UI researchers find new protein linked to epilepsy
University of Iowa researchers have determined that a protein already being targeted in some cancer patients may also be linked to seizures in epilepsy. Their research further shows that removing or inhibiting this protein actually prevents seizures in fruit flies (the team's experimental model of seizures). The findings published in the journal PLOS Genetics.
Researchers hope these findings will eventually lead to a new targeted drug therapy for seizures in humans.
“We know we already have a drug available that blocks the function of this protein, so we fed that to the seizure-prone flies and we were able to decrease their seizures,” says Alexander Bassuk, MD, PhD, UI associate professor of pediatrics and associate professor of neurology, and one of the lead authors of the study. “So it looks like, in the fly, this is an epilepsy drug.”
Researchers have known for some time that mutations in the so-called PRICKLE genes, PRICKLE 1 and PRICKLE 2, are involved in epilepsy, but have not examined how these mutated genes work. For this study the UI team wanted to determine which other proteins were associated with the PRICKLE proteins and might also be linked to epilepsy.
“We found some (proteins) that we already knew about, but then we found one that we didn’t know about, and we became interested in this protein as a candidate (for causing epilepsy) for many reasons,” Bassuk says. “Primarily, it’s an enzyme and it’s already been studied in cancer so there are already pharmacological agents that block it or manipulate it in some way.”
The newly identified protein is ubiquitin-specific peptidase 9 X-linked, or Usp9x. Bassuk and collaborator Vinit Mahajan, MD, PhD, UI assistant professor of ophthalmology and visual sciences, discovered that Usp9x not only interacts with the PRICKLE proteins by coming into physical contact with them, but that as an enzyme, Usp9x actually affects the levels of the PRICKLE proteins.
One of Bassuk's collaborators in Australia used a mouse model in which the Usp9x protein is absent and found the PRICKLE proteins were also affected.
“We saw this wasn’t just a biochemical interaction, this was a real biologic interaction. This involved an actual living organism,” Bassuk says. “That was very exciting for us.”
The team then looked at human patients, and found patients with epilepsy who has mutations in the Usp9x protein.
“Now we have statistical evidence that Usp9x might be involved in epilepsy,” Bassuk says.
Not wanting to stop there, the team investigated whether manipulating the Usp9x protein would affect seizures. For these experiments collaborators in John Manak’s laboratory used fruit flies that are prone to having seizures because they have mutated PRICKLE genes. Manak, PhD, is a UI associate professor of biology and an associate professor of pediatrics, specializing in fly genetics and human diseases.
Using the cancer drug that already exists to target Usp9x, Bassuk and his team fed the drug to the fruit flies.
“It turns out that if we get rid of the Usp9x in the fly, we can actually cure the seizures,” Bassuk says.
There is still work to be done before experiments with fruit flies can translate to treatments for humans, but Bassuk says this most recent research shows that targeting the Usp9x protein might eventually lead the way to preventing or diminishing seizures.