Genetic brain disorder reversed in mice

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Genetic brain disorder reversed in mice

Researchers at Japan’s RIKEN Frontier Research Cluster have reported that Kleefstra syndrome, a genetic disorder that leads to intellectual disability, can be reversed in a mouse model of the disease after birth. The team’s experiments, published in the journal iScience, showed that postnatal treatment improved symptoms in both the brain and behavior.

Usually we get two good copies of most genes, one from each parent. In Kleefstra syndrome, one copy of the EHMT1 gene is mutated or missing. This results in half the normal amount of GLP, a protein whose job it is to control genes related to brain development through a process called H3K9 methylation. Without enough GLP, H3K9 methylation is also reduced and the connections between neurons in the brain do not develop normally. The result is intellectual disability and autistic symptoms.

On the grounds that additional GLP might be an effective treatment, the researchers conducted a series of experiments on mice engineered to have only one good copy of the EHMT1 gene. The brains of these mice show features of the human condition, including 40% less GLP and 30% less H3K9 methylation. The mice also display various behaviors seen in people with Kleefstra syndrome, such as: B. Reduced locomotion and greater anxiety.

The researchers artificially induced GLP production after birth in two experiments, one in the whole brain and one specifically for adult neurons in the brain. Treatment in juvenile mice quickly rescued brain methylation levels of GLP and H3K9 in both tests. Behavior improved a few weeks later, but only when GLP was elevated throughout the brain. Thus, brain and behavioral symptoms were successfully rescued by treatment that increased GLP levels throughout the brain after mice became juvenile.

Next, the researchers wanted to know why their treatment only worked fully when GLP was increased throughout the brain, not just neurons. Believing that the disease may abnormally activate microglial cells in the brain that are known to control immune responses such as inflammation, the team looked for and found a known inflammatory response in the brain of the model mice, along with increased amounts of activated microglial cells. Turning off a key protein involved in the inflammatory response reversed some of the brain abnormalities caused by inflammation, but did not change behavior.

“That means encephalitis is only part of the story,” said lead author Ayumi Yamada. “To fully understand the disease, we need to find out what happens in other non-neuronal cells when we increase GLP.”

Since this is the first report of neuroinflammation in Kleefstra syndrome, the next step is to find out if it also occurs in humans. Study leader Yoichi Shinkai believes the odds are high and said he wouldn’t be surprised if other neurological disorders caused by epigenetic dysregulation are also related to abnormal inflammation in the brain.

“While we do not yet know if our results are applicable to patients with Kleefstra syndrome, we have shown that a cure is possible after childbirth and believe that this will give hope to patients and their families,” he said.

Photo credit: © stock.adobe.com / au / Sergey Nivens

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