Hereditary brain disease reversed after birth

(Left) Mouse model of Kleefstra syndrome. Decreased H3K9 methylation causes neuroinflammation through excessive active microglia and pruning of dendritic spines, leading to the behavior characteristic of the syndrome. Postnatal supply of GLP (Ehmt1) in (central) neurons. Neuroinflammation is prevented, but immature spines remain and behavior remains unchanged. (Right) Postnatal supply of GLP to the entire brain (body). Neurological and behavioral symptoms are reversed.Credit: RIKEN

Researchers at the RIKEN Pioneering Research Cluster (CPR) in Japan report that Criefstra syndrome, a hereditary disease that leads to intellectual disability, may revert after birth in a mouse model of the disease. ..Published in scientific journals iScienceA series of experiments led by Yoichi Shinkai showed that postnatal treatment results in improved symptoms both in the brain and in behavior.

Usually, you get two good copies of most genes, one from each parent. At Kleefstra syndrome, One copy of the EHMT1 gene is mutated or missing. This leads to half the normal amount of GLP, a protein whose job is to regulate genes involved in brain development through a process called H3K9 methylation. Without sufficient GLP, H3K9 methylation is also reduced and connections between neurons in the brain do not develop normally.Result is Intellectual disability Symptoms like autism. “Whether Kleefstra Syndrome is a curable disease after birth, or how this epigenetic dysregulation is Neuropathy“Shinkai says. mouse It provided new information on the causes of behavioral disorders associated with the syndrome and showed that cure is a viable future potential. “

Additional GLP Effective treatment, Researchers conducted a series of experiments in mice designed to have only one good copy of the EHMT1 gene. The brains of these mice are characterized by a human condition, including 40% less GLP and 30% less methylation of H3K9. Mice also exhibit some of the behaviors found in humans with Cliefstra syndrome, such as decreased movement and increased anxiety. After each experiment, the researchers measured these factors and compared them to normal mice to see if the treatment was effective.

Researchers artificially induced GLP production after birth in two experiments. Once specific to the entire brain and once to adult neurons in the brain. Treatment in 3-4 week old juvenile mice rapidly rescued GLP and H3K9 methylation levels in the brain in both tests. Behavior improved after a few weeks, but only if GLP increased throughout the brain. Therefore, brain and behavioral symptoms were successfully rescued by treatment that increased GLP levels throughout the brain after the mice were already young.

Next, the researchers wanted to know why treatment works perfectly only when GLP is increased not only in neurons but throughout the brain.Perhaps the team searched and found well-known ones, believing that this disorder abnormally activates microglial cells in the brain, which are known to control immune responses such as inflammation. Inflammatory reaction In the brain of a model mouse, along with a large amount of activated microglial cells. Knocking out important proteins involved in the inflammatory response reversed some of the inflammatory-induced brain abnormalities, but did not change behavior. “This means that inflammation of the brain is only part of the story,” explains lead author Ayumi Yamada. “To fully understand this disease, we need to know what happens to other non-neurons when we increase GLP.”

Since this is the first report of neuroinflammation in Cliefstra syndrome, the next step is to find out if it also occurs in the human condition. Shinkai believes that other neurological disorders caused by epigenetic dysregulation are also likely. brain.. “We are not yet sure if our findings are applicable to patients with Cliefstra syndrome, but they show that postnatal treatment is possible and we believe this will bring hope to patients and their families. “He says.

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For more information:
Ayumi Yamada, Repression of inflammation-related genes is associated with microglial activation and defective neural maturation in a mouse model of Cliefstra syndrome, iScience (2021). DOI: 10.1016 / j.isci.2021.102741

Quote: Https: // Reversed after birth (September 21, 2021) obtained on September 21, 2021 Hereditary brain disease

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Hereditary brain disease reversed after birth

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