Scientists at the Fralin Biomedical Research Institute at the VTC are researching the dark side of the common gene
In children diagnosed with severe and debilitating epileptic brain disease, the prognosis is often bleak. Babies born with a rare form of CASK-linked epileptic encephalopathy called Ohtahara syndrome have seizures soon after they are born. There is no treatment or cure, and children with the disorder do not usually survive beyond infancy. Those who do this have severe neurological, cognitive, and behavioral disorders.
Sarika Srivastava, research assistant professor at the Fralin Biomedical Research Institute at VTC, believes that the loss of CASK gene function could affect the brain cells’ ability to produce much-needed energy and trigger the increasingly worse seizures.
Srivastava, who is also an assistant professor in the Department of Internal Medicine at Virginia Tech Carilion School of Medicine, is conducting a five-year study to investigate the mechanisms of CASK-Loss of Function-Mutation-Associated Epileptic Encephalopathy, funded by a grant in $ 2 million from the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health.
Researchers are still learning about the diverse functions of the CASK gene. The gene is found throughout the animal kingdom and its dysfunction has been linked to neurological, cognitive, and developmental problems. Since the CASK gene is located on the X chromosome in mammals, the mutations with loss of function affect more men who have a copy of the X chromosome. Females have two copies of the X chromosome. As long as the gene in one copy of the chromosome is normal, they are less affected.
Srivastava hypothesizes that one of the roles of CASK is to control the function of mitochondria – tiny structures that serve as the cell’s powerhouses. Mitochondria convert chemical energy from the food we eat into a form of energy that the cell can use. When the mitochondria stop working, the cell loses energy. Neurons require a lot of energy and are most affected by defective mitochondria.
“Nobody has studied this connection,” said Srivastava. “It is completely unknown how CASK controls or regulates mitochondrial function.”
To conduct the research, Srivastava’s laboratory developed a new mouse model in which the CASK gene is deleted from neurons. Lacking the CASK gene in brain cells, these mice mimick human disease states, including severe underdevelopment, seizure-like traits, and early death.
Srivastava’s preliminary research using the mouse model found that clearing CASK from neurons affects mitochondrial function and reduces their number in the brain. This impairment decreases the energy supply to the brain, potentially leading to a complete loss of energy and triggering the seizures that characterize a rare condition like Ohtahara syndrome.
She wants to confirm whether the CASK deletion mutation affects mitochondrial function, determine the effects on energy metabolism, and test whether drugs known to increase mitochondrial energy production can decrease the onset or progression of the disease, or both.
Srivastava will do most of the major parts of the study in her laboratory, but studies of the brain’s electrical signals will be performed by her fellowship staff, including Howard Goodkin, professor of neurology who studies pediatric epilepsy at the University of Virginia School of Medicine, and Konark Mukherjee, assistant professor at the Fralin Biomedical Research Institute at VTC, who studies the effects of CASK mutations.
“Our goal is to find a potential treatment strategy for an extremely devastating neurological condition for which there is no cure,” said Srivastava, “but it could help alleviate these patients’ symptoms and extend their lives.”
Written by Matt Chittum