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The role of methyl group in developing schizophrenia

The search for the genetic causes of schizophrenia has been underway for a long time, but has not yielded definite results. Geneticists from the Mental Health Research Center are proposing a new method of studying mental disorders.

Фото: Reuters
Фото: Reuters

Schizophrenia is a disease characterized by pathological changes in various spheres of mental condition – emotional, behavioral and cognitive. Although the clinical criteria for this disorder were defined over a hundred years ago, it remains unclear if this disorder is an independent condition or is a combination of separate syndromes or diseases.

Impaired cognitive functions are one of the important manifestations of schizophrenia. Specifically, it concerns attention, ability to use previously acquired knowledge, ability to use critical reasoning to make decisions by separating the main factors from the secondary and to understand the feelings and intentions of the people around. Such impaired functions are jointly called cognitive deficit. The degree to which such cognitive deficit is manifested greatly affects the patients’ ability for social adjustment. It is believed that cognitive disorders represent an independent type of diseases due to the following facts:

  • They are IQ independent,
  • They are observed in patients with no medication treatment and patients with the first psychotic episode. Sharp deterioration of the cognitive functions takes place immediately after the onset of the disease.
  • They appear before the onset of psychosis.

One serious factor in favor of understanding the nature of this phenomenon is the fact that presently there are no treatment methods that can substantially restore deteriorated cognitive functions in case of schizophrenia.

Cognitive deficit is of genetic nature – changes in the cognitive area can be detected in close blood relatives of schizophrenia patients. However, the search for specific genes responsible for the deterioration of the cognitive function has not been successful, despite its great scale and the methodological complexity of conducted research. One of the reasons for the absence of progress can be related to the fact that researchers study gene segments responsible for encoding specific proteins. At the same time, latest research in the field of schizophrenia genetics point out that gene segments responsible for regulating genes’ activity (expression) play a more significant role in the development of the disease.

Methylation is an important mechanism of expression regulation, in other words addition of a methyl group (CH3-) to cytosine, one of the DNA nucleotides. Such modification can change the transcription process and cause further pathological changes leading to the development of schizophrenia. This is proved by the difference in the level of DNA methylation in the blood cells of identical twins, one of who has schizophrenia, while the other is healthy, as well as the differences between the groups of sick and healthy people observed during the posthumous study of brain samples.

The link between DNA methylation and cognitive deficit in schizophrenia has not been researched so far. Scientists from the Clinical Genetics Laboratory with the support of the Russian Science Foundation (project No. 16-15-00056) decided to fill in the gap and attempt to reveal molecular and biological mechanisms that form the basis for the impairment of the cognitive functions. To meet the goal of the project the researchers plan to study allele-specific methylation, i.e. methylation that depends on the specific genetic variant (point mutation).

 Allele-specific methylation helps understand how gene expression can be controlled by point mutation. A specially designed program selects genomic segments, which transform and create methylation islands (CpG). The project also includes a large-scale analysis of the methylation status in specific genes, which have proved link with schizophrenia. Determining the methylation status will be performed with high technology methods of DNA study with subsequent DNA sequencing of genome segments. Studying of methylation profiles will be conducted not only in peripheral blood as it is done in most research projects, but also in a model new for the research of mental diseases, specifically in primary cell cultures of stem nerve cells of olfactory epithelium. Olfactory epithelium contains stem cells that preserve the ability to reproduce and transform into neuron precursors, which in turn form mature neurons. Thus, olfactory epithelium is often called “a window to the brain”. The neurons that we have grown are presented in the picture.

It is expected that the project will result in detection of epigenetic biomedical markers (methylated DNA), linked to the cognitive deficit in schizophrenia, as well as discovery and study of functional elements that regulate the work of relevant genes. Finding the epigenetic mechanisms that form the basis for the cognitive deficit will shed the light on the biological mechanisms of the syndrome’s onset.

Prof. Vera Golimbet, PhD in Biology,

Head of the Clinical Genetics Laboratory at the Mental Health Research Center, RAS

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