Scientists at Virginia Tech’s Fralin Biomedical Research Institute at VTC have discovered how an experimental therapy can help brain cells overcome the effects of a disease-causing genetic deletion. Instead of repairing the deletion and its immediate consequences, the therapy redirects brain development by helping at-risk neurons grow and connect more normally
The findings, published in Disease Models & Mechanisms, suggest that some genetic brain disorders may be treated by targeting the cellular mechanisms disrupted by a genetic change rather than repairing the genetic change itself
The research focused on 22q11.2 deletion syndrome, the second most common genetic deletion disorder and among the strongest known genetic risk factors for schizophrenia in humans. The syndrome affects approximately one in every 2,000 to 4,000 births and is also associated with autism spectrum disorder and a range of cognitive and developmental challenges
Using a mouse model of 22q11.2 deletion syndrome, the researchers identified oxidative stress — a buildup of harmful oxygen-containing molecules inside brain cells — as a key contributor to abnormal brain development.
They then treated mice with N-acetyl cysteine (NAC), an antioxidant that effectively crosses the blood-brain barrier, to determine whether reducing that stress could restore healthy growth and connectivity.
The treatment improved the health of mitochondria, strengthened connections between neurons, and restored the growth of dendrites — the branch-like extensions on neurons that receive synaptic signals from other neurons, mediating communication within the brain’s neural networks
“Think of it as a detour around a network of winding roads where several trees have fallen,” said Anthony-Samuel LaMantia, professor at the Fralin Biomedical Research Institute at VTC and the study’s corresponding author. “The detour still gets you to your destination even though the original route remains blocked. In this case, the therapy activates a different set of genes that helps neurons form functional brain circuits despite the genetic deletion.”
The researchers discovered that the therapy did not restore the activity of genes disrupted by the deletion. Instead, it activated a different network of genes that enabled neurons to achieve many of the same developmental results
“That was surprising because the assumption behind most therapies is that you have to restore gene expression to its normal ground state,” said LaMantia, who is the director of the institute’s Center for Neurobiology Research. “Our findings suggest that may not always be possible or even necessary. There can be therapeutic benefits from taking an alternate route.”
The study also helps explain why the therapy improves brain function. Rather than replacing lost neurons, the treatment strengthened the connections among the neurons that remained, restoring the cumulative strength of communication signals within brain circuits that underlie learning and cognitive flexibility.
In the mouse model, these improvements were accompanied by better performance on behavioral tasks that depend on those circuits
Although additional research will be needed before the findings can be translated into human therapies, the study points to a new way of thinking about treatments for genetic brain disorders, LaMantia said. Rather than trying to correct every disrupted gene or molecular pathway, researchers may be able to harness the natural ability of gene networks to help brain cells develop more normally
“Gene networks are remarkably flexible,” LaMantia added. “We may be able to develop therapies that engage that flexibility instead of trying to correct a specific genetic or molecular disruption that may be too difficult to manipulate directly.”
The study was led by LaMantia with colleagues Shah Rukh, Daniel Meechan, Abra Roberts, Connor Siggins, Zachary Erwin, and Thomas Maynard of the Fralin Biomedical Research Institute. LaMantia is also a professor in the Department of Biological Sciences of the College of Science
The research was supported by the National Institute of Mental Health of the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Red Gates Foundation
Original study: DOI 10.1242/dmm.052786
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