal of Human Genetics, showing that mutations in prickle genes are associated with seizures in humans, mice, and flies.
'Mad scientist' moment
Manak was co-first author on the paper and spearheaded the work on the fruit flies, while his friend and UI colleague, Alexander Bassuk, senior author on the paper, showed that mutations in the gene result in seizures in mice. Bassuk had previously found that human orthologs (genes in different organisms that are direct evolutionary counterparts) of prickle in flies are associated with human myoclonic epilepsy — featuring seizures that involve brief involuntary twitching in specific muscle groups, such as the face, trunk, or limbs.
"It started after a conversation over coffee with Alex, a pediatric neurologist who had identified mutations in human prickle genes as being causative for myoclonic epilepsy," Manak says. "I had one of those 'mad scientist' moments where I told Alex I would obtain some prickle fly mutants from the fly stock center we use and test whether they had epilepsy.
"One Sunday morning after receiving the mutant flies, I was tending to my collection of various fly stocks when I noticed that one vial in particular contained flies that were jumping off the bottoms and sides of the vial, flipping on their backs, acting in a hyper-excitable way. Remarkably, it was the vial containing the prickle mutant flies."
According to epilepsy.com, the disorder affects over three million Americans — more than multiple sclerosis, cerebral palsy, muscular dystrophy, and Parkinson's disease combined.
"We are very fortunate to have a situation only a handful of labs have — both an invertebrate model (fruit flies) and a vertebrate model (mouse) of a human disease," Manak said.
Proof of principle for medication studies
The researchers showed they could reduce the prickle-associated seizures in flies with the human anti-epileptic drug valproic acid, providing proof-of-principle that human anti-epileptic drugs can also work in flies, and thus paving the way for screening novel compounds for anti-seizure properties.
"We can start to perform both genetic and drug screens in flies, which are more tractable than mice for these kinds of experiments," Manakexplains. "Any drugs we identify that show anti-epileptic properties in flies, we can then elevate to our mouse model and, if effective there, we can eventually bring them to human trials."
The American Hospital Formulary Service says valproic acid may cause serious damage to the human liver. Most anti-epileptic drugs have varying degrees of serious side effects, demonstrating the need for new drugs to be developed and increasing the importance of Manak's work.
The next step is to identify the prickle genes' specific role in the occurrence of myoclonic epilepsy. To identify other components of the epilepsy pathway, Manak and his colleagues also plan to conduct a genome-wide genetic screen to identify other genetic mutations that modify the epilepsy behavior in the prickle mutant flies. This can then lead to identification of other crucial epilepsy-causing mutations in humans.