Amyotrophic lateral sclerosis
Boris Margulis, Post-ScienceAmyotrophic lateral sclerosis (ALS) is one of the five most common neurodegenerative pathologies, the first place in which belongs to Alzheimer's disease.
In English, BASS is read as Amyotrophic Lateral Sclerosis (ALS), and in Greek A means "no", denial, myo - muscular, trophic — nutrition, that is, "no muscle recharge". Lateral means areas of the spinal cord, they contain nerve cells that control the activity of muscles and the death of which causes scarring of nerve tissue, sclerosis (sclerosis).
1. Signs of ALSThe disease covers a certain part of the neurons of the spinal cord, and their extinction leads to disruption of the function of many muscles responsible for the functioning of the entire body.
The primary sign of ALS is weakness in the arms and legs, which increases with simultaneous weakening, atrophy of the muscles of the tongue, soft palate, vocal cords. Swallowing and speech disorders occur, choking occurs when eating, food enters the nose, and pathological changes associated with reflexes of the tendon systems of the arms and legs appear. In most patients, the disease is diagnosed at the age of 40 to 70 years. Statistics show that on average 1-3 patients with proven ALS account for 100,000 people. There are correlations with gender (men are more susceptible to pathology) and even with origin; for example, there is evidence that in the USA amyotrophic lateral sclerosis is more common in representatives of the Caucasian race.
2. Causes of ALSThere are several causes of ALS.
These include hereditary forms of transmission of pathology, ethnogeographic factors, the influence of diet and adverse environmental changes. The most well-known examples of a high incidence of ALS on a geographical basis include the inhabitants of the Kii Peninsula (Japan), the Chamorro people on the island of Guam or veterans of the Gulf War. Cases of pathology as a result of heavy metal poisoning or viral infection have been recorded. There are many reasons for the development of the disease, and work on their study continues. Modern bioinformatics methods are increasingly involved in these studies, with the help of which it is planned to get a fairly complete picture of the spread of neurodegenerative pathologies, including ALS, in the next 5-10 years.
3. The relationship of ALS with genetics and molecular biologyALS is one of the five most common neurodegenerative pathologies.
Most of these diseases are associated with mutations in various genes that lead to dysfunction and eventually death of certain groups of brain cells. About 80% of ALS cases are sporadic, that is, they do not have a clear hereditary nature, and are determined by point mutations in genes encoding different proteins. The remaining 20% are so-called family cases, that is, mutations are transmitted from generation to generation (hereditary mode of transmission). There are several genes in which mutations are most often observed: these include the genes of superoxide dismutase (SOD1) and the protein TDP-43. It is essential that mutations in the genes of the same proteins can be inherited and lead to familial forms of ALS. In addition to those indicated in the development of ALS pathology, mutations in the gene of the neurofilament protein or DNA/RNA-binding protein may participate. As is known, mutations along the "coding gene — mRNA — protein" chain can lead to the appearance of protein molecules with an incorrect structure. Of course, some mutations may not cause serious changes in the protein and, thus, do not stimulate the pathological process. To date, databases have been accumulated, in particular on mutations in genes involved in the process of ALS pathogenesis. It should be noted that in large cities there are clinical and genetic consultations, in which, based on the analysis of your genetic material, they can give a prognostic assessment of the likelihood of the disease. There are several consequences of mutations and, accordingly, the appearance of incorrect proteins: firstly, such proteins lose their function; for example, SOD1 ceases to control the removal of reactive oxygen species, which can lead to cell death. Secondly, "bad" proteins form aggregates that disrupt all the processes of cell activity.
4. What happens in a neuron affected by ALSNeurons are highly specialized cells aimed at transmitting signals in the form of chemical compounds, peptides through the brain, and in the case of neuromuscular systems — to muscles.
Due to their highly specialized purpose, neurons receive a lot (defense systems, trophic and other factors) from neighboring glial cells and neuroendocrine/neuroepithelial cell structures. In the neuron itself, the systems that should protect it from the action of reactive oxygen species, the accumulation of "bad" proteins and other stress factors do not act very effectively, and therefore inflammatory or pathogenic stimuli cause dysfunction, and then the death of large groups of neurons. This situation is typical for neurons producing mutant proteins in the process of ALS pathogenesis: molecules of mutant SOD1 or TDP-43 are assembled in the cell first into small complexes, and then into large aggregates, with which the quality control systems of cellular proteins are no longer able to cope.
These pathogenic aggregates disrupt the vital processes of the cell as a whole, interfere with the transport of nutrients and other substances through the cell, suppress the function of energy factories, mitochondria, turn off the RNA and protein synthesis systems, and the neuron ceases to work as a transmitter of important information to the muscle. Muscle cells that do not receive impulses from the neurons that control them experience a lack of contractile activity and just as quickly lose their main function. Many active people at retirement cannot switch to another way of life and begin to experience all the disadvantages of old age; neurons and muscle cells that have lost their basic functions behave the same way. I must say that the process of stopping the function and the onset of mass cell death is stretched for years, if not decades; muscle activity fades gradually, but irrevocably, covering all new tissues and organs.
5. Medical treatment of ALSThe main obstacle to the development of primary pharmacological treatments for ALS is the fact that the disease is diagnosed at a rather late stage, when it is already difficult to stop, it is only possible to reduce the severity of symptoms.
Existing drugs confirm such a bleak state of the problem. For example, the use of antidepressants and sleeping pills is considered very important in relieving symptoms; there are a lot of such drugs on the market, and the most effective of them can improve the quality of life of a patient for a period of up to several months. Painful muscle contractions (including uncontrolled ones) can be relieved by taking muscle relaxants, and the pain joint syndrome characteristic of some forms of ALS is weakened by the action of nonsteroidal anti-inflammatory drugs. In 1995, the American regulatory authority FDA approved the use of the antiglutamate drug Riluzole, which is able to extend the duration of a functionally active lifestyle in patients even in the late stages of ALS. What is very important: according to pharmacological tests, the drug can prolong the duration of life for several months or delay the development of signs of the disease.
6. Prospects of ALS researchThe tasks that are set for pharmacologists involved in the design of drugs for the treatment of neurodegenerative pathologies can be classified as little feasible, since everyone understands perfectly well that it would be necessary to treat the causes of the disease, not its consequence.
In other words, — and this is a problem of all modern pharmacology — we do not have reliable markers for the development of pathology, and genetic ones do not always work, since the probability that a mutation in the above genes will cause a complete picture of pathology is not 100%. Hundreds of laboratories are dealing with the problem of disease markers, and a large number of methods are involved, in particular from the field of proteomics, metabolomics and other so-called omics, in order to understand which biomolecules distinguish a diseased cell from a healthy one.
The second problem for pharmacologists is the identification of targets, that is, those proteins or peptides that are associated with the pathogenic mechanism, neutralizing which can defeat the disease in a single cell, and then in the tissue. For such targeted pharmacological technologies, virtual screening methods are used, in which a model of the interaction of the desired drug with a protein molecule, for example, SOD1, which it should bind and thus inactivate, is presented on a computer. It is safe to say that such methods in combination will soon lead us to the discovery of so—called valid targets for drugs, and then to the drugs themselves.
About the author:
Boris Margulis – Doctor of Biological Sciences, Chief Researcher
Laboratories of Cell Defense Mechanisms of the Institute of Cytology of the Russian Academy of Sciences.
Portal "Eternal youth" http://vechnayamolodost.ru03.09.2014