Life without a genome: what are prions. Not a virus, not a protein, but its name is prion. Prions for short

This term has other meanings, see Prions (meanings).

They should not be confused with preons - hypothetical elementary particles.

Prions(English) prion from protein- “protein” and infection- “infection”, the word was proposed in 1982 by Stanley Prusiner) is a special class of infectious agents represented by proteins with an abnormal tertiary structure and not containing nucleic acids. This position underlies prion hypothesis, however, there are other points of view regarding the composition of prions, see Hypotheses about the composition of prions.

Prions are able to increase their numbers using the functions of living cells (in this respect, prions are similar to viruses). A prion is a protein with an abnormal three-dimensional (tertiary) structure that is capable of catalyzing the conformational transformation of a normal cellular protein homologous to it into a similar one (prion). As a rule, when a protein transitions to the prion state, its α-helices transform into β-sheets. The prions that appear as a result of such a transition can, in turn, rearrange new protein molecules; Thus, a chain reaction is started, during which a huge number of incorrectly folded molecules are formed. Prions are the only known infectious agents whose reproduction occurs without the participation of nucleic acids. The question of whether prions should be considered a form of life is currently open.

All known prions cause the formation of amyloids - protein aggregates that include densely packed β-sheets. Amyloids are fibrils that grow at ends, and fibril fracture results in four growing ends. The incubation period of a prion disease is determined by the rate of exponential growth in the number of prions, and it, in turn, depends on the rate of linear growth and fragmentation of aggregates (fibrils). For prion propagation, the initial presence of a normally folded cellular prion protein is necessary; organisms that lack the normal form of prion protein do not suffer from prion diseases.

The prion form of the protein is extremely stable and accumulates in the affected tissue, causing tissue damage and ultimately death. The stability of the prion form means that prions are resistant to denaturation by chemical and physical agents, making it difficult to destroy these particles or contain their growth. Prions exist in several forms - strains, each with a slightly different structure.

Prions cause the diseases transmissible spongiform encephalopathies (TSEs) in various mammals, including bovine spongiform encephalopathy (“mad cow disease”). In humans, prions cause Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease (vCJD), Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, and kuru. All known prion diseases affect the brain and other neural tissues and are currently incurable and ultimately fatal.

All known mammalian prion diseases are caused by the PrP protein. Its form with a normal tertiary structure is called PrP (from the English. common- regular or cellular- cellular), and the infectious, abnormal form is called PrP (from the English. scrapie- sheep scrapie (scrapie), one of the first diseases with an established prion nature) or PrP (from the English. Transmissible Spongiform Encephalopathies ).

Proteins that form prions have also been found in some fungi. Most fungal prions do not have a noticeable negative effect on survival, but there is still debate about the role of fungal prions in host physiology and role in evolution. Elucidation of the mechanisms of reproduction of fungal prions turned out to be important for understanding similar processes in mammals.

In 2016, a message appeared about the presence of Arabidopsis thaliana proteins with prion properties.

Story

Description of prion diseases

The first open transmissible spongiform encephalopathy was sheep scrapie. Its first cases were noted in Great Britain in the 1700s. With this disease, sheep suffered from severe itching, causing the animals to constantly rub themselves. scrape) about trees, which is where the name of the disease comes from. In addition, the sheep experienced pain when moving their legs and suffered from severe seizures. All of these symptoms are classic signs of brain damage, and this strange disease has been confusing scientists. Much later, in 1967, Chandler (eng. Chandler) found that scrapie can also affect mice, which was undoubtedly progress in the study of this disease.

In the twentieth century, human prion diseases were also described. In the 1920s, Hans Gerhard Creutzfeldt and Alfons Maria Jacob investigated a new incurable disease of the human nervous system, the main symptom of which was the formation of cavities in brain tissue. Subsequently, this disease was named after them.

In 1957, Carlton Gajduzek and Vincent Zigas described a neurological syndrome common among the Fore people living in the highlands of Papua New Guinea. This disease was characterized by tremor, ataxia, and in the early stages - athetoid movements. These symptoms were subsequently supplemented by weakness and dementia, and the disease inevitably ended in death. In the Fore language, this disease is called "kuru", which translated means "trembling" or "spoilage"; This is the name by which the disease is still known today. It turned out that the reason for the spread of kuru was ritual cannibalism, which was not uncommon among the Fore. During religious rituals, they ate the organs of their murdered relatives. At the same time, children ate the brain, since it was believed that it “increased intelligence” in children. The incubation period for the disease can be up to 50 years, but in girls, who are especially susceptible to kuru, it can be as little as four years or less. Carlton Gajduzek was awarded the Nobel Prize in Physiology or Medicine in 1976 for his discovery of the infectious nature of Kuru disease.

Development of ideas about prions

In the 1960s in London, two researchers, radiobiologist Tikvah Alper (eng. Tikvah Alper) and mathematician John Stanley Griffith, hypothesized that some transmissible spongiform encephalopathies are caused by pathogens composed entirely of proteins. Alper and Griffith thus tried to explain the fact that the mysterious infectious agent that causes scabies in sheep and Creutzfeldt-Jakob disease is very resistant to ionizing radiation. The dose of radiation required to destroy half of the particles of an infectious agent depends on their size: the smaller the particle, the less likely it is to be hit by a charged particle. So it was determined that the prion was too small for the virus.

Francis Crick recognized the importance of Griffith's protein hypothesis in explaining the spread of scabies in sheep in the second edition of The Central Dogma of Molecular Biology (1970). Although Crick argued that the flow of information from protein to protein or from protein to DNA or RNA was impossible, he noted that Griffith's hypothesis contained a possible contradiction to this (however, Griffith himself did not view his hypothesis that way). He later formulated his refined hypothesis taking into account the existence of reverse transcription, discovered in 1970 by David Baltimore and Howard Temin.

In 1982, Stanley Prusiner of the University of California, San Francisco reported that his group had isolated a hypothetical infectious agent (a prion) and that it consisted primarily of a single protein (although they did not isolate this protein until two years after Prusiner's report). For his research on prions, Prusiner was awarded the Nobel Prize in Physiology or Medicine in 1997.

Structure

Isoforms

The protein that makes up prions (PrP) can be found in all parts of the body in healthy people and animals. However, PrP is present in the affected tissues, which has an abnormal structure and is resistant to proteases (enzymes that hydrolyze proteins). As stated above, the normal form is called PrP, and the infectious form is called PrP. Under certain conditions, folding of more or less structured PrP isoforms can be achieved in vitro, which are capable of infecting healthy organisms, although with a lesser degree of efficiency than those isolated from diseased organisms.

PrP

PrP is a normal mammalian membrane protein that is encoded by the gene in humans PRNP. mRNA PRNP human encodes a polypeptide with a length of 253 amino acid residues (aa), which is shortened by cellular enzymes during maturation. The mature form of PrP consists of 208 amino acid residues and has a molecular weight of 35-36 kDa. In addition to limited proteolysis, PrP undergoes other post-translational modifications: N-glycosylation at positions Asn-181 and Asn-197, addition of glycosylphosphatidylinositol to Ser-230, and formation of a disulfide bond between Cys-179 and Cys-214. The amino acid residues involved in all of these post-translational modifications are highly conserved among mammals.

The spatial structure of PrP includes an unstructured N-terminal region (aa 23-125 in humans) and a globular domain (aa 126-231), consisting of three α-helices and a double-stranded antiparallel β-sheet.

Several topological forms of PrP are known in relation to the membrane: two transmembrane and one anchored on the membrane by a glycolipid anchor.

PrP is formed in the ER and further matured in the Golgi complex, from where it is delivered to the plasma membrane using membrane vesicles. After this, it is either anchored on the membrane after the destruction of the endosome, or undergoes endocytosis and is destroyed in lysosomes.

Unlike the normal, soluble form of the protein, prions are sedimented by high-speed centrifugation, which is the standard test for the presence of prions. PrP has a high affinity for cuprous cations. The significance of this fact is unclear, but it may have something to do with its structure or function. There is evidence that PrP plays an important role in cell attachment and the transmission of intracellular signals, and therefore may be involved in the communication of brain cells. However, the functions of PrP are not well understood.

PrP

The infectious isoform of PrP - PrP - is capable of converting the normal PrP protein into the infectious isoform by changing its conformation (i.e., tertiary structure); this in turn alters PrP's interactions with other proteins. Although the exact spatial structure of PrP is unknown, it has been established that it is dominated by β-sheets instead of α-helices. These abnormal isoforms aggregate into highly structured amyloid fibers, which accumulate to form plaques. It is unclear whether these formations are the cause of cell damage or just a byproduct of a pathological process. The end of each fiber serves as a kind of seed to which free protein molecules can attach, causing the fibril to grow. In most cases, only PrP molecules that are identical in the primary structure of PrP can attach (therefore, prion transmission is usually species specific). However, cases of interspecies transmission of prions are also possible.

Mechanism of prion reproduction

The first hypothesis explaining the reproduction of prions without the participation of other molecules, in particular nucleic acids, was heterodimeric model. According to this hypothesis, one PrP molecule binds to one PrP molecule and catalyzes its transition to the prion form. The two PrP molecules then separate and continue to convert other PrPs into PrPs. However, the prion propagation (replication) model must explain not only the mechanism of prion propagation, but also why the spontaneous appearance of prions is so rare. Manfred Eigen (lat. Manfred Eigen) showed that the heterodimeric model requires PrP to be a fantastically efficient catalyst: it must increase the frequency of a normal protein converting to the prion form by 10-fold. This problem does not arise if we assume that PrP exists only in an aggregated (for example, amyloid) form, where cooperativity acts as a barrier to spontaneous transition to the prion form. In addition, despite efforts, it was not possible to isolate monomeric PrP.

Alternative fibrillar model suggests that PrP exists only as fibrils, with the ends of the fibrils binding PrP, where it is converted to PrP. If this were the case, then the number of prions would increase linearly. However, as prion disease progresses, there is an exponential increase in the amount of PrP and the total concentration of infectious particles. This can be explained by taking fibril fracture into account. In the body, the breaking of fibrils is carried out by chaperone proteins, which usually help clear the cell of aggregated proteins.

The growth rate of the number of infectious prion particles is largely determined by the square root of the PrP concentration. The length of the incubation period is determined by the growth rate, and this is confirmed by research in vivo on transgenic mice. The same fundamental dependence is observed in experiments with various amyloid proteins in vitro.

The mechanism of prion replication has implications for drug development. Since the incubation period of prion diseases is extremely long, an effective drug does not need to destroy all prions, it is enough just to reduce the rate of exponential growth in their number. Modeling predicts that the most effective drug would be one that binds to the ends of fibrils and blocks their growth.

Functions of PrP

One explanation for prion-induced neurodegeneration may be disruption of PrP function. However, the normal function of this protein is poorly understood. Data in vitro indicate many different roles, and experiments on mice knocked out for this gene provided relatively little information, since these animals showed only small deviations from the norm. Recent studies in mice have shown that cleavage of PrP in peripheral nerves activates the repair of their myelin layer by Schwann cells and that the absence of PrP leads to demyelination of the nerves.

In 2005, it was suggested that PrP normally plays a role in maintaining long-term memory. In addition, in mice lacking the gene Prnp, altered hippocampal long-term potentiation is observed.

In 2006, scientists from the Whitehead Institute for Biomedical Research showed that gene expression Prnp in hematopoietic stem cells is necessary for self-maintenance of the bone marrow. The study found that long-lived hematopoietic stem cells carry PrP on the cell membrane, and hematopoietic tissues with stem cells lacking PrP have greater sensitivity to cellular depletion.

Hypotheses about the composition of prions

According to the most established point of view, prions are purely protein infectious agents. However, this hypothesis ( "pure protein" hypotheses) have their drawbacks, and therefore alternative opinions about the essence of prions have appeared. All of the above hypotheses are discussed below.

"Pure protein" hypothesis

Before the discovery of prions, it was believed that all infectious agents use nucleic acids for reproduction. The "pure protein" hypothesis postulates that a protein structure can multiply without the participation of nucleic acids. This hypothesis was initially thought to contradict the central dogma of molecular biology that nucleic acids are the only means of transmitting hereditary information, but it is now believed that although prions are capable of transmitting information without the participation of nucleic acids, they are unable to transmit information to nucleic acids.

Evidence supporting the “pure protein” hypothesis:

• Prion diseases could not be reliably associated with either viral, bacterial or fungal pathogens, although in yeast Saccharomyces cerevisiae non-lethal prions are known, for example, Sup35p (see fungal prions);
• prion infectivity is not known to be associated with nucleic acids; prions are resistant to nucleases and ultraviolet radiation, which have a detrimental effect on nucleic acids;
• prions do not cause an immune response;
• in an organism infected with a prion from another species, PrP with the amino acid sequence of the prion of the donor species is not detected. Consequently, replication of the donor prion does not occur;
• In families with a mutation of the PrP gene, hereditary prion diseases occur. Mice with a mutation of this gene also develop prion disease, despite strict control of housing conditions to exclude infection from the outside;
• animals that do not have the PrP protein are not susceptible to prion diseases.

Multicomponent hypothesis

The low infectivity of prions obtained from pure protein in vitro has led to the emergence of the so-called multicomponent hypothesis, which postulates that other cofactor molecules are required for the formation of an infectious prion.

In 2007, biochemist Surachai Supattapone and his colleagues at Dartmouth College obtained purified infectious prions from PrP, a copurifying lipid protein, and a synthetic polyanionic molecule. They also showed that the polyanionic molecule required for prion formation had a high affinity for PrP and formed complexes with it. This gave them reason to assume that the infectious prion contains not only protein, but also other molecules of the body, including lipids and polyanionic molecules.

In 2010, Jiyan Ma and colleagues from Ohio State University obtained an infectious prion from recombinant PrP, phospholipid POPG and RNA synthesized by bacterial cells, which also confirms the multicomponent hypothesis. In contrast, in other experiments only weakly infective prions could be obtained from recombinant PrP alone.

In 2012, Supattapone and colleagues isolated a membrane lipid phosphatidylethanolamine as an endogenous cofactor that is capable of catalyzing the formation of a large number of recombinant prions of various strains without the participation of other molecules. They also reported that this cofactor is required to maintain the infectious conformation of PrP and also determines the strain properties of infectious prions.

Viral hypothesis

The "pure protein" hypothesis has faced criticism from those who believe that the simplest explanation for prion diseases is their viral nature. For more than ten years, Yale University neurohistologist Laura Manuelides Laura Manuelidis) is trying to prove that prion diseases are caused by an unknown slow virus. In January 2007, she and her colleagues reported that they had found the virus in 10% (or less) of scrapie-infected cells in culture.

The viral hypothesis states that TSEs are caused by replication-competent messenger molecules (most likely nucleic acids) binding to PrP. There are known strains of prions associated with TSE, including bovine spongiform encephalopathy and scrapie, which are characterized by specific biological properties, which, according to supporters of the viral hypothesis, cannot be explained by the “pure protein” hypothesis.

Arguments in favor of the viral hypothesis:

• Variation between strains: prions vary in infectivity, incubation period, symptoms and rate of disease progression, reminiscent of differences between viruses, especially RNA viruses(viruses containing RNA as the only hereditary material);
• The long incubation period and rapid development of symptoms of prion diseases resemble lentiviral infection. For example, HIV-induced AIDS proceeds in a similar way;
• In some cells of lines infected with scrapie or Creutzfeldt-Jakob disease, virus-like particles not consisting of PrP were found.

Recent studies of the spread of bovine spongiform encephalopathy in cage-free systems and in chemical reactions with purified components clearly argue against the viral nature of this disease. In addition, the above-mentioned work by Jiyan Ma speaks against the viral hypothesis.

Prion diseases

Prions cause neurodegenerative diseases because they form extracellular aggregates in the central nervous system and form amyloid plaques that destroy normal tissue structure. The destruction is characterized by the formation of "holes" (cavities) in the tissue, and the tissue takes on a spongy structure due to the formation of vacuoles in neurons. Other histological changes observed in this case are astrogliosis (an increase in the number of astrocytes due to the destruction of nearby neurons) and the absence of inflammatory reactions. Although the incubation period for prion diseases is typically very long, once symptoms appear, the disease progresses rapidly, leading to brain destruction and death. The resulting neurodegenerative symptoms may include convulsions, dementia, ataxia (disorder of motor coordination), behavioral and personality changes.

All known prion diseases, collectively known as transmissible spongiform encephalopathies (TSEs), are incurable and fatal. A special vaccine has been developed for mice; perhaps this will help develop a vaccine against prion diseases for humans. In addition, in 2006, scientists announced that using genetic engineering they had obtained a cow that lacked the gene necessary for the formation of prions, that is, theoretically, it is immune to TSE. This conclusion is based on the study that mice lacking the normal form of prion protein were resistant to scrapie prion.

Prions affect many different mammalian species, and the PrP protein is very similar in all mammals. Because of the slight differences between PrPs among different species, transmission from one species to another is unusual for prion disease. However, a variant of human prion disease (Creutzfeldt-Jakob disease) is caused by a prion that usually affects cows and causes bovine spongiform encephalopathy, which is transmitted through contaminated meat.

Ways of occurrence

It is believed that prion disease can be acquired in 3 ways: through direct infection, hereditary or sporadic (spontaneous) infection. In some cases, a combination of these factors is required for the disease to develop. For example, for scrapie to develop, both infection and genotype-specific sensitivity are necessary. In most cases, prion diseases occur spontaneously for unknown reasons. Hereditary diseases account for about 15% of all cases. Finally, a minority are the result of environmental action, that is, they are iatrogenic in nature or result from prion infection.

Spontaneous occurrence

Sporadic (that is, spontaneous) prion disease occurs in a population in a random individual. This is, for example, the classic version of Creutzfeldt-Jakob disease. There are two main hypotheses regarding the spontaneous occurrence of prion diseases. According to the first of them, a spontaneous change occurs in the hitherto normal protein in the brain, that is, a post-translational modification takes place. An alternative hypothesis is that one or more cells in the body at some point undergo a somatic mutation (that is, not inherited) and begin to produce the defective PrP protein. Be that as it may, the specific mechanism for the spontaneous occurrence of prion diseases is unknown.

Heredity

Main article: PRNP

The gene encoding the normal PrP protein, PRNP, localized on chromosome 20, was identified. In all hereditary prion diseases, a mutation of this gene occurs. Many different mutations (about 30) of this gene have been isolated, and the resulting mutant proteins are more likely to fold into an abnormal (prion) form. All such mutations are inherited in an autosomal dominant manner. This discovery showed a hole in the general theory of prions, which states that prions can convert only proteins of identical amino acid composition into the prion form. Mutations can occur throughout the gene. Some mutations lead to stretching of the octapeptide repeats at the N-terminus of the PrP protein. Other mutations leading to hereditary prion disease can occur at positions 102, 117 and 198 (Gerstmann-Straussler-Scheinker syndrome), 178, 200, 210 and 232 (Creutzfeldt-Jakob disease) and 178 (fatal familial insomnia).

Infection

According to modern research, the main way to acquire prion diseases is through eating contaminated food. It is believed that prions can remain in the environment in the remains of dead animals, and are also present in urine, saliva and other body fluids and tissues. Because of this, infection with prions can also occur during the use of unsterile surgical instruments (for more information, see the “Sterilization” section). They can also persist in the soil for a long time by binding to clay and other soil minerals.

A team of researchers from the University of California, led by Nobel laureate Stanley Prusiner, proved that prion infection can develop from prions contained in manure. And since manure is present around many bodies of water and on pastures, this provides an opportunity for prion diseases to spread widely. In 2011, the discovery of prions transmitted through the air in aerosol particles (i.e., airborne droplets) was reported. This discovery was made during an experiment on mice infected with scrapie. Also in 2011, preliminary evidence was published that prions can be transmitted by urine-derived human menopausal gonadotropin, used to treat infertility.

Sterilization

The propagation of infectious agents containing nucleic acids depends on nucleic acids. However, prions increase their numbers by changing the structure of the normal form of the protein to a prion form. Therefore, sterilization against prions must involve denaturing them to a state in which they are unable to change the configuration of other proteins. Prions are generally resistant to proteases, heat, radiation, and formalin storage, although these measures reduce their infectivity. Effective disinfection against prions must include hydrolysis of prions or damage/destruction of their tertiary structure. This can be achieved by treating with bleach, sodium hydroxide and strongly acidic detergents. Spending 18 minutes at 134°C in a sealed steam autoclave will not deactivate prions. Ozone sterilization is currently being studied as a potential method for deactivating and denaturing prions. Renaturation of a completely denatured prion to an infectious state has not been recorded, but for partially denatured prions under some artificial conditions this is possible.

Prions and heavy metals

Recent studies suggest that abnormal heavy metal metabolism in the brain plays an important role in PrP-associated neurotoxicity, although it is difficult to explain the mechanism behind this with the information available to date. There are hypotheses that explain this phenomenon by the fact that PrP plays some role in the metabolism of metals, and its disruption due to the aggregation of this protein (in the form of PrP) into fibrils causes an imbalance in the metabolism of heavy metals in the brain. According to another point of view, the toxicity of PrP is enhanced by the inclusion of PrP-bound metals in aggregates, which leads to the formation of PrP complexes with redox activity. The physiological significance of some PrP metal complexes is known, but that of others is not. The pathological effects of PrP-bound metals include metal-induced oxidative damage and, in some cases, conversion of PrP to a PrP-like form.

Potential Treatment and Diagnosis

Thanks to computer modeling, scientists were able to find compounds that could be a cure for prion diseases. For example, one compound could bind to a groove in PrP and stabilize its structure, reducing the amount of harmful PrP.

Recently, antiprion antibodies have been described that can cross the blood-brain barrier and act on cytosolic prions.

In the last decade, some progress has been made in inactivating prion infectivity in meat using ultrahigh pressure.

In 2011, it was discovered that prions can be decomposed by lichens.

The problem of diagnosing prion diseases, in particular bovine spongiform encephalopathy and Creutzfeldt-Jakob disease, is of great practical importance. Their incubation period ranges from months to decades, during which time the individual does not experience any symptoms, even though the process of converting normal brain PrP proteins into PrP prions has already begun. Currently, there is virtually no way to detect PrP other than by testing brain tissue with neuropathological and immunohistochemical methods after death. A characteristic feature of prion diseases is the accumulation of the prion form of the PrP protein, but it is found in very low concentrations in readily available body fluids and tissues, such as blood and urine. Researchers have tried to develop a method for measuring the proportion of PrP, but there are still no fully accepted methods for using materials such as blood for this purpose.

In 2010, a group of researchers from New York described a way to detect PrP even when its proportion in brain tissue is equal to one in a hundred billion (10). This method combines amplification with a new technology called Surround Optical Fiber Immunoassay (SOFIA) and some specific antibodies against PrP. After amplification to concentrate all PrP possibly contained in the sample, the sample is labeled with a fluorescent dye with antibodies for specificity and finally loaded into a microcapillary tube. Then this tube is placed in a special apparatus so that it is completely surrounded by optical fibers and all the light emitted onto the tube is absorbed by the dye, previously excited by the laser. This technique makes it possible to detect PrP even after a small number of cycles of transition to the prion form, which, firstly, reduces the possibility of distorting the result by experimental artifacts, and, secondly, speeds up the procedure. The researchers used this technique to test the blood of apparently healthy sheep that were actually infected with scrapie. When the disease became apparent, their brains were also examined. Thus, the researchers were able to compare blood and brain tissue tests from animals with symptoms of the disease, those with latent disease, and those not infected. The results clearly showed that the above technique makes it possible to detect PrP in the body long before the first symptoms appear.

Antiprion activity was found in astemizole.

Fungal prions

Main article: Fungal prions

Proteins capable of transmitting their conformation by inheritance, that is, non-Mendelian heredity, were discovered in yeast Saccharomyces cerevisiae Reed Wickner Reed Wickner) in the early 1990s. Because of their similarity to mammalian prions, these alternative heritable protein conformations were called yeast prions. Later, prions were discovered in the fungus Podospora anserina.

Susan Lindquist Group Susan Lindquist) from the Whitehead Institute showed that some fungal prions are not associated with any disease state but may play a beneficial role. However, NIH researchers have provided evidence that fungal prions may reduce cell viability. Therefore, the question of whether fungal prions are pathogenic agents or whether they play some beneficial role remains unresolved.

As of 2012, 11-12 prions are known in fungi, including: seven in Saccharomyces cerevisiae( (see illustration). Such cells have an altered physiological state and an altered level of expression of some genes, which led to the hypothesis that in yeast the formation of prions may play an adaptive role.

The article on the discovery of the Mca1 prion was subsequently rejected because the experimental results could not be reproduced. Notably, most fungal prions are based on glutamine/asparagine-rich repeats, with Mod5 and HET-s being exceptions.

Studies of fungal prions strongly support the “pure protein” hypothesis, as purified proteins isolated from cells with proteins in prion form demonstrated the ability to rearrange proteins of normal form into prion form in vitro, and at the same time the properties of this prion strain are preserved. Some light was also shed on prion domains, that is, protein domains that change the conformation of another protein into a prion one. Fungal prions have helped to introduce a possible mechanism of transition from the normal form to the prion form, which applies to all prions, although fungal prions differ from infectious mammalian prions in the absence of a cofactor necessary for reproduction. Features of the prion domain may vary among species. For example, the properties inherent in the prion domains of fungal prions are not found in mammalian prions.

As mentioned above, fungal prions, unlike mammalian prions, are passed on to the next generation. In other words, mushrooms have a mechanism prion (protein) inheritance, which can serve as a striking example of true cytoplasmic inheritance.

" - unconfirmed discovery.

Prions must be understood as a special class of infectious proteins with an abnormal tertiary structure, devoid of nucleic acids.

Prions cannot be classified as living microorganisms, but their reproduction occurs due to the functions of living cells. Prions are protein molecules with an abnormal three-dimensional structure that have the ability to accelerate the transformation of normal proteins and convert them into similar ones. In most cases, at the moment of transition of proteins from the normal form to the prion form, α-helices begin to transform into β-sheets. This makes it possible for the resulting infectious agents to rearrange new protein molecules, resulting in the launch of a chain reaction due to which a huge number of incorrectly folded molecules are formed.

These infectious agents can exist in several forms - strains, the structure of each is slightly different.

The proteins that make up prions (PrP) can be found in all organs and systems of humans and mammals. But in the affected tissues one can find PrP with an abnormal structure, which is also resistant to proteases (enzymes that hydrolyze proteins).

The normal three-dimensional form of the protein is called PrPC, and the abnormal infectious form is called PrPSc. If we talk about the infectious isoform of PrP - PrPSс, then it has the ability to convert the normal PrPС protein into an infectious isoform, that is, replace its three-dimensional structure, which affects the further relationship of PrP with other proteins.

Information on the physicochemical properties of prions

Prions are characterized by a fairly high level of resistance to chemical and physical factors. Prions are unchanged at high temperatures (90 °C). Their molecules are hydrophobic (they are afraid of contact with water). Infectious forms of prions (PrPSс) are resistant to many physical factors and reagents, such as ultraviolet irradiation and ionizing radiation, nucleases, organic solvents, aldehydes, ionic and nonionic detergents.

Prion diseases: classification

Prions can cause various pathologies in animals (mad cow disease, transmissible spongiform encephalopathy). In humans, these infectious agents can cause the following conditions:

• kuru disease;
• amyotrophic leukospongiosis;
• fatal familial insomnia;
• Gerstmann-Straussler-Scheinker syndrome;
• Creutzfeldt-Jakob disease.

As for the incubation period for prion diseases, it varies from several months to 15-30 years.

All of the diseases listed above affect the brain, central nervous system, and today are incurable, which always ends in death.

Prions can cause neurodegenerative diseases; this is a consequence of the formation and accumulation of amyloid plaques in the central nervous system, which contribute to the destruction of normal tissue structure. Destruction means the formation of cavities in tissues, as a result of which their structure becomes spongy.

It is generally accepted that prion diseases can be acquired in 3 ways:

• Spontaneously;
• By direct infection;
• Hereditary.

In some cases, a complex combination of these factors is necessary for the occurrence of the disease. But, as a rule, all of the above prion diseases arise sporadically for unknown reasons. If we talk about hereditary factors of morbidity, then this option accounts for about 15% of all known cases. Prion infection can occur in the following cases:

• ingestion of poorly thermally processed food of animal origin, for example: meat, brains of cows that suffer from spongiform encephalopathy;
• during surgical interventions - cornea transplantation, blood transfusion, taking dietary supplements and hormones of animal origin, using contaminated or poorly sterilized surgical instruments or catgut;
• hyperproduction of RgR and other conditions during which the process of transition of RgR to RgR is stimulated.

According to recent studies, the main route of infection is consumption of contaminated food. It is known that prions thrive in the tissues and organs of dead animals (saliva, urine and other liquids).

Prions are found in the environment, so infection can occur spontaneously through the use of poorly treated or unsterile surgical instruments. They are perfectly preserved in the soil due to the fact that they easily bind to most soil minerals.

How to diagnose prion diseases?

To date, no methods have been developed to accurately diagnose prion infections. There are only the following methods:

• Electroencephalogram (EEG);
• Molecular genetic research (immunoblotting method using MKA-15VZ monoclonal antibodies, which can be used to recognize PrPSc and PrPc).

• MRI (with its help you can detect brain atrophy).
• CSF examination (test for neurospecific protein 14-3-3 in spontaneous cases of Creutzfeldt-Jakob disease).

• Polymerase chain reaction (PCR) methods.
• immunological examination (identification of prions using the immunoblotting method in peripheral lymphocytes).
• Study of autopsy material (detection of Status spongiosis, signs of cerebral amyloidosis, formation of amyloid plaques).

When diagnosing prion infections, it is necessary to differentiate them from all pathologies, the characteristic feature of which is acquired dementia, for example, neurosyphilis, Parkinson's and Alzheimer's disease, vasculitis, streptococcal meningitis, herpetic encephalitis, myoclonus epilepsy, etc.)

Information about the treatment of prion diseases

Today, thanks to computer technology, scientists have been able to find substances that can become a cure for neurodegenerative pathologies characterized by slowly progressive brain damage with a fatal outcome.

Several years ago it was discovered that prions have the ability to decompose when exposed to lichens. The problem of studying diseases such as spongiform encephalopathy and Creutzfeldt disease is of great importance. The danger of these diseases is that it can take from a month to 10-12 years before the first symptoms appear. At the moment, there is practically no way to determine an infectious lesion during life. The only optimal way is to study brain tissue after the patient's death.

Scientists have tried to develop research methods in which it would be possible to use urine or blood for analysis. But, unfortunately, the developments have not yet been successful.

To date, all known diseases caused by an infectious prion protein are incurable, but treatment methods are actively discussed throughout the world. In spongiform encephalopathies, there is no immune response to prion infection, this is the result of the fact that the normal form of the PrP protein is always present in the human body.

Patients with clinical symptoms of prion infections are disabled. All pathologies are characterized by an unfavorable prognosis; the disease always ends in death for the patient.

The article was prepared by doctor Tyutyunnik D.M.

Prions (English prion from protein - “protein” and infection - “infection”).

The term was proposed by the person who laid out the foundations of modern knowledge about these proteins - Stanley Prusiner in 1982.

Now we know that these are pathological proteins that cause a number of encephalopathies in humans (Creutzfeldt disease - Jacobus syndrome Gerstmann - Straussler - Schenker, fatal familial insomnia, Kuru, etc.), livestock (mad cow disease, scrapie in sheep) and birds. Type of transmission, pathogenesis, etc. in these diseases it is not similar to viruses or bacteria. But first things first.

Story

The first disease from the list of prion diseases described by humans is scrapie - sheep scabies. In 1700, in England (the country with the largest population of domestic sheep at that time), the following symptoms were described - severe itching, pain in the limbs when moving, and convulsive seizures. The disease progressed within a week. Outbreaks occurred in different counties. Veterinarians and doctors shrugged their shoulders, not knowing the source of the disease. All symptoms pointed to brain damage.

By the 20th century, no new data had been added about what kind of disease affected the poor sheep. And so, in the 1920s, Hans Gerhard Creutzfeldt and Alfons Maria Jacob separately (both in 1920, but Creutzfeldt earlier) described an incurable lesion of the human nervous system, which was later named after them.

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The pathological picture was described (focal lesions of brain tissue). A first attempt was made to classify symptoms. The definition of the disease was “spastic pseudosclerosis or encephalopathy with scattered foci in the anterior horns of the spinal cord, extrapyramidal and pyramidal system.”

Histological specimen of the brain showing microcavities

Hans Gerhard Creutzfeldt, as a German neurologist, had his ties to Nazism. Not being a party member, he acted as a medical expert on issues of heredity, that is, he resolved issues of forced sterilization and euthanasia.

There are different versions about his activities in this area. Some write that Creutzfeldt saved people from these procedures by concealing pathologies and correcting medical histories, others that the doctor was still involved in sending people to death camps and to the Kiel clinic (where “euthanasia” was carried out).

In any case, the British occupation authorities found no traces of crime in his case and the 60-year-old doctor continued his activities in Munich.

The history of prion diseases developed further. In 1957, Carlton Gajdushek and Vincent Zigas discovered a disease similar in clinical picture to Creutzfeldt-Jakob disease (the disease now bore the names of these two doctors). If the disease discovered in the 20s affected residents of Western Europe, then the new one affected representatives of one tribe in New Zealand.

It was suggested that this pathology is caused by a virus. The clinical picture, characterized by tremor, convulsions, and headache, was studied.

Based on the fact that neighboring tribes did not practice cannibalism and brain eating and did not suffer from similar pathologies, theories began to appear that the virus was located in brain tissue and could be transmitted through nutrition.

In 1967, the first successful experiment was carried out with the infection of experimental mice with the biological fluids of sheep infected with scrapie. The result was positive. The mice developed the same symptoms as the “donors.” The evidence for the contagiousness of the disease has increased.

Interestingly, in 1976, Gaidushek was awarded the Nobel Prize for discoveries concerning new mechanisms of the origin and spread of infectious diseases associated with the study of the Fore tribe disease. Until the end of his life, he was sure that it was caused by viruses.

As mentioned above, the foundations of knowledge about prions were laid by Stanley Prusiner.

A little from his biography. Born in the USA in 1942. His ancestors are emigrants from the Russian Empire, of Jewish origin, forced to leave the country due to Jewish pogroms.

Stanley Prusiner himself graduated from the University of Pennsylvania in 1968 and worked as a neurology resident at the University of California School of Medicine (San Francisco).
In 1970, he first encountered Creutzfeldt-Jakob disease.

The patient who was being treated by Prusiner had no pathogen detected.

Having become closely involved in this research, the neurologist turned to the works of another doctor, Siggurdson, who identified certain patterns in diseases that were incomprehensible at that time. These patterns became:

- unusually long (months and years) incubation period;

- slowly progressive nature of the course;

- unusual damage to organs and tissues;

- inevitability of death.

The diseases known at that time that met these criteria were Creutzfeldt-Jakob disease, Kuru in humans and scrapie, which began to affect not only sheep, but also goats.

It was from biological fluids (cerebrospinal fluid, urine, seminal fluid, saliva) of sheep suffering from frequent diseases that preparations for infection and further research were prepared.

Experiments were carried out on mice. It was found that the incubation period lasts 100-200 days. The disease develops in all experimental mice.

Progress was made after the appearance of hamsters in the laboratory. Their incubation period was much shorter, but the clinical manifestations were still the same.

So, after 10 (!) years of painstaking work on infection, slaughter of animals, cleaning and examination of the material, a pathogenic object was identified. Experiments strongly suggested that it consisted of a single protein, which Prusiner called a prion.

Despite the enormous evidence base collected over years of research, the theory has not received universal acceptance. Most virologists of that time (and it was already 1982) treated the statement with distrust.

The main reason for this was the pathogen’s lack of its own genotype. There were only amino acids, no nucleic acids.
Without losing his inspiration, Siggurdson continued to study the strange agent. Its amino acid sequence was revealed. Further, the production of antibodies to the prion protein made it possible to determine its localization in the cell membrane.

The scientist's career was going well. In 1980 he became a professor of neurology and in 1988 a professor of biochemistry.
In 1982, he published a scientific paper on a completely new type of pathogen.

The doctor and scientist received universal recognition in the 90s. In 1997, he received the Nobel Prize for his discovery of prions, a new biological principle of infection.

Another reason for the increasing interest in this pathology is the epidemic of mad cow disease, or bovine spongiform encephalopathy, that swept the UK (there were 179 thousand heads of cattle with symptoms of the disease).

What are prions and what is their mechanism of action on the body (modern ideas)?

In fact, the human body and many other living things contain PrP C proteins. In Russian - the normal form of prion proteins (they were discovered after Siggurdson’s research, which is why the name is so strange). Its length, amino acid sequence, and secondary structure are known. It is important to know that the final structure consists of three α-helices and a double-stranded antiparallel β-sheet.

They have an interesting property, namely they are precipitated by high-speed centrifugation, which is a standard test for the presence of prions. There is evidence that PrP plays an important role in cell attachment and the transmission of intracellular signals, and therefore may be involved in the communication of brain cells. However, the functions of PrP are not well understood.

(a) normal (b) pathology

Experiments in mice lacking these proteins show that the absence of PrP leads to nerve demyelination. It is possible that prion proteins normally support long-term memory.

But this is normal.

Sometimes “problems” happen and proteins called PrP Sc (infectious prions) appear. They differ in that instead of α-helices, β-sheets predominate in them.

This leads to changes in the interaction of other proteins with the new protein.
It wouldn’t be so bad if only one protein was produced per body. The trouble is that, once formed, the protein (!) itself begins to change the structure of others.
Let's consider the main mechanisms of reproduction of PrP Sc

To begin with, the mechanisms of their appearance in the body

It is believed that prion disease can be acquired in 3 ways: through direct infection, hereditary or sporadic (spontaneous) or combinations thereof.

Sporadic (i.e. spontaneous) prion disease occurs in a population in a random individual. This is, for example, the classic version of Creutzfeldt-Jakob disease. There are two main hypotheses regarding the spontaneous occurrence of prion diseases. According to the first of them, a spontaneous change occurs in the hitherto normal protein in the brain, that is, a post-translational modification takes place. An alternative hypothesis states that one or more cells in the body at some point undergo a somatic mutation (that is, not inherited) and begin to produce the defective PrP Sc protein. Be that as it may, the specific mechanism for the spontaneous occurrence of prion diseases is unknown.

The second is infection.. According to modern research, the main way to acquire prion diseases is through eating contaminated food. It is believed that prions can remain in the environment in the remains of dead animals, and are also present in urine, saliva and other body fluids and tissues (blood, cerebrospinal fluid). Because of this, infection with prions can also occur during the use of unsterile surgical instruments. This makes it difficult to sterilize surgical instruments or devices in the slaughterhouse. Prions are generally resistant to proteases, heat, radiation, and storage in formalin, although these measures reduce their ability to become infected.

Effective disinfection against prions must involve hydrolysis or damage/destruction of their tertiary structure. This can be achieved by treating with bleach, sodium hydroxide and strongly acidic detergents. Spending 18 minutes at 134°C in a sealed steam autoclave will not deactivate prions.

Ozone sterilization is currently being studied as the main modern method for deactivating and denaturing prions. Renaturation of a completely denatured prion to an infectious state has not been recorded, but for partially denatured prions under some artificial conditions this is possible.

It is also worth remembering that these proteins can remain in the soil for a long time due to binding to clay and other soil minerals. Don't get paranoid, but theoretically they could be everywhere.

In 2011, the discovery of prions transmitted through the air in aerosol particles (i.e., airborne droplets) was reported. Also in 2011, preliminary evidence was published that prions can be transmitted by urine-derived human menopausal gonadotropin, used to treat infertility.

Theoretically, with just one sick animal with prion disease, it is possible to destroy entire nations and countries by simply adding its bone meal to feed additives and selling them to the desired state.
A similar situation occurred in the late 80s in Britain (mad cow disease epidemic). Then, most likely out of ignorance (and not out of malicious intent), the above process occurred, which claimed the lives of about 200 people (as of 2009) and 179 thousand heads of cattle.

Prion propagation

The third mechanism is genetic. It was opened recently and does not fit into the overall picture at all. The gene encoding the normal PrP protein, PRNP, localized on chromosome 20, was identified. In all hereditary prion diseases, a mutation of this gene occurs.

A “distorted” prion protein that has entered in one way or another begins to change the structures of proteins close to it in structure, turning them into the same pathogenic agents.

The main hypothesis that most closely reflects this process is very simple. One PrP Sc molecule attaches to one PrP C molecule and catalyzes its transition to the prion form. The two PrP Sc molecules then separate and continue to convert other PrP Sc into PrP Sc.

But the scheme raises more questions than answers.

Clinic

Let's talk about diseases and clinical manifestations.

Theoretically, it can occur in all living beings that have PrP c

Here are some examples.

In sheep and goats, as mentioned above, the main manifestation is scrapie.

Cows are characterized by mad cow disease (bovine spongiform encephalopathy).

In minks - Transmissible mink encephalopathy. And so on.

Manifestations of diseases have been recorded in cats, wild artiodactyls, and ostriches.

But we are interested in human diseases.

Creutzfeldt-Jakob disease. ICD-10 code A81.0; F02.1.
Code A corresponds to infectious diseases (A81 - infectious diseases of the nervous system).

Code F – mental disorders, F02 – dementia.

Dark green spread K-Y Light green - mad cow disease

Basic clinical criteria for diagnosis

• rapidly progressing - over 2 years - (“devastating”) dementia with disintegration of all higher cortical functions; pyramidal disorders (spastic paresis);
• extrapyramidal disorders (choreoathetosis);
• myoclonus;
• ataxia, akinetic mutism;
• dysarthria;
• epileptic seizures;
• visual disturbances (diplopia)

Stages of the disease:

1. Prodromal period- symptoms are nonspecific and occur in approximately 30% of patients. They appear weeks and months before the onset of the first signs of dementia and include asthenia, disturbances in sleep and appetite, attention, memory and thinking, weight loss, loss of libido, and changes in behavior.
2. Initial period- The first signs of the disease are usually characterized by visual disturbances, headaches, dizziness, unsteadiness and paresthesia. In the majority of patients, it gradually develops, less often - an acute or subacute onset. In some cases, as in the so-called amyotrophic forms, neurological signs may precede the onset of dementia.
3. Expanded period- There is usually progressive spastic paralysis of the limbs with accompanying extrapyramidal signs, tremor, rigidity and characteristic movements. In other cases, there may be ataxia, decreased vision, or muscle fibrillation and upper motor neuron atrophy.

There are several clinical forms:

Spontaneous - classical (sCJD)

According to modern concepts (prion theory), prions in this form of the disease arise spontaneously in the brain, without any visible external cause. The disease usually affects people over the age of 50 and occurs with a probability of 1-2 cases per million inhabitants. Initially, it manifests itself in the form of brief memory loss, mood changes, and loss of interest in what is happening around. Further, the symptoms of dementia progress with all the ensuing consequences.

Hereditary (fCJD)

The disease occurs in families where damage to the gene for the prion protein is inherited. A defective prion protein is much more susceptible to spontaneous conversion into a prion. The signs and course of the disease are similar to the classical form.

Iatrogenic (1CJD)

The disease is caused by the unintentional introduction of prions into the patient's body during medical intervention. The source of prions used to be certain drugs, instruments or meninges that were taken from dead people and used to close the wound during brain surgery. The signs and course of the disease are similar to the classical form.

New option (nvCJD)

The disease first appeared in 1995 in the UK and since then no more than 100 people have died from it. Most likely, they became infected with meat products containing bovine prions.

• mental disorders and sensory impairments,
• Global cognitive impairment and ataxia are characteristic.
• Several cases of the disease that began with cortical blindness (Heidenhain variant) have been described.
• The episyndrome is also represented by myoclonic seizures.
• cerebellar symptoms are detected in 100%.

The main diagnostic method is intravital brain biopsy. MRI and PET methods are also used. There are pathognomonic symptoms of electroencephalography.

Gerstmann-Straussler-Scheinker syndrome is a rare, usually familial, fatal neurodegenerative disease that affects patients between 20 and 60 years of age. Code A81.9. Nine here means “Slow viral infections of the central nervous system, unspecified.”

The syndrome occurs in people aged 40-50 years and is characterized mainly by cerebellar ataxia, swallowing and phonation disorders, progressive dementia over 6 to 10 years (the average duration of the disease is 59.5 months), after which death occurs. The incubation period lasts from 5 to 30 years.

Little studied. Research is being conducted on laboratory mice and hamsters.

Fatal familial insomnia - a rare incurable hereditary (dominantly inherited prion) disease in which the patient dies from insomnia. Only 40 families are known to be affected by this disease.

The ICD code is the same as the previous one.

The disease begins between the ages of 30 and 60, with an average of 50. The disease lasts from 7 to 36 months, after which the patient dies.

There are 4 stages of disease development.

• The patient suffers from increasingly severe insomnia, panic attacks and phobias. This stage lasts on average 4 months.
• Panic attacks become a serious problem, and hallucinations join them. This stage lasts on average 5 months.
• Complete inability to sleep, accompanied by rapid weight loss. This stage lasts on average 3 months.
• The patient stops speaking and does not react to his surroundings. This is the last stage of the disease, lasting on average 6 months, after which the patient dies.

Sleeping pills don't help. At all.

Kuru, almost never occurs nowadays, due to the eradication of cannibalism.

Interestingly, in 2009, American scientists made an unexpected discovery: some members of the Fore tribe, thanks to a new polymorphism of the PRNP gene that appeared in them relatively recently, have innate immunity to kuru.

Currently, there is not a single means of stopping or inhibiting the development of prion diseases.

There is a lot of research going on.
Main directions:

• Medicine – a drug that can cure or stop/slow down the progression of a disease
• Vaccine is a means to prevent disease
• Genetic engineering methods are also used to produce animals that are immune to prion diseases.

How changes in the genotype and protein composition will affect their life is still a mystery.

One of the greatest discoveries of geneticists turned out to be little noticed by the world press. The titanic work of the world's leading scientists to decipher the human genome has been completed - now we know the chemical structure of all our genes. But for some reason there was no sensation. It turned out that not all the information necessary for the normal growth and development of the human body is recorded in genes. Although about 100,000 genes have been deciphered, only one third actually “works” in the human body. Why this happens is still unknown, but it is well known that the chemical structure of genes encodes mainly the chemical structure of the proteins that make up our body. But where the information about the spatial organization of our body, the character and abilities of a person is recorded, science does not yet know. Scientists have once again become convinced that man's empirical, material knowledge of the Wisdom of God is an endless process.

One of the largest discoveries in biology of the 20th century is prions. The American biochemist Stanley Prusiner who discovered them was deservedly awarded the Nobel Prize in 1997. The fact is that protein molecules in living organisms have three levels of spatial structure. The first two are the primary and secondary helix, reminiscent of the double helix of an electric lamp. The tertiary structure is the most complex, outwardly reminiscent of a ball, volumetric spatial configuration of this two-level spiral. The most important functions performed by protein in a living cell and the body as a whole directly depend on the tertiary structure.

Mad cow disease. This disease affects the brain of cows, but can also be transmitted to humans through beef consumed as food. Infection is rare - but if it occurs, it is almost impossible to prevent death.

It must be said that such diseases - the so-called slow infections - have been known to doctors for quite some time (for a long time it was believed that they were caused by a certain “slow” virus, which was never isolated). These include kuru, familial fatal insomnia, and similar diseases in mammals. Their infectious nature was first established in 1957 for kuru, discovered by American virologist Daniel Carleton Gajdushek in New Guinea. This disease was common among the Fore tribe, whose traditions prescribed that sons eat the raw brains of their deceased parents. Gaidushek proved the connection between Kuru infection and ritual cannibalism and spent a lot of effort to eradicate this dangerous custom. The disease was defeated, and in 1976, Gajdushek, together with Baruch Blumberg, was awarded the Nobel Prize.

The mysterious agents of “slow infection” were discovered only in 1982 by the American biochemist Stanley Prusiner, and in 1997 his discovery was awarded the Nobel Prize.

This researcher proposed the term “prion” (from the English prion - protein infection) to designate the protein that causes a number of serious diseases. Prions are extremely unusual and in many ways still mysterious formations. The term “prion” itself is still unfamiliar even to many biologists, not to mention the general public. At the same time, the discovery of prions is, of course, one of the brightest achievements of molecular genetics of the last twenty years.

It is clear that the pathogenic agent must multiply, otherwise it does not pose a threat to the infected organism. Until now, science knew only one way to reproduce viruses and living organisms (from single-celled to higher animals) - through carriers of heredity, DNA and RNA molecules (deoxyribonucleic and ribonucleic acids).

Prions - not cells or viruses, but just special protein molecules - do not contain either DNA or RNA. However, once in a cell, prions are able to infect it and, in a certain sense, multiply in it.

Prusiner found out what the dense cords and plaques that form in the brain of an animal affected by prion disease are made of. It turned out that the molecules of one of the proteins exist in the cells of the nervous tissue in two forms - normal and “abnormal” (prion). Both types of protein have an identical sequence of amino acids, but their molecules differ in spatial packaging. And if a normal protein does not in any way interfere with the cell’s life (although it is still not entirely clear what its function is), then the “abnormal” protein (aka prion), once in the nervous tissue, forms insoluble aggregates.

But here’s the strangest thing: it turns out that normal protein molecules, as soon as they come into contact with prions, themselves turn into them and change their spatial structure! Only a small number of prionizing molecules are enough to start a chain reaction that is destructive to the cell. A prion acts as an infectious agent that infects normal molecules and in this way reproduces its spatial structure. This is his method of reproduction.

What has been said clearly does not fit into the existing ideas about the ways of transmitting hereditary information in a cell.

We were taught at school that all the properties of a protein molecule are determined by the sequence of its amino acids, which is read from an RNA molecule, which, in turn, is synthesized on a gene, that is, on a DNA matrix. The discovery of prions showed, however, that the sequence of amino acids does not determine all of its properties.

A Brief History of the Discovery of Prions

All properties (characters) of living organisms are determined by genes. Changes in characteristics occur as a result of changes (mutations) in genes. This is due to the fact that in the DNA from which genes are composed, information about the structure of proteins and RNA, the main molecules that perform cellular functions, is “recorded” in a special way. When a mutant cell divides, the daughter cells receive a mutant copy of the gene; This is how inheritance of altered characteristics occurs. The patterns of inheritance of mutations follow certain rules known as Mendelian patterns. This truth is immutable and beyond doubt, however, as it has become clear in recent years, it needs significant addition. This addition is associated with the study of some traits in a model genetic object - Saccharomyces yeast (known in everyday life as baker's yeast).

The value of yeast as a genetic object is due to the fact that, on the one hand, it is a single-celled organism; on the other hand, the yeast cell is very similar in its organization to the cells of higher organisms, including humans. Suffice it to say that out of the 24 thousand genes that make up the human genome, about 2 thousand genes are similar to yeast genes in structure and function.

Excellent genetic study of yeast has made it possible to show that the appearance and inheritance of some traits cannot be explained within the framework of classical concepts. The frequency of their occurrence is several orders of magnitude higher than the frequency of mutations; treating cells with certain chemical agents in very low concentrations “cure” them (that is, they return to their normal state), but this cure is reversible - the change occurs again. The inheritance of these characteristics in a series of cell generations does not correspond to Mendelian laws.

An explanation of their nature was first proposed by the American geneticist Reed Wikner in 1994. He suggested that

These characteristics are determined not by mutations in DNA, but by a special conformational change in protein molecules, supported autocatalytically, which determines the possibility of their inheritance.

An analogue of protein hereditary determinants are mammalian prions - a special class of infectious agents, purely protein, in contrast to viruses that do not contain nucleic acids, causative agents of such neurodegenerative diseases as “mad cow disease”, Creutzfeldt-Jakob disease in humans, etc. Prion transformation is based on The proteins of yeast and mammals undergo similar transformations in the structure of the protein molecule. Wikner's hypothesis concerned only two prion hereditary determinants known at that time. In subsequent years, five more prions were found in yeast, and one prion was discovered in the subspora mold.

It gradually became clear that prion (protein) inheritance in lower organisms is not something exceptional. Moreover, ideas began to be expressed that prion protein conversion allows cells to adapt to the changing conditions of yeast existence more effectively than occurs due to the classical mechanism associated with the occurrence of mutations and subsequent natural selection. In the case of protein heredity, a change in the properties of a cell occurs without changing its genetic material, that is, it is reversible.

The discovery of S. Prusiner forced scientists to talk about a new type of heredity - prion, protein heredity, i.e. information transfer can occur not only through the chemical structure of genes. Currently, the existence of such heredity has been proven by both domestic and foreign scientists. It is especially important for us that here we observe the transfer from protein to protein of structural, three-dimensional information, which can encode the spatial organization of living organisms (the structure of our body, the individual anatomical features of different people, nations and races).

A much more ancient discovery of humanity is telegony. For the first time, livestock breeders encountered this phenomenon. They quickly became convinced that the most important thing for preserving the breed was to protect purebred animals from accidental crossing, since even if conception did not occur, such a female would never produce a pure breed in the future. That is, somehow there is a transfer of hereditary information that is included in the hereditary apparatus of the female, and her subsequent offspring are formed on the basis of this heredity spoiled by the “stranger.” *

* Kapitsa S.P., Kurdyumov S.P., Malinetsky G.G. Synergetics and future forecasts. - M., 2001

A striking example is the experiments carried out in the first half of the 20th century on crossing thoroughbred horses with more hardy ungulates - zebras. When, after a series of unsuccessful crossings with male zebras, the mares were again transferred to stud farms, they began to give birth to foals from thoroughbred stallions with a color that replicated the vertical stripes of a zebra, which was never observed in normal horses.

And the second example. 1957, Moscow. World Festival of Youth and Students. This holiday - “the apotheosis of freedom and love” - ended for some of our lovers of “African passions” with the birth of black children, and for those who managed, so to speak, to do “without consequences,” such “consequences” occurred for their sons and daughters. Yes, yes, it was their white children, born in a legal marriage from white husbands, who suddenly began to have black children! This means that our ancestors were not so stupid, who preserved the honor of their daughters and said: “An honest house is more valuable than life!” And a dissolute life obviously doesn’t suit the youngsters for future use. Such people rarely boast of health and longevity.

The mechanism of this mysterious phenomenon was inexplicable from the point of view of classical genetics of the 20th century, but now, knowing about the existence of prion heredity, we can take a fresh look at this problem. When preparing the article, material from the publication Gazeta.ru was used.