Baylor College of Medicine

An illustration of the human brain.

Study reveals new pathway, potential treatment for neurological disorders

Graciela Gutierrez


Houston, TX -
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Dr. Mauro Costa-Mattioli, professor and Cullen Foundation Endowed Chair of Neuroscience and director of the Memory and Brain Research Center

Many individuals with neurodevelopmental disorders, such as autism spectrum disorder and intellectual disability, suffer from these mental conditions without knowing the specific cause. In a multidisciplinary study, researchers at Baylor College of Medicine have revealed how dysfunction in a key quality control mechanism leads to neurological dysfunction in humans, mice and files.

Their findings, published in the current edition of Neuron, show that inhibition of nonsense-mediated decay (NMD) cause brain inflammation, and more importantly, that two FDA-approved drugs were able to help reverse the neuronal and behavioral deficits in NMD-deficient animals.

Cells have ways to assure whether proteins are appropriately synthesized. If there are errors in the template (mRNA) of proteins, aberrant proteins will be synthesized and this could be ultimately deleterious to the cell. NMD is a central quality control mechanism ensuring that mRNAs, and ultimately proteins with potentially harmful effects, are not synthesized. Mutations in genes encoding NMD components have been identified in some individuals with autism spectrum disorder and intellectual disability. However, the mechanism by which deficient NMD leads to a neurodevelopmental disorder is unknown. Thus, there are no current treatment options for these conditions.

Together with investigators in Australia, researchers at Baylor first identified patients with new mutations in UPF2, a central NMD factor in humans with neurodevelopmental disorders (including speech and language problems), and showed that UPF2 is deficient in these individuals. To investigate what compromised Upf2-dependent NMD, they removed Upf2 in the brains of mice, which then were shown to have impaired NMD.

“We modeled this in mice lacking Upf2 and saw that not only did they have impaired NMD, but also memory, social and communication behavior deficits, similar to the patients,” said Dr. Jennifer Johnson, a former graduate student in Dr. Mauro Costa-Mattioli’s laboratory at Baylor College of Medicine. “The function of Upf2 in the brain seems to be evolutionarily conserved because investigators also showed that flies lacking Upf2 showed memory problems.”

Because the human patients showed language problems, Yuwei Liu, a current graduate student in Costa-Mattioli’s lab, studied ultrasonic vocalization, a behavior that’s thought to reflect a type communication in mice, and discovered that mice lacking Upf2 exhibit altered vocalization patterns.

So, what went wrong in the brains of these mice? Not only were the neurodevelopmental deficits seen, but there also was an unexpected elevation in the expression of immune genes and indications of brain inflammation.

“We were totally surprised when we found that there was a significant increase in the total number of immune cells in the brain of the mice lacking Upf2,” said Dr. Loredana Stoica, a former graduate student in the lab of Costa-Mattioli.

The next step was to determine if reducing the immune response would have an effect on the deficits seen. Using two FDA approved drugs used to treat diseases with an aberrant immune response, such as autoimmune disease, researchers were able to decrease the immune response and, more importantly, showed an improvement in the behavior deficits of Upf2-deficient mice.

“We employed two FDA-approved immunosuppressants and we were able to show that the overactivation of the immune response led to the behavioral and neurophysiological deficits in Upf2-deficient mice,” said Costa-Mattioli, professor and Cullen Foundation Endowed Chair in neuroscience and director of the Memory and Brain Research Center at Baylor.

Amazingly, the vocalization call patterns and call rates of the mice were also improved by the treatments.

“This study is in a mouse model for the disease, but we believe the vocalization deficits could be similar to humans who have speech and communication deficits as a result of impaired NMD,” said Yuwei Liu.

The investigators are excited with their results because they might have discovered a new pathway implicated in speech and language function and even and new way to treat speech disorders.

However, before discussing the possibility of doing experiments in humans, Costa-Mattioli and his team wish to know how disruption in NMD leads to an activation of the immune response, and, when the immune system is dampened using drugs, what communication is taking place on the molecular level that then improves or reverses behavioral deficits.

“The importance of NMD as a key regulator of gene expression required for proper brain function is largely unappreciated,” Costa-Mattioli said. He also wonders whether NMD is implicated in normal aging or other major neurological disorders like Alzheimer’s disease.

While it is far too early to know if these two FDA approved drugs could be quickly repurposed for the treatment of brain disorders with deficient NMD, it remains an interesting possibility.

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