Genetic mechanisms of epilepsy
Alexander the Great and Caesar, Peter the Great and Napoleon suffered from epilepsy as an “outstanding disease”, “an epilepsy” or, as the Greeks called it. As you know, in addition to the psychotherapeutic method for the treatment of this disease, doctors use medication and even neurosurgery, but at the same time we have to admit that there are no reliable means against this ailment. The pathogenesis of such conditions, as geneticists say, is polymorphic.
With this state of affairs, modern medicine is constantly faced. It quickly became clear that the genetics of insulin-independent diabetes is fundamentally different from type I diabetes, that about a thousand genes that are already known today can lead to the appearance of tumors, but no one can guarantee that in the end we will not talk about a dozen thousand
To this must be added the “diversity” of the gene itself. In the embryonic state, a gene can perform a morphogenetic function, determining the development of the spine or organ, and in the adult state, the same gene acts as a protector gene, protecting cells from tumor transformation and the body from cancer. That is why today it is so difficult to study and understand the true causes of the development of a disease or true pathogenesis: we see the pathology, but we don’t know the genes at its core. And it is unlikely that the true pathogenesis will become clear until the completion of the program for a complete reading of the human genome, which is expected at the beginning of the XXI century. But we still know something today.
A nerve cell, like any other, is not able to support life without protein enzymes, the molecules of which can be located in the membrane membrane and cytoplasm, interconnecting different parts of the cellular structure. Particular attention is currently being paid to membrane receptors and submembrane enzyme complexes.
The suppression of the activity of “pain” neurons is carried out by blocking the influx of calcium ions into the cell and potassium from the cell. This is achieved by means of ion channels – membrane proteins having an opening – a “pore” through which ions are transported. Between the receptor and the channel there is a connection in the form of the so-called G-proteins.
They are called so because they receive energy due to the breakdown of guanosine triphosphate (GTP), due to which they can regulate the enzyme systems responsible for the operation of the same channels, and therefore the excitation of neurons. One of these enzymes is phospholipase C – PLC. Korean scientists from Pusan University managed to turn off the PLC beta subunit gene in the mouse, as a result of which the connection of receptors with their cellular “targets” and normal signal transmission in the neuron were disrupted.
The decision to turn off the beta subunit was due to the fact that neurochemists have long paid attention to its activity in the cerebral cortex and especially in the hippocampus, or the convolution of the seahorse based on the hemisphere, which is often affected morphologically and functionally with epilepsy of various origins. In the hippocampus, the beta subunit is associated with the receptors of an active transmitter such as acetylcholine, and in the cerebellum, with the receptors of glutamate (glutamine amino acid), also a powerful activator of neurons.
In mice with the PLC gene turned off, motor neurons die, leading to ataxia. Mice lag behind in growth and die on the 3rd week after birth against the background of epileptic status: hyper-excitation in the hippocampus due to the death of “restraining” neurons containing somatostatin (a neurohormone that regulates growth processes); recurring convulsions of the whole body (tono-clonic). This picture is very reminiscent of experimental convulsions caused by epileptogens.
Thus, the shutdown of the gene of the enzyme responsible in the neurons for the breakdown of fats, which is extremely necessary for providing nerve cells with energy, leads to the most deplorable results due to the interruption of the stimulating acetylcholine signal. It ends in death.
The role of the serotonin receptor is also great – the “good mood substance” in our brain (it is believed that depressive and obsessive states are caused precisely by its lack). It is also associated with G-protein and PLC, stimulating a neuron through them. It was previously shown that mutants at the serotonin receptor suffer from epilepsy. But such studies in their accuracy cannot be compared with experiments in which it is possible to turn off the gene of interest.
It turned out that the serotonin receptor gene gives different commands for the synthesis of this protein. Scientists at Vanderbilt University in Nashville, Tennessee, USA, isolated the receptor DNA from the subcortical nuclei of rats that control movement. In one of the intracellular loops of the receptor protein, there are three amino acids valine-serinvaline, the presence of which is very important for the functioning of the receptor.
If the amino acids in this place are replaced by others, for example, as a result of mutations, then the efficiency of the interaction of the receptor with its G-protein can decrease by 10-15 times, which leads to the development of epileptogenic status. Moreover, the replacement of these amino acids can occur at the level of not the gene (DNA), but its RNA copy. This is a new mechanism for the occurrence of epilepsy at the genetic level. This result is confirmed by the death of mice with the serotonin receptor gene turned off, as well as the action of antagonists of this receptor.
In 1991, the discovery of a completely new mechanism for the occurrence of genetic diseases was made. We are talking about the “expansion” of three-letter nucleotide repeats in DNA, about the hereditary mental retardation associated with the so-called fragmentary X chromosome. This is the female “sex” chromosome, at the end of which, for not clear reasons, the number of repetitions of the “letters” of the gene code begins to increase: CAG, CTG, CGG and CCG. Normally, such triples should not be more than 30-35, but in some cases their number “rolls over” for a hundred, or even one and a half. And then the tip of the X chromosome breaks off, that is, it is fragmented.
Now there are already more than a dozen genetic diseases associated with this amazing phenomenon. In 1996, it was discovered that with ataxia of Friedrich, the number of GAA triples increases. Ataxia can be considered a closer “relative” of epilepsy, which actually turned out to be, since a similar mechanism was also discovered with myoclonic epilepsy (according to the Unferricht – Lundborg type). This is a rare autosomal disease, its gene is not located on the sex chromosome. Interestingly, it is localized on the famous 21st chromosome, in the same place as the gene for Down syndrome and Alzheimer’s disease. The epilepsy gene in this case encodes a proteinase enzyme inhibitor – cystatin B, which is also reduced in lymphoblastoid cells with “malfunctions” of white blood.
A more detailed analysis of the gene in patients revealed a huge insertion (insertion) of 600-900 “letters” of the genetic code – nucleotides, which was a numerous repetition, but not triples, but dodecamers, or 12-members of the OSCGCCCCGCG! These repeats did not block protein synthesis, but the regulatory part of the gene.
This discovery was made in the laboratory of human genetics, University of Geneva. The advantage of the work of Swiss scientists is that the new mechanism for the occurrence of epilepsy was discovered not in an experiment on laboratory animals, but in two families of patients.
Of course, doctors most often have to deal with post-traumatic epilepsy, as well as diseases caused by organic damage to a particular part of the brain. There is no time for relatively rare genetic disorders.
But you can look at the problem from the other side. Indeed, a significantly larger number of people suffered traumatic brain injuries, but only a small number of victims developed epilepsy after this. When you have to face a different reaction to the same external influence, we can only talk about the genetic polymorphism of the population and the “syndrome”, which we have in the case of epilepsy.
To date, only a few genetic mechanisms of the pathogenesis of this condition have been identified. But this short list also shows that there can be no single cure for epilepsy, since not only different genes are involved, but also their different parts – protein coding and regulatory, which have no relation to protein synthesis.