A possible treatment for Rett syndrome

Study suggests molecule can reverse some symptoms
CAMBRIDGE, Mass.— A molecule that promotes brain development could serve as a possible treatment for Rett syndrome, the most common form of autism in girls, according to researchers at MIT's Picower Institute for Learning and Memory and the Whitehead Institute for Biomedical Research.
The researchers found that injecting the molecule into mice that have an equivalent of Rett syndrome helped the animals' faulty brain cells develop normally and reversed some of the disorder's symptoms.
The work, reported in the Feb. 10 online edition of the Proceedings of the National Academy of Sciences (PNAS), is expected to lead to new human clinical trials for a derivative of growth factor-1 (IGF-1), currently used to treat growth disorders and control blood glucose. The MIT study indicates that IGF-1 could potentially lessen the severity of symptoms of Rett syndrome.
"We demonstrate that a major underlying mechanism behind Rett syndrome in mice is that synapses in the brain remain immature and show persistent, abnormal plasticity into adulthood," said Daniela Tropea, a postdoctoral fellow at the Picower Institute and lead author of the study. "We also propose that a therapeutic based on this mechanism would be directly applicable to humans."
Injecting mice with a peptide fragment of IGF-1, used by the brain for neuronal and synaptic development, reverses a large number of symptoms of mice genetically engineered to display Rett syndrome-like symptoms.
"IGF-1 is critical for brain development. It activates molecules within neurons that make synapses mature," said study co-author Mriganka Sur, the Newton Professor of Neuroscience at the Picower Institute and head of the MIT Department of Brain and Cognitive Sciences. "This is a mechanism-based therapeutic for Rett syndrome. It is possible that this or similar therapeutics would apply to other forms of autism, which also have as their basis a persistent immaturity of synapses."
HELPING NERVE CELLS MATURE
Rett syndrome, an inherited neurological disorder, causes loss of speech, reduced head size, breathing and heart abnormalities and autism-like symptoms in one out of 10,000 girls.
In 85 percent of girls with Rett syndrome, the culprit is a faulty gene coding for methyl CpG-binding protein 2, (MeCP2), critical for nerve cell maturation. A deficit in MeCP2 stops neurons from growing spines, the branch-like projections needed for cell-to-cell communication.
Recent genetic studies have shown that increasing MeCP2 expression in mice led neurons to grow new spines, indicating that the disease could be reversible. Increased IGF-1 seems to make up for the lack of MeCP2.
Daily injections of the insulin-like growth factor IGF-1 extended the life spans of infant Rett syndrome mice, improved their motor function and breathing patterns and reduced irregularities in their heart rates. In addition, their brains had more nerve-cell spines.
IGF-1 affects almost every cell in the human body, especially in muscle, cartilage, bone, liver, kidney, nerves, skin and lungs. In addition to its insulin-like effects, IGF-1 also regulates cell growth and development in nerve cells.
"This is the first realistic way for a drug-like molecule injected into the bloodstream to relieve Rett syndrome symptoms," said Whitehead member Rudolf Jaenisch, whose lab participated in the research.

ScienceDaily

Exercise could improve brain disorder

Mental and physical exercise could help improve symptoms of young girls suffering from the devastating brain disorder Rett syndrome, tests on lab rats suggest.
A discovery by Melbourne brain scientists offers hope that enriching the environment of Rett patients could slow the progression of coordination and movement problems when used alongside drug therapy.
Professor Anthony Hannan from the Howard Florey Institute said the find was preliminary and still needed to be verified in humans but could one day bring relief to the children and their parents.
"This is a very severe disorder, both physically and mentally, so it's not as simple as just get these girls moving," Prof Hannan said.
"The idea is if you had a drug that showed enough improvement to get one of these girls out of their wheelchair and moving then the increased mental and physical activity could boost the drug's effect even more.
"That could dramatically reduce symptoms, and might even reverse them."
Rett syndrome is caused by a single gene mutation on the X chromosome, almost exclusively affecting girls who are normal at birth but undergo severe mental and physical regression after six months.
There are no effective treatments or cures for the disease.
The researchers bred mice with the mutation to test the impact of an enriched environment, which has already proven beneficial in people with Huntington's and Alzheimer's diseases.
Half of the Rett syndrome mice were given a range of mazes, toys and exercise equipment to stimulate them both mentally and physically.
"We found that the ones in a normal environment have very severe problems with their coordination and movement," Prof Hannan said.
"But the ones with enrichment were just like their litter mates without the mutation."
Interestingly, they also found that a special brain chemical called BDNF, which is usually low in Rett mice, was at a normal level in those whose environment had been "enriched".
The researchers hope the molecule and others yet to be discovered could become targets for drug therapies to use alongside the stimulation treatment.
"The next step is for us to look at the effects of environmental enrichment on anxiety and cognition in the mice, as these are common problems in Rett syndrome," he said.
Source: European Journal of Neuroscience.

Reciprocal co-regulation of EGR2 and MECP2 is disrupted in Rett syndrome and autism

Mutations in MECP2, encoding methyl-CpG-binding protein 2 (MeCP2), cause the neurodevelopmental disorder Rett syndrome (RTT).While MECP2 mutations are rare in idiopathic autism, reduced MeCP2 levels are common in autism cortex. MeCP2 is critical for postnatal neuronal maturation and a modulator of activity-dependent genes such as Bdnf and JUNB.The activity-dependent early growth response gene 2 (EGR2), required for both early hindbrain development and mature neuronal function, has predicted binding sites in the promoters of several neurologically relevant genes including MECP2. Conversely, MeCP2 family members MBD1, MBD2 and MBD4 bind a methylated CpG island in an enhancer region located in EGR2 intron 1. This study was designed to test the hypothesis that MECP2 and EGR2 regulate each other's expression during neuronal maturation in postnatal brain development. Chromatin immunoprecipitation analysis showed EGR2 binding to the MECP2 promoter and MeCP2 binding to the enhancer region in EGR2 intron 1. Reduction of EGR2 and MeCP2 levels in cultured human neuroblastoma cells by RNA interference reciprocally reduced expression of both EGR2 and MECP2 and their protein products. Consistent with a role for MeCP2 in enhancing EGR2, Mecp2-deficient mouse cortex samples showed significantly reduced EGR2 by quantitative immunofluorescence. Furthermore, MeCP2 and EGR2 show coordinately increased levels during postnatal development of both mouse and human cortex. In contrast to age-matched controls, RTT and autism postmortem cortex samples showed significant reduction of EGR2. Together, these data support a role for dysregulation of an activity-dependent EGR2/MeCP2 pathway in RTT and autism.

Source: http://hmg.oxfordjournals.org/cgi/content/short/ddn380v1