Running from dementia
Physical activity restores the normal phenotype of hippocampal neurons
LifeSciencesToday based on DKFZ materials: Exercise rescues mutated neural stem cellsThe German Cancer Research Center received important information about CHARGE syndrome
CHARGE syndrome is a severe developmental disorder affecting many organs: Coloboma of the eye, heart defects, Atresia of the choanae, severe Retardation of growth and development, Genital abnormalities, anomalies of the ears (Ear abnormalities). According to world statistics, it occurs in one out of every 8,500 newborns. Most of these patients carry a mutation in the CHD7 gene. How one mutation causes such a wide range of symptoms characteristic of CHARGE has remained a mystery until now.
The CHD7 gene encodes one of the so–called chromatin remodelers, an important class of epigenetic regulators. The DNA molecule is wound on a structure consisting of histone proteins. The string of bead-like nucleosomes is then twisted into a structure called chromatin. The more nucleosomes a gene occupies, the less active it is. Chromatin remodelers, such as CHD7, play an important role in the regulation of gene activity, as they create nucleosome-free regions in the regulatory sequences of genes. Thus, a mutation in one gene encoding one of the chromatin remodelers can lead to inadequate regulation of a wide range of genes.
Dr. Haikun Liu's laboratory at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) is studying the regulation of adult neural stem cells. Scientists pay special attention to the role of adult neural stem cells in the development of human diseases, including mental retardation and brain tumors. Patients with CHARGE syndrome suffer from mental retardation and are unable to learn, which gives good reason to consider a defect of the central nervous system as the basis of the disease.
To understand the molecular role of a mutation in the CHD7 gene in the CHARGE syndrome phenotype, scientists used genetically modified mice. The newly created model makes it possible to turn off the CHD7 gene at certain stages of development only in neural stem cells and trace how CHD7-deficient cells proliferate, differentiate and mature throughout the animal's life.
This work has yielded amazing results. When CHD7 was turned off, both in fetal and adult neural stem cells, mutant cells behaved the same way: they lost the ability to effectively differentiate into mature neurons – the main functional units of the human brain and other animals. Mature neurons normally have a very complex morphology, which allows them to create networks that are essential for information processing. As for mutant neurons with the CHD7 gene turned off, they are apparently unable to form such networks.
But the most striking thing was that physical exercise completely restores the normal phenotype of neurons in the hippocampus – the main area of the brain responsible for learning and memory. After training on the "squirrel" wheel – rodents love this activity very much – CHD7-mutant neurons in CHD7-deficient animals have fully recovered: they began to create functional networks.
That running causes a sharp increase in neurogenesis in adults has been confirmed in both animals and humans. "We are very pleased that the effects of CHD7 deficiency in cells can be circumvented by using an unknown mechanism activated by physical exercise, including running. Now we are working hard to find this mechanism," Dr. Liu comments on the results of his research.
Article by Feng et al. The Chromatin Remodeler CHD7 Regulates Adult Neurogenesis via Activation of SoxC Transcription Factors is published in the journal Cell Stem Cell.
Neurologists believe that this discovery will lead to a better understanding of the molecular basis of CHARGE syndrome and, perhaps, even indicate a way to reactivate the CHD7 pathway and thus weaken the symptoms of the disease in humans.
The CHD7 gene is also associated with the development of cancer; mutations in this molecule are present in many different types of human cancers, including lung, colon and brain cancers. The newly identified mechanism gives a clear explanation for this: a mutation in CHD7 leads to blocking of stem cell differentiation, which is the main cause of carcinogenesis.
In addition, the CHD7 gene is considered to be associated with a high risk of developing autism, and many patients with CHARGE syndrome show signs of this disease. Apparently, this gene plays an important role in the regulation of many other physiological processes. Similar to the neural stem cell study, Dr. Liu and colleagues plan to use their excellent mouse model to study the role of CHD7 in other cell types.
Portal "Eternal youth" http://vechnayamolodost.ru12.07.2013