Undoing Brain Damage

RESULTS OF A TEST in mice offer hope that Rett syndrome and other autism-related disorders could be cured in humans. Rett syndrome primarily strikes girls, who develop mental retardation and lose muscle tone, the use of their hands, and the ability to speak.

"The findings are extraordinary and are of relevance not only to Rett syndrome but to a much broader class of disorders, including autism and schizophrenia," says Baylor College of Medicine professor Huda Y. Zoghbi.

Back in 1999, Zoghbi discovered that Rett syndrome is caused by mutations in the gene for methyl-CpG-binding protein 2 (MeCP2). Adrian Bird of the University of Edinburgh and colleagues now report that these mutations disrupt binding of MeCP2 to another protein called ATRX (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0608056104). Bird proposes that the two proteins collaborate during normal brain development to bind to DNA and regulate its function. He believes the mutations that disturb the proteins' interactions interfere with neuronal function, leading to mental retardation.

Bird and another team of colleagues created a model of the disease in mice by blocking the animals' production of MeCP2. When the researchers unblocked MeCP2 production, the mice—some of which were near death—shocked the team by recovering (Science, DOI: 10.1126/science.1138389).

"We expected that giving MeCP2 to mice that were already sick would not work," Bird says. "The idea that you could put back an essential component after the damage to the brain is done and recover an apparently normal mouse seemed farfetched, as nerve cells that developed in the absence of a key component were assumed to be irrevocably damaged." The results indicate that the neurons affected by the disease do not degenerate but remain alive and may respond to therapy.

"If we can develop therapies to address the loss of MeCP2, we may be able to reverse neurological damage in children and adults with Rett, autism, and related neuropsychiatric disorders," Zoghbi says.