Джоанна Доу
сентябрь 2015.
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Что такое прионная болезнь? Объясните не для биолога понятным языком

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Попробую на кулаках объяснить механизм прионных болезней. В случае внешнего инфицирования в организм человека попадает прионный белок, В качестве примера возьмем прионный белок под названием PrPSc. Он попадает в организм, далее неким способом умудряется пробраться в нейрон и там начинает модифицировать нормальный белок (назовем его PrPc) превращая его в себе подобный - PrPSc.

То есть еще раз совсем примитивно: есть "кособокий" белок-прион, который проникает в нервную клетку, там начинает превращать нормальные белки нервной клетки в кособокие. С этом кособоким белком клетка ничего сделать не может - не может разрушить, не может удалить. Этот белок накапливается в чрезмерных количествах и приводит к нарушению функции клетки и потом к ее гибели. Процесс этот неспешный, но необратимый.

Есть и другой - неинфекционный путь развития прионных болезней - генетический. При этом имеется мутация определенного гена, что приводит к тому, что синтезируется белок с прионными свействами. Этот белок также превращает другие белки в прионные. В результате дистрофия клетки и ее гибель.

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Не хотелось бы Вас обижать - тем более, что все равно не в Ваш огород камень - но это чистейший домысел. Если про ретровирусы и механику их воспроизводства, например, мы хоть что-то знаем, то все сведения о прионах строятся на фантазиях. "Как-то превращают" - это, пардон,ненаучно.

Напрягает то, что, так же, как Эбола, птичий грипп, атипичная пневмония и тэпэ - упоминания возникают и исчезают в соответствии с поитической и экономической ситуацией.

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Я бы все-таки вам посоветовал почитать научные источники, прежде чем что бы то ни было относить к домыслам. Если например медиа устраивает ненужный шум по поводу птичьих, свиных и прочих гриппов это вовсе не отрицает того, что H1N1 существует.

Второе, вы наверное немного зациклились на губчатом энцефалите, а я же больше имел ввиду механизм развития семейной фатальной бессонницы. "Как-то превращает" - если вам это так интересно, то вы и в Википедии сможете прочитать подробности. Я тут давал ответ чайнику в биологии.

Если вам нужны ссылки на научные статьи по теме, то извольте, я вам дам немного, чтобы ваши фантазии по теме прионных болезней направились в более конструктивное русло. Надеюсь, что литература на английском для вас не проблема.

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Я понимаю, что медработнику не пристало общаться с ветеринарным врачом, как с коллегой. Но извольте, я никогда не против того, чтобы узнать что-то интересное. Впрочем, "мне, в моей работе - это не пригодится" ((с) Ш.Холмс)

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Да и мне в работе это, с одно стороны, тоже не сильно надо, но лишних знаний не бывает)

Вы прям зря так о медиках ей-богу. Я никогда стараюсь не относиться к людям предвзято. Тем более, что, например, знания ветеринаров в области паразитологии заткнут за пояс любого.

Вот попробую закинуть сюда статью с сайта uptodate.com по биологии прионов. uptodate.com - это медицинский справочник, стоящий на принципах доказательной медицины. Так то, что там пишут можно воспринимать всерьез. И тут ограничение на комментарий в 16 тыс символов, так что что влезло, то влезло.

Biology and genetics of prions

Authors

Henry G Brown, MD, PhD

John M Lee, MD, PhD

Section Editors

Steven T DeKosky, MD, FAAN, FACP, FANA

Benjamin A Raby, MD, MPH

Deputy Editor

Janet L Wilterdink, MD

INTRODUCTION — Prion diseases are neurodegenerative diseases that have long incubation periods and progress inexorably once clinical symptoms appear. Five human prion diseases are currently recognized: kuru, Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob disease (vCJD also known as new variant CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI) [1-4]. Bovine spongiform encephalopathy (BSE), one of a number of prion infections affecting animals, has helped to focus more widespread public attention on these diseases with its possible link to vCJD [5,6].

These human prion diseases share certain common neuropathologic features including neuronal loss, proliferation of glial cells, absence of an inflammatory response, and the presence of small vacuoles within the neuropil which produces a spongiform appearance. Current evidence indicates that prion diseases are associated with the accumulation of an abnormal form of a host cell protein, designated the prion protein (PrP) [7].

BIOLOGY OF PRIONS

One of the characteristic features of prions is their resistance to a number of normal decontaminating procedures. These pathogens are resistant to processes affecting nucleic acids, such as hydrolysis or shearing [9]. However, agents that digest, denature or modify proteins do have activity against prions [7]. The prion protein purified from the brains of scrapie-infected animals (PrPSc) can be inactivated by prolonged autoclaving (at 121ºC and 15 psi for 4.5 h), or immersion in 1N NaOH (for 30 min, repeat three times), or in concentrated (>3 M) solutions of guanidine thiocyanate [10]. However, certain cautions prevail; it appears that inadequate autoclaving can establish heat resistant subpopulations which fail to diminish with a further cycle of autoclaving [11]. Stainless steel instruments also may retain infectivity even after treatment with 10 percent formaldehyde [12,13].

Newer decontamination techniques are being investigated. There has been some success in sterilization using a combination of SDS, proteinase K and pronase [14]. A radio-frequency gas-plasma treatment has been shown to effectively decontaminate surgical instruments [15]. Another group has tested a decontamination formula combining copper metal ions with hydrogen peroxide [16].

Prion protein — Scrapie prions have been used as a model for prion diseases. PrPSc is a conformational isomer of PrPC, a membrane-bound glycophosphatidylinositol-anchored protein found in the brains of normal animals on both neuronal and non-neuronal cells [17,18]. Similar proteins are also found in yeast [19].

The normal function of PrPC is unknown. A number of studies have shown that the prion protein is capable of reversibly binding to copper ions, suggesting that the prion protein could play a role in copper homeostasis [3,20]. Copper, itself, plays a role in endocytosis and neurotransmission. Furthermore, PrPC acts as a mediator of copper superoxide dismutase involved in the cellular response to oxidative stress [21,22], and it may play a role in regulating apoptosis [23]. PrPC is also expressed throughout the cells of the immune system, red blood cells, and platelets [24]. One study found that prion protein was upregulated during T cell activation and that antibody cross-linking of surface PrP led to increased phosphorylation of signaling proteins, suggesting a role for PrPC in immune function [25].

PrPC exists primarily in an alpha helical conformation, while PrPSc is beta helical and appears to result from a yet uncharacterized conformational alteration in PrPC [26,27]. Recombinant forms of prion protein show a large unstructured protein motif, which may more easily convert to a beta structure [28,29]. The PrPSc molecules form amyloid fibrils, which show apple-green birefringence upon polarization after Congo red staining. The fibrils are made of a continuous array of beta sheets that are oriented perpendicular to the fibril axis. The resistance of PrPSc to digestion with proteases and its tendency to polymerize into scrapie-associated fibrils or prion rods differentiates PrPSc from PrPC [30,31]. The hydrophobicity of this protein, which may in turn affect aggregation, and its beta-sheet conformation may play a role in neurotoxicity [32,33].

Conversion of PrPC to PrPSc — In contrast to PrPC, PrPSc accumulates within cells and does not normally appear on the cell surface. PrPSc is found predominantly in cytoplasmic vacuoles and secondary lysosomes [42]. Conversion of PrPC to PrPSc may occur in caveolae-like membranous domains [43].

Studies in mice either devoid of PrPC or with abnormal isoforms indicate that host PrPC must be present for the development of prion disease. Prion diseases appear to result from accumulation of abnormal isoforms of the PrP which is dependent upon conversion of normal PrPC into PrPSc [44,45]. This conversion appears to be the result of a conformational change in PrPC, rather than a chemical modification.

One group developed a peptide, iPrP13, that can break a beta-sheet conformation [46]. This peptide was able to reduce the protease resistance of PrPSc and to delay the onset of symptoms in transmission experiments in mice. It has been hypothesized that another as yet unidentified host factor, designated protein X, may facilitate conversion of normal PrP to PrPSc by binding to the carboxy terminus of PrPC and interacting with a site near the N-terminus of the protein to effect a conformational change [47].

Another study used transgenic mice with an abnormal form of PrPC lacking the glycophospholipid cell membrane anchor [48]. When inoculated with PrPSc, these mice accumulated abnormal PrP in abundant amyloid plaques but were asymptomatic and did not accumulate PrPSc or develop titers of infectivity at nearly the same rate as wild-type mice. The PrP membrane anchor appears necessary in the pathogenesis of prion disease. This study also emphasizes the specific neurotoxic role of PrPSc beyond amyloid deposition [49].

How the first molecule of PrPSc appears in the host remains a mystery, but the initial appearance, which may be de novo, probably triggers the replication of PrPSc. This process has been compared to crystallization in solution where a single seed crystal serves as a nidus [6]. It is hypothesized that the initiating PrPSc molecule is derived from an exogenous source in sporadic and iatrogenic prion diseases, while mutations are invariably detected within the gene encoding PrP in familial forms [50]. These mutations could destabilize PrPC, which might lead to spontaneous conversion to PrPSc. Studies of yeast prion Sup53 have shown that small, specific, elements of the primary amino acid sequence are responsible for initial nucleation as well as for specific prion conformations [51].

Possible role for immune response in early pathogenesis — Prior to transport to the nervous system, follicular dendritic cells within germinal centers of lymphoid tissue appear to act as a reservoir for the protein. Two reports suggest that complement plays a role in early pathogenesis. Mice deficient in C3 or C1q had decreased stores of PrPSc in the spleen and delayed onset of neurologic disease following peripheral inoculation in one study [52]. A companion report showed partial or full protection against spongiform encephalopathy in mice deficient in C3, C1q, Bf/C2, or complement receptors [53]. Other studies have shown variable immune responses to different experimental conformations of the prion protein [54].

Transport of PrPSc to the nervous system — Transport of PrPSc to the nervous system, once it appears in the host, occurs via axons [55]. Previous investigations suggested that the predominant mechanism was by slow axoplasmic transport [56]. However, several studies provide data showing that rapid anterograde axonal transport also occurs [57,58]. In one of these reports, a specific isoform of the protein was transported via this route in a hamster model compared to several other isoforms found within neural tissues, which appeared to arrive by a slower transport mechanism [58].

The finding of PrPC and PrPSc in olfactory sensory neurons has suggested that the olfactory system may serve as an entry pathway for infection [59]. However, the lymphoreticular system appears to play the more critical role in the initiation and/or propagation of some prion diseases [60,61]. Studies in mice indicate that for some prion diseases acquired by innoculation (including intranasal inoculation), a period of replication in lymphoreticular tissue is required [60,62]. Other studies found PrPSc expressed in the spleens of mice that were inoculated with prion disease directly into the brain [61]. Splenectomized mice developed prion disease more slowly than nonsplenectomized mice after intracerebral inoculation. Involvement of the lymphoreticular system seems more likely for certain types of exogenously acquired prion diseases, such as iatrogenic CJD, kuru, and perhaps vCJD, than for sporadic and genetic forms of prion diseases.

Neurotoxicity of prion protein — PrPSc appears to be neurotoxic; accumulation of this protein or fragments of it in neurons leads to apoptosis and cell death [63,64]. As an example, the PrP fragment containing amino acids 106-126 induces death of hippocampal neurons following exposure in vitro [63]. PrPC must be present for this effect to occur; PrP106-126 does not destroy neurons in mice which do not express PrPC [64]. However, abnormal PrP released by astrocytes still destroys PrP negative neurons in mice, suggesting that the neuronal injury is not caused by a loss of function of normal neuronal PrP or any interaction between normal and abnormal forms [65].

Misfolded PrP is transported in a retrograde fashion to the cytosol for degradation [66]. Even small amounts of this protein in the cytosol are highly neurotoxic, and this accumulation may be an important step in prion disease pathogenesis [66,67].

GENETICS OF HUMAN PRION DISEASES — The gene encoding PrP ("PRNP") in humans is located on the short arm of chromosome 20 [80]. A strong link was established between mutations in the PRNP gene and forms of prion disease with a familial predisposition (fCJD, GSS, FFI). More than 50 different mutations have been identified, including point and premature STOP codon mutations as well as the insertion of octapeptide repeats [81,82]. Some experts have advocated classifying prion diseases based upon the responsible mutation rather than the traditional classifications such as fCJD or GSS since a single mutation can produce different clinical phenotypes in different individuals or families (ie, genetic pleiotropy) [80,83-85]. As an example, the D178N mutation, in which asparagine substitutes for aspartic acid in codon 178, occurs in families with FFI, fCJD, and GSS [80]. Pedigrees with this mutation often demonstrate marked variability in the age of onset as well as the disease phenotype [84]. A large English and Irish kindred has been described containing individuals diagnosed with a variety of conditions including CJD, vCJD, and GSS [85]. However, when the PRNP gene was examined, all affected individuals had a valine for alanine substitution at codon 117 regardless of the clinical diagnosis.

PRNP point mutations appear to influence the glycoform ratios and conformation of PrPSc; while these can differ among patients with the same inherited mutation, they are distinct from PrPSc seen in sporadic, iatrogenic, and variant CJD [40]. This may indicate that strain variation is a composite of both abnormal conformation and glycosylation.

Familial CJD — In familial CJD (fCJD), a missense mutation involving the substitution of lysine for glutamine in codon 200 is the most common PRNP gene mutation, and this has been observed in many regions including from Libya, Chile, and Hungary [91-93]. In Slovakia, this mutation underlies more than 70 percent of all prion diseases [94]. One study described a differing presentation of this syndrome with codon 129 phenotype changes [95]. When the mutant codon 200 was linked to a valine at codon 129, PrP deposits were observed in the cerebellum and the prion protein was resistant to type 2 protease, neither of which have been described with methionine at codon 129.

One group has proposed a molecular classification scheme for sCJD based upon codon 129 polymorphism and characterization of the properties of PrPSc which was used to evaluate 300 sCJD patients [105]. As examples, a pattern of type 1 PrPSc plus at least one methionine at codon 129 was demonstrated in 70 percent while type 2 PrPSc plus codon 129 homozygous or heterozygous for valine was present in 25 percent and associated with ataxia. (See "Creutzfeldt-Jakob disease", section on 'Molecular subtypes of sCJD'.)

Fatal familial insomnia — As noted above, the D178N mutation has been the predominant mutation found in nearly all families with FFI [120]. This mutation also occurs in fCJD. It appears that patients with this mutation who are homozygous for methionine at codon 129 develop an FFI-like clinical syndrome whereas those homozygous for valine develop fCJD [86,87]. Heterozygosity at codon 129 may prolong the duration and slow the temporal progression of FFI [121].

SUMMARY AND RECOMMENDATIONS — Prion diseases are neurodegenerative diseases that have long incubation periods and progress inexorably once clinical symptoms appear.

Prions are small infectious pathogens containing protein but apparently lacking nucleic acid. The prion protein is the critical component of these agents and may, in fact, be its exclusive constituent. (See 'Biology of prions' above.)

One characteristic feature of prions is their resistance to a number of normal decontaminating procedures. (See 'Biology of prions' above.)

Prion diseases appear to result from accumulation of abnormal isoforms of the prion protein, a membrane-bound glycophosphatidylinositol-anchored protein found in the brains of normal animals on both neuronal and non-neuronal cells. These changes are due to both variation in amino acid sequence as well as glycosylation of the prion protein. (See 'Prion protein' above.)

Transport of the abnormal prion protein to the nervous system, once it appears in the host, occurs via axons and appears to be neurotoxic; accumulation of this protein or fragments of it in neurons leads to apoptosis and cell death. (See 'Transport of PrPSc to the nervous system' above.)

The gene encoding the prion protein in humans is located on the short arm of chromosome 20. A strong link was established between mutations in this gene and forms of prion disease with a familial predisposition (familial Creutzfeldt Jakob Disease, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia). A single mutation can produce different clinical phenotypes in different individuals or families. (See 'Genetics of human prion diseases' above.)

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REFERENCES

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Прионы - белки, якобы, обладающие болезнетворным эффектом.

Такие болезни крайне медленно развиваются, а способ воспроизводства возбудителя и заражения им не установлен. Единственная получившая широкую известность "прионная болезнь" - губчатая энцефалопатия, или "коровье бешенство". Ее существование также вызывает множество вопросов - она возникла и пропала, как только исчезла конкурентная конъюнктура в европейском животноводстве.

Поэтому в большинстве случаев само существование патогенных "прионов" сомнительно.

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