Rett syndrome is a rare, debilitating disease in which patients progressively lose brain function and the ability to walk.
Rett syndrome affects girls almost exclusively, occurring in 1 of every 10,000 to 15,000 births and usually diagnosed by age 2. It is characterized by developmental regression, autistic traits, slow brain development, lack of speech, repetitive hand movements, seizures, and problems with walking. Many patients live beyond middle age, though not enough data exist to reliably estimate life expectancy beyond age 40.
Relatively little is known about the neuronal causes of Rett syndrome, but UT Southwestern Medical Center scientists have now identified a process in the brains of mice that might explain the repetitive actions that could be a key step in developing treatments to eliminate symptoms that drastically impair the quality of life in Rett patients.
The study demonstrated that MeCP2 , the protein which does not work properly in Rett syndrome, is among a group of three proteins that affect the function of a gene previously linked to obsessive compulsive disorder. Researchers were able to induce and then suppress repetitive behaviors in mice by changing the levels of these three proteins at the synapse - the communication junction between nerve cells.
The research is a significant advancement in the understanding of how dysfunction in MeCP2 leads to key symptoms associated with Rett syndrome. Although MeCP2 was identified less than two decades ago as the cause of the postnatal neurological disorder, the link between the protein's dysfunction and the specific neurological symptoms characteristic of the disease remains elusive.
While current medications and behavioral therapy can sometimes diminish symptoms such as seizures and hand behaviors, no treatment exists to eradicate or reverse the disorder and the repetitive stereotyped behaviors, due to a lack of knowledge about how MeCP2 dysfunction gives rise to these and other symptoms.
Scientists have known that MeCP2 is essential for normal brain development and acts as a molecular switch that affects how other genes function. Patients with Rett syndrome and some cases of autism spectrum disorder do not produce MeCP2 or have too much of it, respectively, causing other genes to operate abnormally. But scientists have not yet identified many of the precise mechanisms by which this dysfunction occurs.
Dr. Monteggia's team found that MeCP2 controls the function of a gene called SAPAP3, which has been linked to obsessive compulsive disorder in humans. Disrupting the interaction between MeCP2 and the target gene SAPAP3 caused mice to groom themselves excessively; this repetitive behavior stopped after researchers reintroduced SAPAP3 into a particular brain region that is involved in obsessive compulsive behaviors. The research group also identified that MeCP2 formed a complex with histone deacetylase proteins, HDAC1 and HDAC2, to regulate SAPAP3's function.
"It is important to take these findings to the next level and seek ways to help patients enjoy their lives as normally as they can by addressing their symptoms," said Dr. Monteggia, holder of the Ginny and John Eulich Professorship at UT Southwestern.
In addition to the Rett-related finding, Dr. Monteggia's team found that the removal of both HDAC1 and HDAC2 from the brain can kill neurons. This outcome is notable because studies elsewhere had demonstrated the potential for treating memory loss by selectively inhibiting the HDAC2 protein.
Dr. Monteggia said this finding does not mean certain HDAC inhibitors can't be effective, but the study does demonstrate that non-specific inhibitors and certain combinations may worsen the problem.