Early study offers framework for developing Rett gene therapies
Researchers uncover molecular changes caused by loss of MeCP2 protein
A new study sheds light on how MeCP2 protein dysfunction leads to brain abnormalities in Rett syndrome, and provides a framework to develop new treatments like gene therapies.
Specifically, researchers conducted a study in adult mice and found the loss of the MeCP2 protein — not problems during development — leads to the dysregulation of hundreds of genes in the brain.
The study, “Acute MeCP2 loss in adult mice reveals transcriptional and chromatin changes that precede neurological dysfunction and inform pathogenesis,” was published in Neuron.
Rett syndrome is mostly caused by mutations in the gene MECP2, which provides instructions to make a protein, also called MeCP2. The MeCP2 protein normally acts to regulate the activity of other genes. Without functional MeCP2, the genetic activity of nerve cells becomes dysregulated, ultimately leading to neurological dysfunction that results in symptoms of Rett syndrome.
Yet, even though the broad strokes about what causes Rett syndrome are well-established, the molecular details remain a matter of debate. Part of the issue is that MeCP2 dysregulation can cause problems in the early development of neurons. Until now, it’s been difficult to tell whether long-term changes in genetic activity are due to problems with MeCP2 itself, or if problems during development lead to changes in genetic activity later on, independent of the dysfunctional protein.
MeCP2 protein production switched off in adult mice in study
To gain insight into this question, scientists conducted a series of experiments in a mouse model. For this model, the mice were engineered so they would express MeCP2 protein normally during early brain development, but then once the mice reached adulthood and the brain was fully developed, production of the MeCP2 protein would be switched off. With this experimental paradigm, the researchers were able to zero in on changes in genetic activity that are specifically attributable to the MeCP2 protein and not caused by abnormal development.
“In the current study, our goal was to better understand the molecular changes that occur upon loss of MeCP2 function,” Sameer Bajikar, PhD, first author of the study currently at The University of Virginia, said in a news story from Baylor College of Medicine. “Previous research has attempted to do this by studying the condition in animals presenting severe symptoms of the disorder. However, it has been difficult to separate the molecular changes caused by loss of MeCP2 from those occurring during development or secondary to sick neurons.”
Of note, the MECP2 gene is located on the sex-determining X chromosome, and as such, female animals tend to have more variability in MeCP2 expression. To simplify the data, the researchers used only male mice in their experiments.
Results showed loss of MeCP2 protein during adulthood led to profound changes in the genetic activity of nerve cells. Within the first week after MeCP2 depletion began, a few dozen genes became dysregulated (either abnormally active or unusually inactive). Within a month after MeCP2 was depleted, this dysregulation spread to affect more than 1,000 genes.
Broadly, the changes in genetic activity seen when MeCP2 was deactivated during adulthood were similar to the changes that have been reported when the protein is dysfunctional from birth. This suggests that most of the changes in genetic activity are due to problems with MeCP2 itself, not consequences of abnormal development.
“We found that adult deletion of Mecp2 changes the expression of many genes very early after Mecp2 loss, some genes’ expression was increased while others reduced,” Bajikar said. “These gene expression changes became more robust over time and mirrored those of the Mecp2 germline [from-birth] knockout mice.”
Data show alterations in genetic activity come before neurological dysfunction
Further tests showed depletion of MeCP2 in adulthood leads to problems with brain electrical activity and also with movement and general health. Importantly, however, the changes in brain activity weren’t detectable until after changes in genetic activity were already evident, which suggests the alterations in genetic activity come before problems with neurological function.
“Our data demonstrate that there is a window of time when molecular events downstream of MeCP2 are occurring, but before overt physiological consequences are measurable,” said Huda Zoghbi, MD, senior study author and professor at Baylor, and whose team made the discovery that MECP2 mutations cause Rett syndrome. “Investigating specific changes during this window will be important for fully characterizing the trajectory of molecular events leading to Rett syndrome.”
Understanding the specific sequence of molecular events between MeCP2 dysfunction and Rett syndrome is crucial for developing new Rett treatments like gene therapies, the researchers noted. Problems can arise when there’s too much or too little MeCP2 protein, so these data may help scientists finetune treatment strategies. As such, this study “has laid the foundation for pursuing gene therapy strategies to treat [Rett syndrome],” the researchers wrote.
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