Dec 24, 2008

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.

Dec 14, 2008

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.


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