MeCP2 duplication syndrome (MDS) is a neurological condition characterized by moderate to severe intellectual disability. But any increase or decrease in the expression of the protein MeCP2 can lead to a range of disorders, including severe motor dysfunction and autistic behavior. Now, Baylor College-led researchers have singled out a potential target for the treatment of MDS—a finding that could have wider implications in neurological disease.
Mutations in the MECP2 gene can cause abnormal expression of the MeCP2 protein. Instead of attacking the gene mutation, a team led by Laura Lombardi, a postdoctoral researcher at Baylor College of Medicine, tried to indirectly influence the abundance of the protein in nerve cells. Using a cell culture-based method, the team screened more than 800 genes in search of those that regulate MeCP2 expression.
After narrowing the group down to four potential targets, they zeroed in on the protein PP2A. Then they administered fostriecin, a PP2A inhibitor, in mouse models of MDS. The compound “markedly decreased” MeCP2 in mice with MDS, and improved their performance on behavioral tests in comparison to mice in a control group. The study is published in Science Translational Medicine.
Targeting PP2A is one of several emerging approaches to treating diseases marked by intellectual disabilities. Earlier this year, McGill University scientists found that the diabetes drug metformin could be a treatment for fragile X syndrome, a genetic disorder that causes a form of autism. The drug restores molecular pathways that are disrupted by the fragile X mental retardation 1 gene (FMR1). And while the researchers are still trying to figure out how it works, they believe metformin could be useful in treating other forms of autism.
The Baylor team is now working on optimizing drugs to target PP2A. “In addition, we believe that it may be necessary to delve further into the mechanism of PP2A’s regulation of MeCP2 to enable more precise pharmacological manipulation,” the researchers wrote in the study.