For fifteen years, scientists have known that mutations in a single gene, MECP2, lead to Rett syndrome, a severe neurological disorder that affects young girls almost exclusively. Even so, they have struggled to understand how the gene functions in the brain in Rett syndrome.
An HMS research team now has discovered that when MECP2 is mutated in a mouse model of Rett syndrome, the brain loses its ability to regulate unusually long genes. Their finding suggests new ways to consider reversing the intellectual and physical debilitation this disruption causes with a drug that could potentially target this error. The team, led by Michael Greenberg, the Nathan Marsh Pusey Professor of Neurobiology at HMS, reported its findings in the March 11 online edition of Nature.
Scientists, including Greenberg, have learned that MECP2 plays a role in sculpting the connections between neurons in the developing brain. These synapses mature as they are exposed to sensory experiences, just the sort of stimulation a young child would encounter as she learns to walk and talk.
MECP2 is present in all cells in the body, but when the brain is forming and its synapses are maturing, MECP2 levels in the brain are nearly ten times higher than in other parts of the body. The Greenberg study links MECP2 mutations to long genes, which may be more prone to errors simply because their length leaves more room for mistakes.
“MECP2 may act like a speed bump, fine-tuning long genes by slowing down the machinery that transcribes them,” says Harrison Gabel, a postdoctoral fellow in Greenberg’s lab and co-first author. In transcription, the information in a strand of DNA is copied onto a new molecule of messenger RNA, which is then turned into a protein. Without MECP2, transcription may move too fast, leading to widespread overexpression of the long genes.
Harrison and co-first author Benyam Kinde, an MD-PhD student in Greenberg’s lab, found the misregulation in multiple mouse models of Rett syndrome and confirmed it in the brain tissue of deceased Rett patients.
As an attempt at a corrective strategy, the researchers chose the cancer drug topotecan because it blocks an enzyme known to be important for long-gene transcription. When they added topotecan to neurons lacking MECP2, the drug reversed the long-gene misregulation. Although topotecan is too toxic to be a therapeutic, derivatives of topotecan might prove worthwhile.
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