Prion Explained

Prion
Specialty:Infectious diseases
Pronounce:, [1] [2]

A prion is a misfolded protein that can induce misfolding of normal variants of the same protein and trigger cellular death. Prions cause prion diseases known as transmissible spongiform encephalopathies (TSEs) that are fatal transmissible neurodegenerative diseases in humans and animals.[3] [4] The proteins may misfold sporadically, due to genetic mutations, or by exposure to an already misfolded protein.[5] The consequent abnormal three-dimensional structure confers on them the ability to cause misfolding of other proteins.

The word prion is derived from the term "proteinaceous infectious particle".[6] [7] The hypothesized role of a protein as an infectious agent stands in contrast to all other known infectious agents such as viroids, viruses, bacteria, fungi, and parasites, all of which contain nucleic acids (DNA, RNA, or both).

Most prions are twisted isoforms of the major prion protein (PrP), a natural protein whose normal function is uncertain. They are hypothesized as the cause of transmissible spongiform encephalopathies (TSEs),[8] including scrapie in sheep, chronic wasting disease (CWD) in deer, bovine spongiform encephalopathy (BSE) in cattle (mad cow disease), feline spongiform encephalopathy (FSE) in felines, and Creutzfeldt–Jakob disease (CJD) and fatal insomnia in humans.

All known prion diseases in mammals affect the structure of the brain or other neural tissue; all are progressive, have no known effective treatment, and are always fatal.[9] All mammalian prion diseases were believed to be caused by PrP, until 2015, when a prion form of alpha-synuclein was hypothesized to cause multiple system atrophy (MSA).

Prions are a type of intrinsically disordered protein, which continuously change their conformation unless they are bound to a specific partner such as another protein. With a prion, two protein chains are stabilized if one binds to another in the same conformation. The probability of this happening is low, but once it does, the combination of the two is very stable. Then more units can get added, making a sort of "fibril". Prions form abnormal aggregates of proteins called amyloids, which accumulate in infected tissue and are associated with tissue damage and cell death.[10] Amyloids are also associated with several other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.[11] [12]

A prion disease is a type of proteopathy, or disease of structurally abnormal proteins. In humans, prions are believed to be the cause of Creutzfeldt–Jakob disease (CJD), its variant (vCJD), Gerstmann–Sträussler–Scheinker syndrome (GSS), fatal familial insomnia (FFI), and kuru.[13] There is also evidence suggesting prions may play a part in the process of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS); these have been termed prion-like diseases.[14] [15] [16] [17] Several yeast proteins have also been identified as having prionogenic properties, as well as a protein involved in modification of synapses during the formation of memories[18] [19] (see). Prion replication is subject to epimutation and natural selection just as for other forms of replication, and their structure varies slightly between species.[20]

Prion aggregates are stable, and this structural stability means that prions are resistant to denaturation by chemical and physical agents: they cannot be destroyed by ordinary disinfection or cooking. This makes disposal and containment of these particles difficult, and the risk of iatrogenic spread through medical instruments a growing concern.

Etymology and pronunciation

The word prion, coined in 1982 by Stanley B. Prusiner, is derived from protein and infection, hence prion, and is short for "proteinaceous infectious particle",[21] in reference to its ability to self-propagate and transmit its conformation to other proteins.[22] Its main pronunciation is,[23] [24] [25] although, as the homographic name of the bird (prions or whalebirds) is pronounced,[25] is also heard.[26] In his 1982 paper introducing the term, Prusiner specified that it is "pronounced pree-on".

Prion protein

See also: Major prion protein.

Structure

Prions consist of a misfolded form of major prion protein (PrP), a protein that is a natural part of the bodies of humans and other animals. The PrP found in infectious prions has a different structure and is resistant to proteases, the enzymes in the body that can normally break down proteins. The normal form of the protein is called PrPC, while the infectious form is called PrPSc – the C refers to 'cellular' PrP, while the Sc refers to 'scrapie', the prototypic prion disease, occurring in sheep.[27] PrP can also be induced to fold into other more-or-less well-defined isoforms in vitro; although their relationships to the form(s) that are pathogenic in vivo is often unclear, high-resolution structural analyses have begun to reveal structural features that correlate with prion infectivity.[28]

PrPC

PrPC is a normal protein found on the membranes of cells, "including several blood components of which platelets constitute the largest reservoir in humans."[29] It has 209 amino acids (in humans), one disulfide bond, a molecular mass of 35–36 kDa and a mainly alpha-helical structure.[30] [31] Several topological forms exist; one cell surface form anchored via glycolipid and two transmembrane forms.[32] The normal protein is not sedimentable; meaning that it cannot be separated by centrifuging techniques.[33] It has a complex function, which continues to be investigated. PrPC binds copper(II) ions (those in a +2 oxidation state) with high affinity.[34] The significance of this property is not clear, but it is presumed to relate to the protein's structure or function. PrPC is readily digested by proteinase K and can be liberated from the cell surface by the enzyme phosphoinositide phospholipase C (PI-PLC), which cleaves the glycophosphatidylinositol (GPI) glycolipid anchor.[35] PrP plays an important role in cell-cell adhesion and intracellular signaling in vivo,[36] and may therefore be involved in cell-cell communication in the brain.[37]

PrPSc

The infectious isoform of PrP, known as PrPSc, or simply the prion, is able to convert normal PrPC proteins into the infectious isoform by changing their conformation, or shape; this, in turn, alters the way the proteins interconnect. PrPSc always causes prion disease. PrPSc has a higher proportion of β-sheet structure in place of the normal α-helix structure.[38] [39] [40] Several highly infectious, brain-derived PrPSc structures have been discovered by cryo-electron microscopy.[41] [42] [43] Another brain-derived fibril structure isolated from humans with Gerstmann-Straussler-Schienker syndrome has also been determined.[44] All of the structures described in high resolution so far are amyloid fibers in which individual PrP molecules are stacked via intermolecular beta sheets. However, 2-D crystalline arrays have also been reported at lower resolution in ex vivo preparations of prions.[45] In the prion amyloids, the glycolipid anchors and asparagine-linked glycans, when present, project outward from the lateral surfaces of the fiber cores. Often PrPSc is bound to cellular membranes, presumably via its array of glycolipid anchors, however, sometimes the fibers are dissociated from membranes and accumulate outside of cells in the form of plaques. The end of each fiber acts as a template onto which free protein molecules may attach, allowing the fiber to grow. This growth process requires complete refolding of PrPC.[46] Different prion strains have distinct templates, or conformations, even when composed of PrP molecules of the same amino acid sequence, as occurs in a particular host genotype.[47] [48] [49] [50] [51] Under most circumstances, only PrP molecules with an identical amino acid sequence to the infectious PrPSc are incorporated into the growing fiber. However, cross-species transmission also happens rarely.[52]

PrPres

Protease-resistant PrPSc-like protein (PrPres) is the name given to any isoform of PrPc which is structurally altered and converted into a misfolded proteinase K-resistant form.[53] To model conversion of PrPC to PrPSc in vitro, Kocisko et al. showed that PrPSc could cause PrPC to convert to PrPres under cell-free conditions [54] and Soto et al. demonstrated sustained amplification of PrPres and prion infectivity by a procedure involving cyclic amplification of protein misfolding.[55] The term "PrPres" may refer either to protease-resistant forms of PrPSc, which is isolated from infectious tissue and associated with the transmissible spongiform encephalopathy agent, or to other protease-resistant forms of PrP that, for example, might be generated in vitro.[56] Accordingly, unlike PrPSc, PrPres may not necessarily be infectious.

Normal function of PrP

The physiological function of the prion protein remains poorly understood. While data from in vitro experiments suggest many dissimilar roles, studies on PrP knockout mice have provided only limited information because these animals exhibit only minor abnormalities. In research done in mice, it was found that the cleavage of PrP in peripheral nerves causes the activation of myelin repair in Schwann cells and that the lack of PrP proteins caused demyelination in those cells.[57]

PrP and regulated cell death

MAVS, RIP1, and RIP3 are prion-like proteins found in other parts of the body. They also polymerise into filamentous amyloid fibers which initiate regulated cell death in the case of a viral infection to prevent the spread of virions to other, surrounding cells.[58]

PrP and long-term memory

A review of evidence in 2005 suggested that PrP may have a normal function in maintenance of long-term memory.[59] As well, a 2004 study found that mice lacking genes for normal cellular PrP protein show altered hippocampal long-term potentiation.[60] [61] A recent study that also suggests why this might be the case, found that neuronal protein CPEB has a similar genetic sequence to yeast prion proteins. The prion-like formation of CPEB is essential for maintaining long-term synaptic changes associated with long-term memory formation.[62]

PrP and stem cell renewal

A 2006 article from the Whitehead Institute for Biomedical Research indicates that PrP expression on stem cells is necessary for an organism's self-renewal of bone marrow. The study showed that all long-term hematopoietic stem cells express PrP on their cell membrane and that hematopoietic tissues with PrP-null stem cells exhibit increased sensitivity to cell depletion.[63]

PrP and innate immunity

There is some evidence that PrP may play a role in innate immunity, as the expression of PRNP, the PrP gene, is upregulated in many viral infections and PrP has antiviral properties against many viruses, including HIV.[64]

Replication

The first hypothesis that tried to explain how prions replicate in a protein-only manner was the heterodimer model.[65] This model assumed that a single PrPSc molecule binds to a single PrPC molecule and catalyzes its conversion into PrPSc. The two PrPSc molecules then come apart and can go on to convert more PrPC. However, a model of prion replication must explain both how prions propagate, and why their spontaneous appearance is so rare. Manfred Eigen showed that the heterodimer model requires PrPSc to be an extraordinarily effective catalyst, increasing the rate of the conversion reaction by a factor of around 1015.[66] This problem does not arise if PrPSc exists only in aggregated forms such as amyloid, where cooperativity may act as a barrier to spontaneous conversion. What is more, despite considerable effort, infectious monomeric PrPSc has never been isolated.[67]

An alternative model assumes that PrPSc exists only as fibrils, and that fibril ends bind PrPC and convert it into PrPSc. If this were all, then the quantity of prions would increase linearly, forming ever longer fibrils. But exponential growth of both PrPSc and of the quantity of infectious particles is observed during prion disease.[68] [69] [70] This can be explained by taking into account fibril breakage.[71] A mathematical solution for the exponential growth rate resulting from the combination of fibril growth and fibril breakage has been found. The exponential growth rate depends largely on the square root of the PrPC concentration. The incubation period is determined by the exponential growth rate, and in vivo data on prion diseases in transgenic mice match this prediction. The same square root dependence is also seen in vitro in experiments with a variety of different amyloid proteins.[72]

The mechanism of prion replication has implications for designing drugs. Since the incubation period of prion diseases is so long, an effective drug does not need to eliminate all prions, but simply needs to slow down the rate of exponential growth. Models predict that the most effective way to achieve this, using a drug with the lowest possible dose, is to find a drug that binds to fibril ends and blocks them from growing any further.[73]

Researchers at Dartmouth College discovered that endogenous host cofactor molecules such as the phospholipid molecule (e.g. phosphatidylethanolamine) and polyanions (e.g. single stranded RNA molecules) are necessary to form PrPSc molecules with high levels of specific infectivity in vitro, whereas protein-only PrPSc molecules appear to lack significant levels of biological infectivity.[74] [75]

Transmissible spongiform encephalopathies

See main article: Transmissible spongiform encephalopathy.

Diseases caused by prions
Affected animal(s)Disease
Sheep, GoatScrapie[76]
CattleBovine spongiform encephalopathy
Camel[77] Camel spongiform encephalopathy (CSE)
MinkTransmissible mink encephalopathy (TME)
White-tailed deer, elk, mule deer, mooseChronic wasting disease (CWD)
CatFeline spongiform encephalopathy (FSE)
Nyala, Oryx, Greater KuduExotic ungulate encephalopathy (EUE)
Ostrich[78] Spongiform encephalopathy
(unknown if transmissible)
HumanCreutzfeldt–Jakob disease (CJD)
Iatrogenic Creutzfeldt–Jakob disease (iCJD)
Variant Creutzfeldt–Jakob disease (vCJD)
Familial Creutzfeldt–Jakob disease (fCJD)
Sporadic Creutzfeldt–Jakob disease (sCJD)
Gerstmann–Sträussler–Scheinker syndrome (GSS)
Fatal insomnia (FFI)[79]
Kuru
Familial spongiform encephalopathy[80]
Variably protease-sensitive prionopathy (VPSPr)

Prions cause neurodegenerative disease by aggregating extracellularly within the central nervous system to form plaques known as amyloids, which disrupt the normal tissue structure. This disruption is characterized by "holes" in the tissue with resultant spongy architecture due to the vacuole formation in the neurons.[81] Other histological changes include astrogliosis and the absence of an inflammatory reaction.[82] While the incubation period for prion diseases is relatively long (5 to 20 years), once symptoms appear the disease progresses rapidly, leading to brain damage and death.[83] Neurodegenerative symptoms can include convulsions, dementia, ataxia (balance and coordination dysfunction), and behavioural or personality changes.[84] [85]

Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all mammals.[86] Due to small differences in PrP between different species it is unusual for a prion disease to transmit from one species to another. The human prion disease variant Creutzfeldt–Jakob disease, however, is thought to be caused by a prion that typically infects cattle, causing bovine spongiform encephalopathy and is transmitted through infected meat.[87]

All known prion diseases are untreatable and fatal.[88] [89]

Until 2015 all known mammalian prion diseases were considered to be caused by the prion protein, PrP; in 2015 multiple system atrophy was found to be transmissible and was hypothesized to be caused by a new prion, the misfolded form of a protein called alpha-synuclein.[21] The endogenous, properly folded form of the prion protein is denoted PrPC (for Common or Cellular), whereas the disease-linked, misfolded form is denoted PrPSc (for Scrapie), after one of the diseases first linked to prions and neurodegeneration.[14] The precise structure of the prion is not known, though they can be formed spontaneously by combining PrPC, homopolymeric polyadenylic acid, and lipids in a protein misfolding cyclic amplification (PMCA) reaction even in the absence of pre-existing infectious prions.[74] This result is further evidence that prion replication does not require genetic information.[90]

Transmission

It has been recognized that prion diseases can arise in three different ways: acquired, familial, or sporadic.[91] It is often assumed that the diseased form directly interacts with the normal form to make it rearrange its structure. One idea, the "Protein X" hypothesis, is that an as-yet unidentified cellular protein (Protein X) enables the conversion of PrPC to PrPSc by bringing a molecule of each of the two together into a complex.[92]

The primary method of infection in animals is through ingestion. It is thought that prions may be deposited in the environment through the remains of dead animals and via urine, saliva, and other body fluids. They may then linger in the soil by binding to clay and other minerals.[93]

A University of California research team has provided evidence for the theory that infection can occur from prions in manure.[94] And, since manure is present in many areas surrounding water reservoirs, as well as used on many crop fields, it raises the possibility of widespread transmission. Although it was initially reported in January 2011 that researchers had discovered prions spreading through airborne transmission on aerosol particles in an animal testing experiment focusing on scrapie infection in laboratory mice,[95] this report was retracted in 2024.[96] Preliminary evidence supporting the notion that prions can be transmitted through use of urine-derived human menopausal gonadotropin, administered for the treatment of infertility, was published in 2011.[97]

Prions in plants

In 2015, researchers at The University of Texas Health Science Center at Houston found that plants can be a vector for prions. When researchers fed hamsters grass that grew on ground where a deer that died with chronic wasting disease (CWD) was buried, the hamsters became ill with CWD, suggesting that prions can bind to plants, which then take them up into the leaf and stem structure, where they can be eaten by herbivores, thus completing the cycle. It is thus possible that there is a progressively accumulating number of prions in the environment.[98] [99]

Sterilization

Infectious particles possessing nucleic acid are dependent upon it to direct their continued replication. Prions, however, are infectious by their effect on normal versions of the protein. Sterilizing prions, therefore, requires the denaturation of the protein to a state in which the molecule is no longer able to induce the abnormal folding of normal proteins. In general, prions are quite resistant to proteases, heat, ionizing radiation, and formaldehyde treatments,[100] although their infectivity can be reduced by such treatments. Effective prion decontamination relies upon protein hydrolysis or reduction or destruction of protein tertiary structure. Examples include sodium hypochlorite, sodium hydroxide, and strongly acidic detergents such as LpH.[101]

The World Health Organization recommends any of the following three procedures for the sterilization of all heat-resistant surgical instruments to ensure that they are not contaminated with prions:

  1. Immerse in 1N sodium hydroxide and place in a gravity-displacement autoclave at 121 °C for 30 minutes; clean; rinse in water; and then perform routine sterilization processes.
  2. Immerse in 1N sodium hypochlorite (20,000 parts per million available chlorine) for 1 hour; transfer instruments to water; heat in a gravity-displacement autoclave at 121 °C for 1 hour; clean; and then perform routine sterilization processes.
  3. Immerse in 1N sodium hydroxide or sodium hypochlorite (20,000 parts per million available chlorine) for 1 hour; remove and rinse in water, then transfer to an open pan and heat in a gravity-displacement (121 °C) or in a porous-load (134 °C) autoclave for 1 hour; clean; and then perform routine sterilization processes.[102]

for 18 minutes in a pressurized steam autoclave has been found to be somewhat effective in deactivating the agent of disease.[103] [104] Ozone sterilization is currently being studied as a potential method for prion denaturation and deactivation.[105] Other approaches being developed include thiourea-urea treatment, guanidinium chloride treatment,[106] and special heat-resistant subtilisin combined with heat and detergent.[107] A method sufficient for sterilizing prions on one material may fail on another.[108]

Renaturation of a completely denatured prion to infectious status has not yet been achieved; however, partially denatured prions can be renatured to an infective status under certain artificial conditions.[109]

Degradation resistance in nature

Overwhelming evidence shows that prions resist degradation and persist in the environment for years, and proteases do not degrade them. Experimental evidence shows that unbound prions degrade over time, while soil-bound prions remain at stable or increasing levels, suggesting that prions likely accumulate in the environment.[110] [111] One 2015 study by US scientists found that repeated drying and wetting may render soil bound prions less infectious, although this was dependent on the soil type they were bound to.[112]

Fungi

See main article: Fungal prion.

Proteins showing prion-type behavior are also found in some fungi, which has been useful in helping to understand mammalian prions. Fungal prions do not always cause disease in their hosts.[113] In yeast, protein refolding to the prion configuration is assisted by chaperone proteins such as Hsp104.[114] All known prions induce the formation of an amyloid fold, in which the protein polymerises into an aggregate consisting of tightly packed beta sheets. Amyloid aggregates are fibrils, growing at their ends, and replicate when breakage causes two growing ends to become four growing ends. The incubation period of prion diseases is determined by the exponential growth rate associated with prion replication, which is a balance between the linear growth and the breakage of aggregates.[115]

Fungal proteins exhibiting templated conformational change were discovered in the yeast Saccharomyces cerevisiae by Reed Wickner in the early 1990s. For their mechanistic similarity to mammalian prions, they were termed yeast prions. Subsequent to this, a prion has also been found in the fungus Podospora anserina. These prions behave similarly to PrP, but, in general, are nontoxic to their hosts. Susan Lindquist's group at the Whitehead Institute has argued some of the fungal prions are not associated with any disease state, but may have a useful role; however, researchers at the NIH have also provided arguments suggesting that fungal prions could be considered a diseased state.[116] There is evidence that fungal proteins have evolved specific functions that are beneficial to the microorganism that enhance their ability to adapt to their diverse environments.[117] Further, within yeasts, prions can act as vectors of epigenetic inheritance, transferring traits to offspring without any genomic change.[118] [119]

Research into fungal prions has given strong support to the protein-only concept, since purified protein extracted from cells with a prion state has been demonstrated to convert the normal form of the protein into a misfolded form in vitro, and in the process, preserve the information corresponding to different strains of the prion state. It has also shed some light on prion domains, which are regions in a protein that promote the conversion into a prion. Fungal prions have helped to suggest mechanisms of conversion that may apply to all prions, though fungal prions appear distinct from infectious mammalian prions in the lack of cofactor required for propagation. The characteristic prion domains may vary between species – e.g., characteristic fungal prion domains are not found in mammalian prions.

Fungal prions
ProteinNatural hostNormal functionPrion statePrion phenotypeYear identified
Ure2pSaccharomyces cerevisiaeNitrogen catabolite repressor[URE3]Growth on poor nitrogen sources1994
Sup35pS. cerevisiaeTranslation termination factor[PSI+]Increased levels of nonsense suppression1994
HET-SPodospora anserinaRegulates heterokaryon incompatibility[Het-s]Heterokaryon formation between incompatible strains
Rnq1pS. cerevisiaeProtein template factor[RNQ+], [PIN+]Promotes aggregation of other prions
Swi1S. cerevisiaeChromatin remodeling[SWI+]Poor growth on some carbon sources2008
Cyc8S. cerevisiaeTranscriptional repressor[OCT+]Transcriptional derepression of multiple genes2009
Mot3S. cerevisiaeNuclear transcription factor[MOT3+]Transcriptional derepression of anaerobic genes2009
Sfp1S. cerevisiaePutative transcription factor[ISP+]Antisuppression2010[120]

Treatments

There are no effective treatments for prion diseases.[121] Clinical trials in humans have not met with success and have been hampered by the rarity of prion diseases.[121] Although some potential treatments have shown promise in the laboratory, none have been effective once the disease has commenced.[122]

In other diseases

Prion-like domains have been found in a variety of other mammalian proteins. Some of these proteins have been implicated in the ontogeny of age-related neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), Alzheimer's disease, Parkinson's disease, and Huntington's disease.[123] [16] [15] They are also implicated in some forms of systemic amyloidosis including AA amyloidosis that develops in humans and animals with inflammatory and infectious diseases such as tuberculosis, Crohn's disease, rheumatoid arthritis, and HIV/AIDS. AA amyloidosis, like prion disease, may be transmissible.[124] This has given rise to the 'prion paradigm', where otherwise harmless proteins can be converted to a pathogenic form by a small number of misfolded, nucleating proteins.[125]

The definition of a prion-like domain arises from the study of fungal prions. In yeast, prionogenic proteins have a portable prion domain that is both necessary and sufficient for self-templating and protein aggregation. This has been shown by attaching the prion domain to a reporter protein, which then aggregates like a known prion. Similarly, removing the prion domain from a fungal prion protein inhibits prionogenesis. This modular view of prion behaviour has led to the hypothesis that similar prion domains are present in animal proteins, in addition to PrP.[123] These fungal prion domains have several characteristic sequence features. They are typically enriched in asparagine, glutamine, tyrosine and glycine residues, with an asparagine bias being particularly conducive to the aggregative property of prions. Historically, prionogenesis has been seen as independent of sequence and only dependent on relative residue content. However, this has been shown to be false, with the spacing of prolines and charged residues having been shown to be critical in amyloid formation.[126]

Bioinformatic screens have predicted that over 250 human proteins contain prion-like domains (PrLD). These domains are hypothesized to have the same transmissible, amyloidogenic properties of PrP and known fungal proteins. As in yeast, proteins involved in gene expression and RNA binding seem to be particularly enriched in PrLD's, compared to other classes of protein. In particular, 29 of the known 210 proteins with an RNA recognition motif also have a putative prion domain. Meanwhile, several of these RNA-binding proteins have been independently identified as pathogenic in cases of ALS, FTLD-U, Alzheimer's disease, and Huntington's disease.

Role in neurodegenerative disease

The pathogenicity of prions and proteins with prion-like domains is hypothesized to arise from their self-templating ability and the resulting exponential growth of amyloid fibrils. The presence of amyloid fibrils in patients with degenerative diseases has been well documented. These amyloid fibrils are seen as the result of pathogenic proteins that self-propagate and form highly stable, non-functional aggregates.[127] While this does not necessarily imply a causal relationship between amyloid and degenerative diseases, the toxicity of certain amyloid forms and the overproduction of amyloid in familial cases of degenerative disorders supports the idea that amyloid formation is generally toxic.[128]

Specifically, aggregation of TDP-43, an RNA-binding protein, has been found in ALS/MND patients, and mutations in the genes coding for these proteins have been identified in familial cases of ALS/MND. These mutations promote the misfolding of the proteins into a prion-like conformation. The misfolded form of TDP-43 forms cytoplasmic inclusions in affected neurons, and is found depleted in the nucleus. In addition to ALS/MND and FTLD-U, TDP-43 pathology is a feature of many cases of Alzheimer's disease, Parkinson's disease and Huntington's disease. The misfolding of TDP-43 is largely directed by its prion-like domain. This domain is inherently prone to misfolding, while pathological mutations in TDP-43 have been found to increase this propensity to misfold, explaining the presence of these mutations in familial cases of ALS/MND. As in yeast, the prion-like domain of TDP-43 has been shown to be both necessary and sufficient for protein misfolding and aggregation.[123]

Similarly, pathogenic mutations have been identified in the prion-like domains of heterogeneous nuclear riboproteins hnRNPA2B1 and hnRNPA1 in familial cases of muscle, brain, bone and motor neuron degeneration. The wild-type form of all of these proteins show a tendency to self-assemble into amyloid fibrils, while the pathogenic mutations exacerbate this behaviour and lead to excess accumulation.[129]

Weaponization

Prions could theoretically be employed as a weaponized agent.[130] [131] With potential fatality rates of 100%, prions could be an effective bioweapon, sometimes called a "biochemical weapon", because a prion is a biochemical. An unfavorable aspect is prions' very long incubation periods. Persistent heavy exposure of prions to the intestine might shorten the overall onset.[132] Another aspect of using prions in warfare is the difficulty of detection and decontamination.[133]

History

In the 18th and 19th centuries, exportation of sheep from Spain was observed to coincide with a disease called scrapie. This disease caused the affected animals to "lie down, bite at their feet and legs, rub their backs against posts, fail to thrive, stop feeding and finally become lame".[134] The disease was also observed to have the long incubation period that is a key characteristic of transmissible spongiform encephalopathies (TSEs). Although the cause of scrapie was not known back then, it is probably the first transmissible spongiform encephalopathy to be recorded.[135]

In the 1950s, Carleton Gajdusek began research which eventually showed that kuru could be transmitted to chimpanzees by what was possibly a new infectious agent, work for which he eventually won the 1976 Nobel prize. During the 1960s, two London-based researchers, radiation biologist Tikvah Alper and biophysicist John Stanley Griffith, developed the hypothesis that the transmissible spongiform encephalopathies are caused by an infectious agent consisting solely of proteins.[136] [137] Earlier investigations by E.J. Field into scrapie and kuru had found evidence for the transfer of pathologically inert polysaccharides that only become infectious post-transfer, in the new host.[138] [139] Alper and Griffith wanted to account for the discovery that the mysterious infectious agent causing the diseases scrapie and Creutzfeldt–Jakob disease resisted ionizing radiation.[140] Griffith proposed three ways in which a protein could be a pathogen.[141]

In the first hypothesis, he suggested that if the protein is the product of a normally suppressed gene, and introducing the protein could induce the gene's expression, that is, wake the dormant gene up, then the result would be a process indistinguishable from replication, as the gene's expression would produce the protein, which would then wake the gene in other cells.

His second hypothesis forms the basis of the modern prion theory, and proposed that an abnormal form of a cellular protein can convert normal proteins of the same type into its abnormal form, thus leading to replication.

His third hypothesis proposed that the agent could be an antibody if the antibody was its own target antigen, as such an antibody would result in more and more antibody being produced against itself. However, Griffith acknowledged that this third hypothesis was unlikely to be true due to the lack of a detectable immune response.[142]

Francis Crick recognized the potential significance of the Griffith protein-only hypothesis for scrapie propagation in the second edition of his "Central dogma of molecular biology" (1970): While asserting that the flow of sequence information from protein to protein, or from protein to RNA and DNA was "precluded", he noted that Griffith's hypothesis was a potential contradiction (although it was not so promoted by Griffith).[143] The revised hypothesis was later formulated, in part, to accommodate reverse transcription (which both Howard Temin and David Baltimore discovered in 1970).[144]

In 1982, Stanley B. Prusiner of the University of California, San Francisco, announced that his team had purified the hypothetical infectious protein, which did not appear to be present in healthy hosts, though they did not manage to isolate the protein until two years after Prusiner's announcement.[145] [146] The protein was named a prion, for "proteinacious infectious particle", derived from the words protein and infection. When the prion was discovered, Griffith's first hypothesis, that the protein was the product of a normally silent gene was favored by many. It was subsequently discovered, however, that the same protein exists in normal hosts but in different form.[147]

Following the discovery of the same protein in different form in uninfected individuals, the specific protein that the prion was composed of was named the prion protein (PrP), and Griffith's second hypothesis that an abnormal form of a host protein can convert other proteins of the same type into its abnormal form, became the dominant theory.[142] Prusiner was awarded the Nobel Prize in Physiology or Medicine in 1997 for his research into prions.[148] [149]

See also

External links

Notes and References

  1. Web site: English pronunciation of prion . Cambridge Dictionary . Cambridge University Press . 30 March 2020 . https://web.archive.org/web/20170424075831/http://dictionary.cambridge.org/pronunciation/english/prion . 24 April 2017 . live.
  2. Web site: Definition of Prion . 2021 . . Random House, Inc. . Definition 2 of 2 . 2021-09-12 . live . 2021-09-12 . https://web.archive.org/web/20210912092658/https://www.dictionary.com/browse/prion#luna-section.
  3. Web site: Transmissible Spongiform Encephalopathies . National Institute of Neurological Disorders and Stroke . 23 April 2023 . en.
  4. Web site: Prion diseases . Diseases and conditions . National Institute of Health . 2018-06-20 . 2020-05-22 . https://web.archive.org/web/20200522095052/https://www.niaid.nih.gov/diseases-conditions/prion-diseases . live .
  5. Book: Kumar V . Robbins & Cotran Pathologic Basis of Disease . 2021 . 10th.
  6. What Is a Prion? . Scientific American . 15 May 2018 . 16 May 2018 . https://web.archive.org/web/20180516174822/https://www.scientificamerican.com/article/what-is-a-prion-specifica/ . live .
  7. Encyclopedia: Encyclopaedia Britannica . Prion infectious agent . 15 May 2018 . 16 May 2018 . https://web.archive.org/web/20180516183206/https://www.britannica.com/science/prion-infectious-agent . live .
  8. Prusiner SB . June 1991 . Molecular biology of prion diseases . Science . 252 . 5012 . 1515–22 . 1991Sci...252.1515P . 10.1126/science.1675487 . 1675487 . 22417182.
  9. Prusiner SB . Prions . Proceedings of the National Academy of Sciences of the United States of America . 95 . 23 . 13363–83 . November 1998 . 9811807 . 33918 . 10.1073/pnas.95.23.13363 . 1998PNAS...9513363P . free .
  10. Dobson CM . The structural basis of protein folding and its links with human disease . Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences . 356 . 1406 . 133–45 . February 2001 . 11260793 . 1088418 . 10.1098/rstb.2000.0758 .
  11. Golde TE, Borchelt DR, Giasson BI, Lewis J . Thinking laterally about neurodegenerative proteinopathies . The Journal of Clinical Investigation . 123 . 5 . 1847–55 . May 2013 . 23635781 . 3635732 . 10.1172/JCI66029 .
  12. Irvine GB, El-Agnaf OM, Shankar GM, Walsh DM . Protein aggregation in the brain: the molecular basis for Alzheimer's and Parkinson's diseases . Molecular Medicine . 14 . 7–8 . 451–64 . 2008 . 18368143 . 2274891 . 10.2119/2007-00100.Irvine .
  13. Web site: Prion diseases . United States Centers for Disease Control and Prevention . 2019-05-03 . 2017-09-08 . 2020-05-18 . https://web.archive.org/web/20200518053638/https://www.cdc.gov/prions/index.html . live .
  14. Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM . Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers . Nature . 457 . 7233 . 1128–32 . February 2009 . 19242475 . 2748841 . 10.1038/nature07761 . 2009Natur.457.1128L .
  15. Olanow CW, Brundin P . Parkinson's disease and alpha synuclein: is Parkinson's disease a prion-like disorder? . Movement Disorders . 28 . 1 . 31–40 . January 2013 . 23390095 . 10.1002/mds.25373 . 38287298 .
  16. Goedert M . 206558562 . NEURODEGENERATION. Alzheimer's and Parkinson's diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein . Science . 349 . 6248 . 1255555 . August 2015 . 26250687 . 10.1126/science.1255555 .
  17. Lee S, Kim HJ . Prion-like Mechanism in Amyotrophic Lateral Sclerosis: are Protein Aggregates the Key? . Experimental Neurobiology . 24 . 1 . 1–7 . March 2015 . 25792864 . 4363329 . 10.5607/en.2015.24.1.1 .
  18. Si K, Lindquist S, Kandel ER . Susan Lindquist . Eric Kandel . A neuronal isoform of the aplysia CPEB has prion-like properties . Cell . 115 . 7 . 879–891 . December 2003 . 14697205 . 10.1016/S0092-8674(03)01020-1 . 3060439 . free .
  19. Brahic M . The surprising upsides of the prions behind horrifying brain diseases . New Scientist . Nov 10, 2021 . November 13, 2021 . November 13, 2021 . https://web.archive.org/web/20211113070338/https://www.newscientist.com/article/mg25233600-700-the-surprising-upsides-of-the-prions-behind-horrifying-brain-diseases/ . live .
  20. Li J, Browning S, Mahal SP, Oelschlegel AM, Weissmann C . Darwinian evolution of prions in cell culture . Science. 327. 5967. 869–872 . 31 Dec 2009 . 20044542 . 2848070 . 10.1126/science.1183218 . 2010Sci...327..869L.
    Lay summary: Web site: 'Lifeless' prion proteins are 'capable of evolution' . January 1, 2010 . BBC News.
  21. Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB, Patel S, Oehler A, Lowe JK, Kravitz SN, Geschwind DH, Glidden DV, Halliday GM, Middleton LT, Gentleman SM, Grinberg LT, Giles K . Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism . Proceedings of the National Academy of Sciences of the United States of America . 112 . 38 . E5308–17 . September 2015 . 26324905 . 4586853 . 10.1073/pnas.1514475112 . 2015PNAS..112E5308P . free.
    Lay summary: Web site: Makin S . A Red Flag for a Neurodegenerative Disease That May Be Transmissible . September 1, 2015 . Scientific American.
  22. Web site: Stanley B. Prusiner – Autobiography . NobelPrize.org . 2007-01-02 . 2013-06-16 . https://web.archive.org/web/20130616122714/http://www.nobelprize.org/nobel_prizes/medicine/laureates/1997/prusiner-autobio.html . live.
  23. Schonberger LB, Schonberger RB . Etymologia: prion . Emerging Infectious Diseases . 18 . 6 . 1030–1031 . June 2012 . 22607731 . 3381685 . 10.3201/eid1806.120271.
  24. Web site: Dorland's Illustrated Medical Dictionary . Elsevier . 2016-07-22 . subscription . dead . 2014-01-11 . https://web.archive.org/web/20140111192614/http://dorlands.com/.
  25. Web site: Merriam-Webster's Unabridged Dictionary . Merriam-Webster . 2016-07-22 . 2020-05-25 . https://web.archive.org/web/20200525084504/https://unabridged.merriam-webster.com/subscriber/login?redirect_to=%2Funabridged%2F . dead . subscription.
  26. Web site: The American Heritage Dictionary of the English Language . Houghton Mifflin Harcourt . 2016-07-22 . dead . 2015-09-25 . https://web.archive.org/web/20150925104737/https://ahdictionary.com/.
  27. Priola SA, Chesebro B, Caughey B . 38459669 . Biomedicine. A view from the top – prion diseases from 10,000 feet . Science . 300 . 5621 . 917–919 . May 2003 . 12738843 . 10.1126/science.1085920 . 2020-07-28 . 2020-07-28 . https://web.archive.org/web/20200728140633/https://zenodo.org/record/1230830 . live.
  28. Artikis . Efrosini . Kraus . Allison . Caughey . Byron . August 2022 . Structural biology of ex vivo mammalian prions . Journal of Biological Chemistry . en . 298 . 8 . 102181 . 10.1016/j.jbc.2022.102181 . free . 9293645 . 35752366.
  29. Robertson C, Booth SA, Beniac DR, Coulthart MB, Booth TF, McNicol A . 15 May 2006 . Cellular prion protein is released on exosomes from activated platelets . Blood . 107 . 10 . 3907–3911 . 10.1182/blood-2005-02-0802 . 16434486. 34141310 . free .
  30. Riek . Roland . Hornemann . Simone . Wider . Gerhard . Glockshuber . Rudi . Wüthrich . Kurt . 1997-08-18 . NMR characterization of the full-length recombinant murine prion protein, m PrP(23–231) . FEBS Letters . en . 413 . 2 . 282–288 . 10.1016/S0014-5793(97)00920-4 . 9280298 . 1997FEBSL.413..282R . 39791520 . 0014-5793.
  31. Donne . David G. . Viles . John H. . Groth . Darlene . Mehlhorn . Ingrid . James . Thomas L. . Cohen . Fred E. . Prusiner . Stanley B. . Wright . Peter E. . Dyson . H. Jane . 1997-12-09 . Structure of the recombinant full-length hamster prion protein PrP(29–231): The N terminus is highly flexible . Proceedings of the National Academy of Sciences . en . 94 . 25 . 13452–13457 . 10.1073/pnas.94.25.13452 . free . 9391046 . 28326 . 1997PNAS...9413452D . 0027-8424.
  32. Hegde RS, Mastrianni JA, Scott MR, DeFea KA, Tremblay P, Torchia M, DeArmond SJ, Prusiner SB, Lingappa VR . 20176119 . A transmembrane form of the prion protein in neurodegenerative disease . Science . 279 . 5352 . 827–34 . February 1998 . 9452375 . 10.1126/science.279.5352.827 . 1998Sci...279..827H . https://web.archive.org/web/20190223062543/http://pdfs.semanticscholar.org/4320/9efc152784dbc7f0b9a1300d0ec9be602a2c.pdf . dead . 2019-02-23 .
  33. Book: Carp RI, Kascap RJ . Taking aim at the transmissible spongiform encephalopathie's infectious agents . Krull IS, Nunnally BK . Prions and mad cow disease . Marcel Dekker . New York . 2004 . 6 . 978-0-8247-4083-2 . https://books.google.com/books?id=WjeuaHopV5UC&pg=PA6 . 2020-06-02 . 2020-08-20 . https://web.archive.org/web/20200820011006/https://books.google.com/books?id=WjeuaHopV5UC&pg=PA6 . live .
  34. Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, Fraser PE, Kruck T, von Bohlen A, Schulz-Schaeffer W, Giese A, Westaway D, Kretzschmar H . 4388803 . The cellular prion protein binds copper in vivo . Nature . 390 . 6661 . 684–87 . 1997 . 9414160 . 10.1038/37783 . 1997Natur.390..684B .
  35. Weissmann C . 20992257 . The state of the prion . Nature Reviews. Microbiology . 2 . 11 . 861–71 . November 2004 . 15494743 . 10.1038/nrmicro1025 .
  36. Málaga-Trillo E, Solis GP, Schrock Y, Geiss C, Luncz L, Thomanetz V, Stuermer CA . March 2009 . Regulation of embryonic cell adhesion by the prion protein . PLOS Biology . 7 . 3 . e55 . 10.1371/journal.pbio.1000055 . 2653553 . 19278297 . free . Weissmann C.
  37. Liebert . Ann . Bicknell . Brian . Adams . Roger . 2014 . Prion Protein Signaling in the Nervous System—A Review and Perspective . Signal Transduction Insights . en . 3 . STI.S12319 . 10.4137/STI.S12319 . 1178-6434. free .
  38. Caughey B, Dong A, Bhat K, Ernst D, Hayes S, Caughey W . Secondary structure analysis of the scrapie-associated protein PrP 27-30 in water by infrared spectroscopy . Biochemistry . 30 . 31 . 7672–80 . August 1991 . 1678278 . 10.1021/bi00245a003 .
  39. Safar . J . Roller . P.P. . Gajdusek . D.C. . Gibbs . C.J. . September 1993 . Conformational transitions, dissociation, and unfolding of scrapie amyloid (prion) protein. . Journal of Biological Chemistry . 268 . 27 . 20276–20284 . 10.1016/s0021-9258(20)80725-x . 8104185 . 0021-9258. free .
  40. Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, Mehlhorn I, Huang Z, Fletterick RJ, Cohen FE . Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins . Proceedings of the National Academy of Sciences of the United States of America . 90 . 23 . 10962–66 . December 1993 . 7902575 . 47901 . 10.1073/pnas.90.23.10962 . 1993PNAS...9010962P . free .
  41. Kraus A, Hoyt F, Schwartz C, Hansen B, Artikis E, Hughson A, Raymond G, Race B, Baron G, Caughey B . High-resolution structure and strain comparison of infectious mammalian prions . Molecular Cell . 81 . 21 . 4540–4551 . November 2021 . 34433091 . 10.1016/j.molcel.2021.08.011 .
  42. Hoyt F, Standke HG, Artikis E, Schwartz CL, Hansen B, Li K, Hughson AG, Manca M, Thomas OR, Raymond GJ, Race B, Baron GS, Caughey B, Kraus A . Cryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains . Nature Communications . 13 . 4005 . July 2022 . 1 . 35831291 . 10.1038/s41467-022-30458-6 . 9279418 . 2022NatCo..13.4005H .
  43. Manka . Szymon W. . Zhang . Wenjuan . Wenborn . Adam . Betts . Jemma . Joiner . Susan . Saibil . Helen R. . Collinge . John . Wadsworth . Jonathan D. F. . 2022-07-13 . 2.7 Å cryo-EM structure of ex vivo RML prion fibrils . Nature Communications . en . 13 . 1 . 4004 . 10.1038/s41467-022-30457-7 . 2041-1723 . 9279362 . 35831275. 2022NatCo..13.4004M .
  44. Hallinan . Grace I. . Ozcan . Kadir A. . Hoq . Md Rejaul . Cracco . Laura . Vago . Frank S. . Bharath . Sakshibeedu R. . Li . Daoyi . Jacobsen . Max . Doud . Emma H. . Mosley . Amber L. . Fernandez . Anllely . Garringer . Holly J. . Jiang . Wen . Ghetti . Bernardino . Vidal . Ruben . September 2022 . Cryo-EM structures of prion protein filaments from Gerstmann–Sträussler–Scheinker disease . Acta Neuropathologica . en . 144 . 3 . 509–520 . 10.1007/s00401-022-02461-0 . 0001-6322 . 9381446 . 35819518.
  45. Wille . Holger . Michelitsch . Melissa D. . Guénebaut . Vincent . Supattapone . Surachai . Serban . Ana . Cohen . Fred E. . Agard . David A. . Prusiner . Stanley B. . 2002-03-19 . Structural studies of the scrapie prion protein by electron crystallography . Proceedings of the National Academy of Sciences . en . 99 . 6 . 3563–3568 . 10.1073/pnas.052703499 . free . 0027-8424 . 122563 . 11891310. 2002PNAS...99.3563W .
  46. Kraus . Allison . Hoyt . Forrest . Schwartz . Cindi L. . Hansen . Bryan . Artikis . Efrosini . Hughson . Andrew G. . Raymond . Gregory J. . Race . Brent . Baron . Gerald S. . Caughey . Byron . November 2021 . High-resolution structure and strain comparison of infectious mammalian prions . Molecular Cell . en . 81 . 21 . 4540–4551.e6 . 10.1016/j.molcel.2021.08.011. 34433091 .
  47. Bessen RA, Kocisko DA, Raymond GJ, Nandan S, Lansbury PT, Caughey B . Non-genetic propagation of strain-specific properties of scrapie prion protein . Nature . 375 . 698–700 . June 1995 . 6533 . 7791905 . 10.1038/375698a0 . 1995Natur.375..698B . 4355092 .
  48. Telling . Glenn C. . Parchi . Piero . DeArmond . Stephen J. . Cortelli . Pietro . Montagna . Pasquale . Gabizon . Ruth . Mastrianni . James . Lugaresi . Elio . Gambetti . Pierluigi . Prusiner . Stanley B. . 1996-12-20 . Evidence for the Conformation of the Pathologic Isoform of the Prion Protein Enciphering and Propagating Prion Diversity . Science . en . 274 . 5295 . 2079–2082 . 10.1126/science.274.5295.2079 . 8953038 . 1996Sci...274.2079T . 0036-8075.
  49. Safar . Jiri . Wille . Holger . Itri . Vincenza . Groth . Darlene . Serban . Hana . Torchia . Marilyn . Cohen . Fred E. . Prusiner . Stanley B. . October 1998 . Eight prion strains have PrPSc molecules with different conformations . Nature Medicine . en . 4 . 10 . 1157–1165 . 10.1038/2654 . 9771749 . 6031488 . 1078-8956.
  50. Hoyt F, Alam P, Artikis E, Schwartz CL, Hughson AG, Race B, Baune C, Raymond GJ, Baron GS, Kraus A, Caughey B . Cryo-EM of prion strains from the same genotype of host identifies conformational determinants . PLOS Pathogens . 18 . e1010947 . November 2022 . 11 . 36342968. 10.1371/journal.ppat.1010947 . free . 9671466 .
  51. Manka SW, Wenborn A, Betts J, Joiner S, Saibil HR, Collinge J, Wadsworth JD . A structural basis for prion strain diversity . Nature Chemical Biology . 19 . 607–613. May 2023 . 5 . 36646960. 10.1038/s41589-022-01229-7 . 10154210 .
  52. Kurt TD, Sigurdson CJ . Cross-species transmission of CWD prions . Prion . 10 . 1 . 83–91 . 2016 . 26809254 . 4981193 . 10.1080/19336896.2015.1118603 .
  53. Riesner D . 2003-06-01 . Biochemistry and structure of PrP(C) and PrP(Sc) . British Medical Bulletin . 66 . 1 . 21–33 . 10.1093/bmb/66.1.21 . 14522846 . free.
  54. Kocisko D, Come J, Priola S, Chesebro B, Raymond G, Lansbury P, Caughey B . August 1994 . Cell-free formation of protease-resistant prion protein . Nature . 370 . 6489 . 471–4 . 1994Natur.370..471K . 10.1038/370471a0 . 7913989 . 4337709 . free . 1721.1/42578.
  55. Saborio GP, Permanne B, Soto C . June 2001 . Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding . Nature . 411 . 6839 . 810–3 . 2001Natur.411..810S . 10.1038/35081095 . 11459061 . 4317585.
  56. Bieschke J, Weber P, Sarafoff N, Beekes M, Giese A, Kretzschmar H . August 2004 . Autocatalytic self-propagation of misfolded prion protein . Proceedings of the National Academy of Sciences of the United States of America . 101 . 33 . 12207–11 . 2004PNAS..10112207B . 10.1073/pnas.0404650101 . 514458 . 15297610 . free.
  57. Healthy prions protect nerves . Nature . Abbott A . 84980140 . 10.1038/news.2010.29 . 2010-01-24 .
  58. Necroptosis in anti-viral inflammation . Nature . Nailwal H, Chan FK . 26 . 1 . 4–13 . 10.1038/s41418-018-0172-x. 30050058 . 6294789 . 2019 .
  59. Shorter J, Lindquist S . 5575951 . Prions as adaptive conduits of memory and inheritance . Nature Reviews Genetics . 6 . 6 . 435–50 . June 2005 . 15931169 . 10.1038/nrg1616 .
  60. Maglio LE, Perez MF, Martins VR, Brentani RR, Ramirez OA . Hippocampal synaptic plasticity in mice devoid of cellular prion protein . Brain Research. Molecular Brain Research . 131 . 1–2 . 58–64 . November 2004 . 15530652 . 10.1016/j.molbrainres.2004.08.004 .
  61. Caiati MD, Safiulina VF, Fattorini G, Sivakumaran S, Legname G, Cherubini E . PrPC controls via protein kinase A the direction of synaptic plasticity in the immature hippocampus . The Journal of Neuroscience . 33 . 7 . 2973–83 . February 2013 . 23407955 . 6619229 . 10.1523/JNEUROSCI.4149-12.2013 .
  62. Sudhakarana IP, Ramaswamia M . Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains . RNA Biology . 14 . 5 . 568–86 . 2016-10-11 . 5449092 . 27726526 . 10.1080/15476286.2016.1244588 .
  63. Zhang CC, Steele AD, Lindquist S, Lodish HF . Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal . Proceedings of the National Academy of Sciences of the United States of America . 103 . 7 . 2184–89 . February 2006 . 16467153 . 1413720 . 10.1073/pnas.0510577103 . 2006PNAS..103.2184Z . free .
  64. Lathe R, Darlix JL . Prion Protein PRNP: A New Player in Innate Immunity? The Aβ Connection . Journal of Alzheimer's Disease Reports. 1 . 1 . 263–275 . December 2017 . 30480243 . 6159716 . 10.3233/ADR-170037 .
  65. Cohen FE, Pan KM, Huang Z, Baldwin M, Fletterick RJ, Prusiner SB . Structural clues to prion replication . Science . 264 . 5158 . 530–31 . April 1994 . 7909169 . 10.1126/science.7909169 . 1994Sci...264..530C .
  66. Eigen M . Prionics or the kinetic basis of prion diseases . Biophysical Chemistry . 63 . 1 . A1–18 . December 1996 . 8981746 . 10.1016/S0301-4622(96)02250-8 .
  67. Vázquez-Fernández . E. . Young . H. S. . Requena . J. R. . Wille . H. . 2017 . The Structure of Mammalian Prions and Their Aggregates . International Review of Cell and Molecular Biology . 329 . 277–301 . 10.1016/bs.ircmb.2016.08.013 . 1937-6448 . 28109330. 978-0-12-812251-8 .
  68. Bolton DC, Rudelli RD, Currie JR, Bendheim PE . Copurification of Sp33-37 and scrapie agent from hamster brain prior to detectable histopathology and clinical disease . The Journal of General Virology . 72 . 12 . 2905–13 . December 1991 . 1684986 . 10.1099/0022-1317-72-12-2905 . free .
  69. Jendroska K, Heinzel FP, Torchia M, Stowring L, Kretzschmar HA, Kon A, Stern A, Prusiner SB, DeArmond SJ . 13098083 . Proteinase-resistant prion protein accumulation in Syrian hamster brain correlates with regional pathology and scrapie infectivity . Neurology . 41 . 9 . 1482–90 . September 1991 . 1679911 . 10.1212/WNL.41.9.1482 .
  70. Beekes M, Baldauf E, Diringer H . Sequential appearance and accumulation of pathognomonic markers in the central nervous system of hamsters orally infected with scrapie . The Journal of General Virology . 77 . 8 . 1925–34 . August 1996 . 8760444 . 10.1099/0022-1317-77-8-1925 . free .
  71. Bamborough P, Wille H, Telling GC, Yehiely F, Prusiner SB, Cohen FE . Prion protein structure and scrapie replication: theoretical, spectroscopic, and genetic investigations . Cold Spring Harbor Symposia on Quantitative Biology . 61 . 495–509 . 1996 . 9246476 . 10.1101/SQB.1996.061.01.050 . July 10, 2024 .
  72. Knowles TP, Waudby CA, Devlin GL, Cohen SI, Aguzzi A, Vendruscolo M, Terentjev EM, Welland ME, Dobson CM . 6267152 . An analytical solution to the kinetics of breakable filament assembly . Science . 326 . 5959 . 1533–37 . December 2009 . 20007899 . 10.1126/science.1178250 . 2009Sci...326.1533K .
  73. Masel J, Jansen VA . Designing drugs to stop the formation of prion aggregates and other amyloids . Biophysical Chemistry . 88 . 1–3 . 47–59 . December 2000 . 11152275 . 10.1016/S0301-4622(00)00197-6 .
  74. Deleault NR, Harris BT, Rees JR, Supattapone S . Formation of native prions from minimal components in vitro . Proceedings of the National Academy of Sciences of the United States of America . 104 . 23 . 9741–6 . June 2007 . 17535913 . 1887554 . 10.1073/pnas.0702662104 . free .
  75. Deleault NR, Walsh DJ, Piro JR, Wang F, Wang X, Ma J, Rees JR, Supattapone S . 6 . Cofactor molecules maintain infectious conformation and restrict strain properties in purified prions . Proceedings of the National Academy of Sciences of the United States of America . 109 . 28 . E1938-46 . July 2012 . 22711839 . 3396481 . 10.1073/pnas.1206999109 . free .
  76. Web site: 90. Prions . ICTVdB Index of Viruses . U.S. National Institutes of Health website . 2002-02-14 . 2010-02-28 . 2009-08-27 . https://web.archive.org/web/20090827131816/http://www.ncbi.nlm.nih.gov/ICTVdb/Ictv/fs_prion.htm . live .
  77. Babelhadj B, Di Bari MA, Pirisinu L, Chiappini B, Gaouar SB, Riccardi G, Marcon S, Agrimi U, Nonno R, Vaccari G . Prion Disease in Dromedary Camels, Algeria . Emerging Infectious Diseases . 24 . 6 . 1029–36 . June 2018 . 29652245 . 6004840 . 10.3201/eid2406.172007 .
  78. Hussein MF, Al-Mufarrej SI . 2004 . Prion Diseases: A Review; II. Prion Diseases in Man and Animals . Scientific Journal of King Faisal University (Basic and Applied Sciences) . 2 . 139 . April 9, 2016 . 5 . April 21, 2016 . https://web.archive.org/web/20160421204236/https://apps.kfu.edu.sa/sjournal/ara/pdffiles/b526.pdf . live .
  79. Mastrianni JA, Nixon R, Layzer R, Telling GC, Han D, DeArmond SJ, Prusiner SB . Prion protein conformation in a patient with sporadic fatal insomnia . The New England Journal of Medicine . 340 . 21 . 1630–1638 . May 1999 . 10341275 . 10.1056/NEJM199905273402104. free .
    Lay summary: Web site: BSE proteins may cause fatal insomnia . May 28, 1999. BBC News.
  80. Nitrini R, Rosemberg S, Passos-Bueno MR, da Silva LS, Iughetti P, Papadopoulos M, Carrilho PM, Caramelli P, Albrecht S, Zatz M, LeBlanc A . Familial spongiform encephalopathy associated with a novel prion protein gene mutation . Annals of Neurology . 42 . 2 . 138–46 . August 1997 . 9266722 . 10.1002/ana.410420203 . 22600579 .
  81. Book: Robbins SL, Cotran RS, Kumar V, Collins T . Robbins pathologic basis of disease . Saunders . Philadelphia . 1999 . 072167335X .
  82. Belay ED . Transmissible spongiform encephalopathies in humans . Annual Review of Microbiology . 53 . 283–314 . 1999 . 10547693 . 10.1146/annurev.micro.53.1.283 . 18648029 .
  83. Web site: Prion Diseases. 2006-01-26. 2010-02-28. US Centers for Disease Control. https://web.archive.org/web/20100304135757/http://www.cdc.gov/ncidod/dvrd/prions/. 2010-03-04. dead.
  84. Imran . Muhammad . Mahmood . Saqib . 2011-12-24 . An overview of human prion diseases . Virology Journal . 8 . 1 . 559 . 10.1186/1743-422X-8-559 . free . 1743-422X . 3296552 . 22196171.
  85. Mastrianni . James A. . 2010-04-01 . The genetics of prion diseases . Genetics in Medicine . 12 . 4 . 187–195 . 10.1097/GIM.0b013e3181cd7374 . 1098-3600 . 20216075. free .
  86. Collinge J . 18915904 . Prion diseases of humans and animals: their causes and molecular basis . Annual Review of Neuroscience . 24 . 519–50 . 2001 . 11283320 . 10.1146/annurev.neuro.24.1.519 . https://web.archive.org/web/20190225162649/http://pdfs.semanticscholar.org/650f/8f4c880880d357e5dd82236ba611065e21cc.pdf . dead . 2019-02-25 .
  87. Ironside JW . Variant Creutzfeldt–Jakob disease: risk of transmission by blood transfusion and blood therapies . Haemophilia . 12 . Suppl 1 . 8–15, discussion 26–28 . March 2006 . 16445812 . 10.1111/j.1365-2516.2006.01195.x . free .
  88. Gilch S, Winklhofer KF, Groschup MH, Nunziante M, Lucassen R, Spielhaupter C, Muranyi W, Riesner D, Tatzelt J, Schätzl HM . Intracellular re-routing of prion protein prevents propagation of PrP(Sc) and delays onset of prion disease . The EMBO Journal . 20 . 15 . 3957–3966 . August 2001 . 11483499 . 149175 . 10.1093/emboj/20.15.3957.
  89. Agarwal . Aishwarya . Mukhopadhyay . Samrat . 2022-01-15 . Prion Protein Biology Through the Lens of Liquid-Liquid Phase Separation . Journal of Molecular Biology . 434 . 1 . 167368 . 10.1016/j.jmb.2021.167368 . 1089-8638 . 34808226.
  90. Moda F . Protein Misfolding Cyclic Amplification of Infectious Prions . Progress in Molecular Biology and Translational Science . 150 . 361–374 . 2017 . 28838669 . 10.1016/bs.pmbts.2017.06.016 . 978-0-12-811226-7 .
  91. Book: Groschup MH, Kretzschmar HA . Prion Diseases Diagnosis and Pathogeneis . Archives of Virology . 16 . New York . Springer . 2001 . 978-3-211-83530-2 .
  92. Telling GC, Scott M, Mastrianni J, Gabizon R, Torchia M, Cohen FE, DeArmond SJ, Prusiner SB . 15235574 . Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein . Cell . 83 . 1 . 79–90 . October 1995 . 7553876 . 10.1016/0092-8674(95)90236-8 . free .
  93. Johnson CJ, Pedersen JA, Chappell RJ, McKenzie D, Aiken JM . Oral transmissibility of prion disease is enhanced by binding to soil particles . PLOS Pathogens . 3 . 7 . e93 . July 2007 . 17616973 . 1904474 . 10.1371/journal.ppat.0030093 . free .
  94. Tamgüney G, Miller MW, Wolfe LL, Sirochman TM, Glidden DV, Palmer C, Lemus A, DeArmond SJ, Prusiner SB . Asymptomatic deer excrete infectious prions in faeces . Nature . 461 . 7263 . 529–532 . September 2009 . 19741608 . 3186440 . 10.1038/nature08289 . 2009Natur.461..529T.
  95. Haybaeck J, Heikenwalder M, Klevenz B, Schwarz P, Margalith I, Bridel C, Mertz K, Zirdum E, Petsch B, Fuchs TJ, Stitz L, Aguzzi A . Aerosols transmit prions to immunocompetent and immunodeficient mice . PLOS Pathogens . 7 . 1 . e1001257 . January 2011 . 21249178 . 3020930 . 10.1371/journal.ppat.1001257 . free .
    Lay summary: Web site: Mackenzie D . January 13, 2011 . Prion disease can spread through air . registration . New Scientist.
  96. ((The PLOS Pathogens Editors)), Haybaeck J, Heikenwalder M, Klevenz B, Schwarz P, Margalith I, Bridel C, Mertz K, Zirdum E, Petsch B, Fuchs TJ, Stitz L, Aguzzi A . Retraction: Aerosols transmit prions to immunocompetent and immunodeficient mice . PLOS Pathogens . 20 . 7 . e1012396 . July 2024 . 39024193 . 11257221 . 10.1371/journal.ppat.1012396 . free .
  97. Van Dorsselaer A, Carapito C, Delalande F, Schaeffer-Reiss C, Thierse D, Diemer H, McNair DS, Krewski D, Cashman NR . Detection of prion protein in urine-derived injectable fertility products by a targeted proteomic approach . PLOS ONE . 6 . 3 . e17815 . March 2011 . 21448279 . 3063168 . 10.1371/journal.pone.0017815 . 2011PLoSO...617815V . free.
  98. News: Beecher C . Surprising' Discovery Made About Chronic Wasting Disease . . June 1, 2015 . 2016-04-08 . 2016-04-28 . https://web.archive.org/web/20160428055600/http://www.foodsafetynews.com/2015/06/researchers-make-surprising-discovery-about-spread-of-chronic-wasting-disease/ . live .
  99. Pritzkow S, Morales R, Moda F, Khan U, Telling GC, Hoover E, Soto C . Grass plants bind, retain, uptake, and transport infectious prions . Cell Reports . 11 . 8 . 1168–75 . May 2015 . 25981035 . 4449294 . 10.1016/j.celrep.2015.04.036 .
  100. Qin K, O'Donnell M, Zhao RY . 28822120 . Doppel: more rival than double to prion . Neuroscience . 141 . 1 . 1–8 . August 2006 . 16781817 . 10.1016/j.neuroscience.2006.04.057 .
  101. Race RE, Raymond GJ . Inactivation of transmissible spongiform encephalopathy (prion) agents by environ LpH . Journal of Virology . 78 . 4 . 2164–65 . February 2004 . 14747583 . 369477 . 10.1128/JVI.78.4.2164-2165.2004 .
  102. Sutton JM, Dickinson J, Walker JT, Raven ND . Methods to minimize the risks of Creutzfeldt–Jakob disease transmission by surgical procedures: where to set the standard? . Clinical Infectious Diseases . 43 . 6 . 757–64 . September 2006 . 16912952 . 10.1086/507030 . free .
  103. Collins SJ, Lawson VA, Masters CL . 23212525 . Transmissible spongiform encephalopathies . Lancet . 363 . 9402 . 51–61 . January 2004 . 14723996 . 10.1016/S0140-6736(03)15171-9 .
  104. Brown P, Rau EH, Johnson BK, Bacote AE, Gibbs CJ, Gajdusek DC . New studies on the heat resistance of hamster-adapted scrapie agent: threshold survival after ashing at 600 degrees C suggests an inorganic template of replication . Proceedings of the National Academy of Sciences of the United States of America . 97 . 7 . 3418–21 . March 2000 . 10716712 . 16254 . 10.1073/pnas.050566797 . 2000PNAS...97.3418B . free .
  105. Web site: Ozone Sterilization . 2005-04-14 . UK Health Protection Agency . 2010-02-28 . https://web.archive.org/web/20070210204514/http://www.hpa.org.uk/hpa/news/articles/press_releases/2005/050414_ozone_sterilizer.htm . February 10, 2007 .
  106. . Rapid chemical decontamination of infectious CJD and scrapie particles parallels treatments known to disrupt microbes and biofilms . Virulence . 6 . 8 . 787–801 . 2015 . 26556670 . 4826107 . 10.1080/21505594.2015.1098804 .
  107. Koga Y, Tanaka S, Sakudo A, Tobiume M, Aranishi M, Hirata A, Takano K, Ikuta K, Kanaya S . 6 . Proteolysis of abnormal prion protein with a thermostable protease from Thermococcus kodakarensis KOD1 . Applied Microbiology and Biotechnology . 98 . 5 . 2113–2120 . March 2014 . 23880875 . 10.1007/s00253-013-5091-7 . 2677641 .
  108. Eraña H, Pérez-Castro MÁ, García-Martínez S, Charco JM, López-Moreno R, Díaz-Dominguez CM, Barrio T, González-Miranda E, Castilla J . 6 . A Novel, Reliable and Highly Versatile Method to Evaluate Different Prion Decontamination Procedures . Frontiers in Bioengineering and Biotechnology . 8 . 589182 . 2020 . 33195153 . 7658626 . 10.3389/fbioe.2020.589182 . free .
  109. Weissmann C, Enari M, Klöhn PC, Rossi D, Flechsig E . Transmission of prions . Proceedings of the National Academy of Sciences of the United States of America . 99 . Suppl 4 . 16378–83 . December 2002 . 12181490 . 139897 . 10.1073/pnas.172403799 . 2002PNAS...9916378W . free .
  110. Zabel M, Ortega A . The Ecology of Prions . Microbiology and Molecular Biology Reviews . 81 . 3 . September 2017 . 28566466 . 5584314 . 10.1128/MMBR.00001-17 .
  111. Kuznetsova A, Cullingham C, McKenzie D, Aiken JM . Soil humic acids degrade CWD prions and reduce infectivity . PLOS Pathogens . 14 . 11 . e1007414 . November 2018 . 30496301 . 6264147 . 10.1371/journal.ppat.1007414 . free .
  112. Yuan Q, Eckland T, Telling G, Bartz J, Bartelt-Hunt S . Mitigation of prion infectivity and conversion capacity by a simulated natural process--repeated cycles of drying and wetting . PLOS Pathogens . 11 . 2 . e1004638 . February 2015 . 25665187 . 4335458 . 10.1371/journal.ppat.1004638 . free .
  113. Lindquist S, Krobitsch S, Li L, Sondheimer N . Investigating protein conformation-based inheritance and disease in yeast . Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences . 356 . 1406 . 169–76 . February 2001 . 11260797 . 1088422 . 10.1098/rstb.2000.0762 .
  114. Aguzzi A . Unraveling prion strains with cell biology and organic chemistry . Proceedings of the National Academy of Sciences of the United States of America . 105 . 1 . 11–12 . January 2008 . 18172195 . 2224168 . 10.1073/pnas.0710824105 . 2008PNAS..105...11A . free .
  115. Masel J, Jansen VA, Nowak MA . Quantifying the kinetic parameters of prion replication . Biophysical Chemistry . 77 . 2–3 . 139–52 . March 1999 . 10326247 . 10.1016/S0301-4622(99)00016-2 . 10.1.1.178.8812 .
  116. Dong J, Bloom JD, Goncharov V, Chattopadhyay M, Millhauser GL, Lynn DG, Scheibel T, Lindquist S . Probing the role of PrP repeats in conformational conversion and amyloid assembly of chimeric yeast prions . The Journal of Biological Chemistry . 282 . 47 . 34204–12 . November 2007 . 17893150 . 2262835 . 10.1074/jbc.M704952200 . free .
  117. Newby GA, Lindquist S . Blessings in disguise: biological benefits of prion-like mechanisms . Trends in Cell Biology . 23 . 6 . 251–59 . June 2013 . 23485338 . 10.1016/j.tcb.2013.01.007 . 1721.1/103966 . free .
  118. Halfmann R, Lindquist S . Epigenetics in the extreme: prions and the inheritance of environmentally acquired traits . Science . 330 . 6004 . 629–632 . October 2010 . 21030648 . 10.1126/science.1191081 . 2010Sci...330..629H . 206527151 .
  119. Halfmann R, Jarosz DF, Jones SK, Chang A, Lancaster AK, Lindquist S . Prions are a common mechanism for phenotypic inheritance in wild yeasts . Nature . 482 . 7385 . 363–368 . February 2012 . 22337056 . 3319070 . 10.1038/nature10875 . 2012Natur.482..363H .
  120. Rogoza T, Goginashvili A, Rodionova S, Ivanov M, Viktorovskaya O, Rubel A, Volkov K, Mironova L . Non-Mendelian determinant [ISP+] in yeast is a nuclear-residing prion form of the global transcriptional regulator Sfp1 . Proceedings of the National Academy of Sciences of the United States of America . 107 . 23 . 10573–77 . June 2010 . 20498075 . 2890785 . 10.1073/pnas.1005949107 . 2010PNAS..10710573R . free .
  121. Aguzzi A, ((Lakkaraju AKK)), Frontzek K . Toward Therapy of Human Prion Diseases . Annual Review of Pharmacology and Toxicology . 58 . 331–51 . January 2018 . 1 . 28961066 . 10.1146/annurev-pharmtox-010617-052745 . 2020-03-05 . 2020-03-12 . https://web.archive.org/web/20200312215409/https://www.zora.uzh.ch/id/eprint/141186/1/Aguzzi_et_al%3B_2017_revised.pdf . live .
  122. Web site: Prion Clinic – Drug treatments. 13 September 2017 . 2020-01-29. 2020-01-29. https://web.archive.org/web/20200129093314/http://www.prion.ucl.ac.uk/clinic-services/research/drug-treatments/. live.
  123. King OD, Gitler AD, Shorter J . The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease . Brain Research . 1462 . 61–80 . June 2012 . 22445064 . 3372647 . 10.1016/j.brainres.2012.01.016 .
  124. Murakami T, Ishiguro N, Higuchi K . Transmission of systemic AA amyloidosis in animals . Veterinary Pathology . 51 . 2 . 363–71 . March 2014 . 24280941 . 10.1177/0300985813511128 . free .
  125. Jucker M, Walker LC . Self-propagation of pathogenic protein aggregates in neurodegenerative diseases . Nature . 501 . 7465 . 45–51 . September 2013 . 24005412 . 3963807 . 10.1038/nature12481 . 2013Natur.501...45J .
  126. Alberti S, Halfmann R, King O, Kapila A, Lindquist S . A systematic survey identifies prions and illuminates sequence features of prionogenic proteins . Cell . 137 . 1 . 146–58 . 2009 . 19345193 . 2683788 . 10.1016/j.cell.2009.02.044 .
  127. . The amyloid state of proteins in human diseases . Cell . 148 . 6 . 1188–203 . March 2012 . 22424229 . 3353745 . 10.1016/j.cell.2012.02.022 .
  128. Ayers JI, Prusiner SB . Prion protein - mediator of toxicity in multiple proteinopathies . Nature Reviews. Neurology . 16 . 4 . 187–188 . April 2020 . 32123368 . 10.1038/s41582-020-0332-8 . 211728879 .
  129. Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP . Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS . Nature . 495 . 7442 . 467–73 . March 2013 . 23455423 . 3756911 . 10.1038/nature11922 . 2013Natur.495..467K .
  130. Web site: What are Biological Weapons? . United Nations, Office for Disarmament Affairs . 21 May 2021 . 21 May 2021 . https://web.archive.org/web/20210521135315/https://www.un.org/disarmament/biological-weapons/about/what-are-biological-weapons/ . live .
  131. Web site: Prions: the danger of biochemical weapons . 21 May 2021 . 9 December 2020 . https://web.archive.org/web/20201209183321/http://www.scielo.br/pdf/cta/v34n3/01.pdf . live .
  132. Web site: The Next Plague: Prions are Tiny, Mysterious and Frightening . 20 March 2017 . American Council on Science and Health . 21 May 2021 . 21 May 2021 . https://web.archive.org/web/20210521135326/https://www.acsh.org/news/2017/03/20/next-plague-prions-are-tiny-mysterious-and-frightening-11018 . live .
  133. Web site: Prions as Bioweapons? - Much Ado About Nothing; or Apt Concerns Over Tiny Proteins used in Biowarfare . 13 September 2019 . Defence iQ . 21 May 2021 . 21 May 2021 . https://web.archive.org/web/20210521135318/https://www.defenceiq.com/air-land-and-sea-defence-services/articles/prions-as-bioweapons . live .
  134. Web site: How Prions Came to Be: A Brief History – Infectious Disease: Superbugs, Science, & Society. 2021-09-17. en-US. 2021-09-17. https://web.archive.org/web/20210917234712/https://sites.duke.edu/superbugs/module-6/prions-mad-cow-disease-when-proteins-go-bad/how-prions-came-to-be-a-brief-history/. live.
  135. Ness . Anthony . Aiken . Judd . McKenzie . Debbie . 2023-12-31 . Sheep scrapie and deer rabies in England prior to 1800 . Prion . en . 17 . 1 . 7–15 . 10.1080/19336896.2023.2166749 . 1933-6896 . 9858414 . 36654484.
  136. Alper T, Cramp WA, Haig DA, Clarke MC . 4195902 . Does the agent of scrapie replicate without nucleic acid? . Nature . 214 . 5090 . 764–66 . May 1967 . 4963878 . 10.1038/214764a0 . 1967Natur.214..764A .
  137. Griffith JS . 4171947 . Self-replication and scrapie . Nature . 215 . 5105 . 1043–44 . September 1967 . 4964084 . 10.1038/2151043a0 . 1967Natur.215.1043G .
  138. Field EJ . Transmission experiments with multiple sclerosis: an interim report . British Medical Journal . 2 . 5513 . 564–65 . September 1966 . 5950508 . 1943767 . 10.1136/bmj.2.5513.564 .
  139. Adams DH, Field EJ . The infective process in scrapie . Lancet . 2 . 7570 . 714–16 . September 1968 . 4175093 . 10.1016/s0140-6736(68)90754-x .
  140. Field EJ, Farmer F, Caspary EA, Joyce G . 4195610 . Susceptibility of scrapie agent to ionizing radiation . Nature . 222 . 5188 . 90–91 . April 1969 . 4975649 . 10.1038/222090a0 . 5188 . 1969Natur.222...90F .
  141. Griffith JS . 4171947 . Self-replication and scrapie . Nature . 215 . 5105 . 1043–44. Sep 1967 . 4964084 . 10.1038/2151043a0 . 1967Natur.215.1043G .
  142. Book: Bolton D . https://www.researchgate.net/publication/235220355 . Prions, the Protein Hypothesis, and Scientific Revolutions . Nunnally BK, Krull IS . Prions and Mad Cow Disease . Marcel Dekker . January 1, 2004 . 21–60 . ResearchGate . 978-0-203-91297-3 . July 27, 2018 . March 22, 2022 . https://web.archive.org/web/20220322123428/https://www.researchgate.net/publication/235220355_Prions_the_Protein_Hypothesis_and_Scientific_Revolutions . live .
  143. Crick F . 4164029 . Central dogma of molecular biology . Nature . 227 . 5258 . 561–63 . August 1970 . 4913914 . 10.1038/227561a0 . 1970Natur.227..561C .
  144. Coffin JM, Fan H . The Discovery of Reverse Transcriptase . Annual Review of Virology . 3 . 1 . 29–51 . September 2016 . 27482900 . 10.1146/annurev-virology-110615-035556 . free .
  145. Taubes G . Gary Taubes . The game of name is fame. But is it science? . Discover . 7 . 12 . 28–41 . December 1986 .
  146. Prusiner SB . 7447120 . Novel proteinaceous infectious particles cause scrapie . Science . 216 . 4542 . 136–44 . April 1982 . 6801762 . 10.1126/science.6801762 . 1982Sci...216..136P . https://web.archive.org/web/20200720113942/https://pdfs.semanticscholar.org/f292/b22e2675419c6392a5e55f6b35b1dfc46917.pdf . dead . 2020-07-20 .
  147. Atkinson CJ, Zhang K, Munn AL, Wiegmans A, Wei MQ . Prion protein scrapie and the normal cellular prion protein . Prion . 10 . 1 . 63–82 . 2016 . 26645475 . 4981215 . 10.1080/19336896.2015.1110293 .
  148. Web site: The Nobel Prize in Physiology or Medicine, 1997 . 2010-02-28 . NobelPrize.org . The Nobel Prize in Physiology or Medicine 1997 was awarded to Stanley B. Prusiner 'for his discovery of Prions - a new biological principle of infection.' . 2018-08-09 . https://web.archive.org/web/20180809231715/https://www.nobelprize.org/nobel_prizes/medicine/laureates/1997/ . live .
  149. Web site: Frazer J . Prions Are Forever. 2021-12-28. Scientific American Blog Network. en. 2022-01-04. https://web.archive.org/web/20220104103748/https://blogs.scientificamerican.com/artful-amoeba/prions-are-forever/. live.

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