X is fragile syndrome, the leading genetic cause of intellectual disability, is caused by a genetic mutation that removes much of the fragile X protein, a key factor for normal brain development and function.
The fragile X protein regulates neuronal functions, including neurons in the so-called GABAergic system that regulates the activity of neural circuits. The absence of protein causes that system to lose weight, and to date, experimental therapies designed to reset the system by compensating for the missing protein’s functions have not been effective in trials. clinical trial.
Researchers at the University of Washington School of Medicine have identified a previously unknown function of the fragile X protein, the loss of which is the leading genetic cause of intellectual disability. Researchers have shown that the protein regulates the way neurons in the brain’s memory center process information, a central part of learning and memory. Image credit: Michael Worful/Washington University in St. Louis, School of Medicine
Now, researchers at Washington University School of Medicine in St. Louis identified a previously unknown role for the fragile X protein in the GABAergic system. They showed that the protein regulates the opening and closing of the GABA-A receptor in neurons from the brain’s memory centers, thereby influencing how those neurons process information, in part. center of learning and memory.
The findings, published in the journal Cell Reports, indicate that the role of fragile X protein is more complex than previously thought, and that finding effective therapies may depend on a deeper understanding of infertility. number of ways in which the loss of this protein affects the brain.
“People think that because fragile X is associated with the loss of a single protein, it’s a simple disease that we can quickly understand and fix,” said the senior author. Vitaly A. Klyachko, PhD, a professor of cell biology and physiology. “But the reality is, the more we study it, the more we understand it’s not that simple. I think part of the reason why clinical trials fail may be because we don’t really understand what’s going on. We may need to correct multiple mechanisms at once for patients to see meaningful improvement.”
People with fragile X syndrome have intellectual or learning disabilities, social and behavioral problems, and characteristic physical features such as large ears and long faces. They are also often noted for their friendly personalities. This condition affects about 1 in 7,000 men and 1 in 11,000 women, with men often being more severely affected. The fragile X gene is located on the X chromosome, so females inherit one good copy and one bad copy of the gene, but males only have the bad copy. There is no treatment that addresses the underlying cause.
The GABAergic system is based on the transmission of gamma-aminobutyric acid (GABA) from one neuron to another. When it arrives, GABA binds to a receptor molecule and causes a chain of events in the receptor neuron that results in the inhibition of that neuron’s activity. The overactive GABAergic system causes people to fall asleep; A child’s lack of hyperactivity has been linked to depression, anxiety, and epileptic seizures.
To better understand the role of fragile X protein in the GABAergic system, Klyachko and first author Pan-Yue Deng, MD, PhD, an associate professor of cell biology and physiology, studied neurons from the brains of mice with and without the fragile X protein. Specifically, they recorded the activity of important information-processing neurons controlled by the GABAergic system in the hippocampus, the brain’s learning and memory center. Such neurons sense the presence of GABA primarily using so-called GABA-A receptors.
The receptor is a channel that can open to allow negatively charged chloride ions to flow into the cell to regulate its activity. The researchers found that the fragile X protein affects how long the GABA-A receptor opens and how much chloride it allows into the cell, thereby establishing a basal electrical charge inside the neuron. This elementary charge, in turn, affects the neuron’s ability to distinguish between multiple incoming signals at nearly the same time, an important pattern-separation mechanism essential for learning and formation. memory.
“The fragile protein X interacts directly with receptors that play a key role in how neurons process information,” Klyachko said. “This is an additional function for the fragile X protein, and it could be an important one. These neuronal receptors are everywhere, and they control many important brain functions.”
But Klyachko cautions against assuming the findings can easily translate into a treatment for people with fragile X syndrome. The GABAergic system is complex, and small tweaks can have far-reaching and unexpected effects on brain function, he says.
“I think there is a very strong desire – an understandable one – to immediately translate each discovery into a clinical trial,” Klyachko said. “But if we don’t understand all of the functions of this protein and we try to pursue one particular mechanism, it can destabilize other mechanisms, and the end result is that people don’t. healthier body. There could be a completely different approach to treating this disease, but I think we need to understand more about how it works first. This is just the first stepping stone in a new direction.”
The source: Washington University in St. Louis
