Virginia Tech researchers identify narrow opportunities to overcome scarcity

The human brain begins to structure itself soon after conception as more and more brain cells are connected to create circuits throughout the brain.

Genes provide blueprints for construction, but sometimes those blueprints are incomplete, connections aren’t made, and circuits fail — sometimes long before the problem can be recognized, let alone repaired.

That’s the case with DiGeorge syndrome, also called 22q11.2 deletion syndrome, a genetic disorder that affects about one in 3,000 babies. It begins with deletion of one of two copies of a small number of genes on human chromosome 22, whose effects include cardiovascular problems, craniofacial development problems, and as children age, autism spectrum disorders and schizophrenia. By the time these symptoms are recognized, the opportunity for medical intervention is long gone.

But now Anthony-Samuel LaMantia, a professor at the Fralin Biomedical Research Institute at VTC, has identified a key factor in a chain of events that reflects fundamental aspects of early errors in the genetic blueprint in individuals with DiGeorge syndrome – and the narrow period in that timeline during which help is possible.

LaMantia, director of the institute’s Center for Neurobiology Research and faculty member in the College of Science, will explore the possibility of capitalizing on that window of opportunity with a five-year, $3.4 million grant by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, part of the National Institutes of Health. .

LaMantia’s research has the potential to inform new treatment strategies that currently do not exist for autism and schizophrenia associated with DiGeorge syndrome. DiGeorge syndrome remains one of several common genetic syndromes associated with a high risk for developing autism and schizophrenia later in life. In addition, understanding the disorders that underlie DiGeorge syndrome’s developing brain provides an opportunity to identify how these disorders may arise due to incomplete genetic instructions for building the brain.

LaMantia’s lab, one of only a handful in the world working on this problem, has been studying DiGeorge syndrome for more than two decades. The lab dives deep into how brain circuits are built to develop a precise understanding of the causes of the syndrome.

“I think 20 years of research has provided a foundation for thinking about this disease differently in the clinic,” says LaMantia. “This is a neurodevelopmental disorder and interferes with very specific and identifiable steps in brain development. And now we’re really trying to look at one of the last steps of brain development that we think is most likely accessible to make adjustments without breaking other things.”

LaMantia believes mitochondria – the powerhouses of cells – are critical to interfering with brain development in DiGeorge syndrome.

In a normally developing brain, the mitochondria in the neurons in the cerebral cortex have enough energy to make long-distance connections to other parts of the brain and turn circuits on and off to make sure everything is working properly.

In DiGeorge syndrome, mitochondria are deprived of oxygen and lack the energy to make the necessary connections. The reasons for this disorder can be traced to some genes in the region of chromosome 22, which are deleted in DiGeorge syndrome. An imbalance in having only half the required number of these genes, the proteins they encode, and the support for the mitochondria they provide, underlies the failure to make a sufficient number of connections during brain development, and dysfunction of the system.

While many of the syndromic impacts occur before birth, or before the disease can be diagnosed, a mitochondrial deficit that interferes with making the final connections occurs late enough in brain development to allow intervention.

“If you’re going to fix it, that’s probably the only decent place to get it fixed, and without creating any other problems in the process,” says LaMantia. “Fortunately this is mitochondrial alteration, because you can support mitochondria in relatively simple and very safe ways, including dietary supplements or more precisely targeted drugs.”

LaMantia is also a professor in Virginia Tech’s Department of Biological Sciences of the College of Science. Co-investigators include Michael Fox of the Fralin Biomedical Research Institute and professor and director of Virginia Tech’s School of Neuroscience; assistant professor Shannon Farris, research assistant professor Daniel Meechan, research associate professor Gregg Crabtree, and Thomas Maynard associate research professor, all from the Fralin Biomedical Research Institute. Allison Tegge, research assistant professor in the College of Science’s Department of Statistics, and Andrew Ottens, professor of anatomy and neurobiology at Virginia Commonwealth University.