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Fixing dysregulated pathways

Yale Medicine Magazine, 2020 - Spring


The laboratory of Angélique Bordey has made important progress in understanding neurodevelopmental disorders associated with epilepsy.

The human brain represents one of the last frontiers of medical research. Inaccessible due to physiological, practical, and ethical barriers, the brain has defied attempts to probe or understand it even while other organs have been mapped and analyzed.

The laboratory of Angélique Bordey, PhD, professor of neurosurgery and of cellular and molecular physiology, has recently made strides in describing the neurological basis of a very old condition—epilepsy—and also the basis of autism, a disorder that entered the clinical lexicon much more recently.

“We have made significant progress in understanding the cellular and molecular basis of seizures and epilepsy,” Bordey said. “We have a recent paper accepted at Science Translational Medicine describing a novel treatment for epilepsy based on this research.”

Genetic dysregulation of a cell signaling pathway

Bordey and her colleague Longbo Zhang, PhD, associate research scientist, replicated the impact of previously identified genetic mutations on the tuberous sclerosis complex-mechanistic target of rapamycin (TSC-mTOR) signaling pathway, and then traced some neurological disabilities to the resulting molecular deregulation. The TSC-mTOR pathway is a point of convergence in cell signaling, as mTOR, a protein, is a master regulator of such important functions as cell division and survival. When the genes that direct this pathway function normally, brain function and development proceed smoothly. When the pathways become dysregulated as a result of genetic mutations, however, neurological disorders known as mTORopathies can result. These mTORopathies include tuberous sclerosis complex (TSC), epilepsy, autism, schizophrenia, and Alzheimer’s disease (AD).

“Our goal was to understand autism and epilepsy,” Bordey said. “Examining TSC closely, we’ve been able to identify molecular players that we believe will lead to novel drug treatments for epilepsy.” The lab’s goal is to move promising drugs into clinical trials with humans.

At the moment, experiments have been limited to animal models. Lena Nguyen, PhD, a postdoctoral fellow in the Bordey Lab, said that treating an abnormality in a cellular pathway that regulates specific ion channels resulted in dramatically reduced incidents of seizures in tests.

“We used genetic modifications to suppress abnormal cell signaling and target molecular components we think contribute to seizures. One treatment completely eliminated seizures. With another, a lot of the subjects—more than 35%—went from having daily seizures to having none during the period evaluated, and the other saw a greater than 50% reduction in seizure frequency,” said Nguyen.

There are no effective drug-related treatments for epilepsy in individuals with TSC or other mTOR-related epilepsies; classical drugs don’t work in these patients. Currently, the most effective option for people suffering from this debilitating disorder is brain surgery, which permanently removes the lesions associated with epilepsy.

Some keys to autism and COVID-19?

Stephanie Getz, PhD, a postdoctoral fellow with expertise in autism, joined the Bordey Lab in August 2019. She said that her work has focused on manipulating genes and gauging the effect of those changes. “We have an ability to target a precise cell population so that we can say ‘This cell population is important for this behavioral phenotype,’” Getz said. Establishing the relationships between cell populations and autistic behavior is crucial to finding effective future treatments.

While the Bordey Lab has clarified the vital role of the TSC-mTOR pathway in epilepsy and seizures, the researchers’ inquiry into the causes of autism is ongoing. While they hoped in the beginning of the year to have results ready for analysis and publication by May, the arrival of COVID-19 has complicated those plans.

“COVID-19 abruptly arrested scientific studies that were unrelated to viral work,” said Bordey. “Our lab has hibernated, resulting in significant delays. However, we hope to soon contribute to COVID-19 work, considering that some of the molecular players involved in epilepsy are key players in SARS-CoV’s viral assembly.”

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