Schizophrenia: from genetics to psychology

Roman Fishman, N+1 

Scientists were able to discover for the first time the molecular mechanism of schizophrenia: the risk of developing a serious disease was higher in people with certain variants of the gene that is involved in the immune system and the "maturation" of synaptic connections in the brain. The results of the work are reported in a detailed publication in the latest issue of Nature (Sekar et al., Schizophrenia risk from complex variation of complement component 4) and a brief note prepared by the editorial board of the journal (Schizophrenia: From genetics to physiology at last). Press releases from Harvard University and the Broad Institute, a biomedical research center working under the auspices of Harvard and the Massachusetts Institute of Technology (Genetic study provides first-ever insight into the biological origin of schizophrenia), also tell about it.

The search for genetic variants that may be associated with an increased risk of developing schizophrenia has been going on for decades. However, to date, all reports of the discovery of "schizophrenia genes" have not withstood strict checks. It took the team of Harvard Professor McCarroll and their partners from 30 countries around the world about five years to obtain DNA samples and conduct a genome-wide search for associations across more than 65 thousand genomes, showing that a potential "culprit" may be hiding on the 6th chromosome, in the area where the genes of the main histocompatibility complex (HCG).

This is one of the most complex and "densely populated" parts of the human genome, which encodes three classes of proteins that play a crucial role in the immune system. The maximum risk of developing schizophrenia was associated with variants of the gene responsible for the synthesis of class III HCG molecules. These proteins are involved in the complement system: circulating in the blood, they are activated with the appearance of pathogenic microorganisms or at the signal of other components of immunity, and, splitting, form enzyme complexes attacking the target cell and causing its lysis.

Scientists received the maximum signal when considering a gene encoding one of the "late" proteins of the complement system (C4). This gene is present in two forms – C4A and C4B, and different people may have different numbers of copies, in a short or long version containing a retroviral insert. Depending on the specific set of these variations, the activity of C4A and C4B in different people may be different. By studying the expression of RNA from these genes, the authors were able to find out exactly how the number of copies and different variants of C4A and C4B affect this activity. In particular, it was shown that an increase in the number of copies is expected to enhance the expression of C4A and C4B products, and the presence of a retroviral insert increases the ratio of C4A to C4B. In the samples of people with schizophrenia, these features were consistently higher.

Earlier, one of the authors of the new work Beth Stevens and colleagues demonstrated that the proteins of the complement system are involved in the process of synaptic pruning – the removal of "extra" connections between neurons of the brain during its maturation. This happens most actively during puberty, that is, exactly when the first signs of schizophrenia are usually detected – no wonder one of its old names is "early dementia". This allowed scientists to suggest that increased C4 activity may disrupt the course of synaptic pruning, leading to the disorderly destruction of interneuronal connections and, ultimately, to what we call schizophrenia.

To prove this, the authors conducted experiments on a line of laboratory mice with a different number of copies of C4 (there are no versions of C4A and C4B in the mouse genome). They were able to show that C4 plays a crucial role in pruning, ensuring the connection of another complement system protein (C3) with the synaptic membrane – this connection "marks" synapses for deletion. The more copies of C4 the mouse had, the more proteins were synthesized from them, and the more active the destruction of synapses was.

Indirectly, the same is indicated by the reduced thickness of the cerebral cortex, characteristic of patients with schizophrenia. Until now, experts could not even answer the question of whether this is the cause or consequence of the development of the disease. Now it becomes clear that all this may be the result of abnormally increased activity of C4 and disturbances in the processes of "maturation" of the brain.

"There are two ways to create medicines," Nature's editorial note says on this occasion. – The first is simple luck, thanks to which working substances are accidentally discovered. However, although such coincidences have led to the appearance of many extremely important drugs, this method cannot be systematized (...) The second, preferred, way is to understand the mechanisms of disease development and purposefully create compounds that affect them." It seems we're on the right track now.

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29.01.2015