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A prion () is a Proteinopathy that induces Protein folding problems in normal variants of the same protein, leading to cellular death. Prions are responsible for , which are fatal and transmissible neurodegenerative diseases affecting animals including humans. These proteins can misfold sporadically, due to genetic mutations, or by exposure to an already misfolded protein, leading to an abnormal three-dimensional structure that can propagate misfolding in other proteins.
The term prion comes from "proteinaceous infectious particle". Unlike other infectious agents such as viruses, bacteria, and fungi, prions do not contain (DNA or RNA). Prions are mainly twisted Protein isoform of the major prion protein (PrP), a naturally occurring protein with an uncertain function. They are the hypothesized cause of various diseases, including scrapie in sheep, chronic wasting disease (CWD) in deer, bovine spongiform encephalopathy (BSE) in cattle (mad cow disease), and Creutzfeldt–Jakob disease (CJD) in humans.
All known prion diseases in affect the structure of the brain or other neuron tissues. These diseases are progressive, have no known effective treatment, and are invariably fatal. Most prion diseases were thought to be caused by PrP until 2015 when a prion form of alpha-synuclein was linked to multiple system atrophy (MSA). Misfolded proteins are also linked to other neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), which have been shown to originate and progress by a prion-like mechanism.
Prions are a type of intrinsically disordered protein that continuously changes conformation unless bound to a specific partner, such as another protein. Once a prion binds to another in the same conformation, it stabilizes and can form a fibril, leading to abnormal protein aggregates called amyloids. These amyloids accumulate in infected tissue, causing damage and cell death. The structural stability of prions makes them resistant to denaturation by chemical or physical agents, complicating disposal and containment, and raising concerns about Iatrogenesis through medical instruments.
An alternative model assumes that PrPSc exists only as , and that fibril ends bind PrPC and convert it into PrPSc. If this were all, then the quantity of prions would increase linear function, forming ever longer fibrils. But exponential growth of both PrPSc and the quantity of infectious particles is observed during prion disease. This can be explained by taking into account fibril breakage. 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.
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.
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.
| +Diseases caused by prions | |
| Domestic sheep, goat | Scrapie |
| Cattle | Bovine spongiform encephalopathy |
| Camel | Camel spongiform encephalopathy |
| Mink | Transmissible mink encephalopathy |
| White-tailed deer, elk, mule deer, moose | Chronic wasting disease |
| Cat | Feline spongiform encephalopathy |
| Nyala, oryx, greater kudu | Exotic ungulate encephalopathy |
| Ostrich | Spongiform encephalopathy (unknown whether transmissible) |
| Human | Creutzfeldt–Jakob disease |
| Iatrogenesis Creutzfeldt–Jakob disease | |
| Variant Creutzfeldt–Jakob disease | |
| Familial Creutzfeldt–Jakob disease | |
| Sporadic Creutzfeldt–Jakob disease | |
| Gerstmann–Sträussler–Scheinker syndrome | |
| Fatal insomnia Lay summary: | |
| Kuru | |
| Familial spongiform encephalopathy | |
| Variably protease-sensitive prionopathy | |
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. (1999). 072167335X, Saunders. 072167335X Other histological changes include astrogliosis and the absence of an inflammation. While the incubation period for human prion diseases is relatively long (5 to 20 years or more), once symptoms appear the disease progresses rapidly, leading to brain damage and death. Neurodegenerative symptoms can include , dementia, ataxia (balance and coordination dysfunction), and behavioural or personality changes.
Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all mammals. 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 that is transmitted through infected meat.
All known prion diseases are untreatable and fatal.
Until 2015 all known mammalian prion diseases were considered to be caused by the prion protein, PRNP. After 2015 this remains true for diseases in the category of "transmissible spongiform encephalopathy" (TSE), which is transmissible and causes a specific sponge-like appearance of infected brain tissue. The endogenous, properly folded form of the prion protein is denoted PrPC (for C ommon or Cellular), whereas the disease-linked, misfolded form is denoted PrPSc (for Scrapie), after one of the diseases first linked to prions and neurodegeneration. 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. This result is further evidence that prion replication does not require genetic information. (2026). 9780128112267 ISBN 9780128112267
The primary method of prion infection in animals is through ingestion of PrPSc. 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.
A University of California research team has provided evidence that infection can occur from prions in feces. Since animal excrement is present in many areas surrounding water reservoirs, and manure is used to fertilize many crop fields, this raises the possibility of widespread transmission. Preliminary evidence suggesting that prions might be transmitted through the use of urine-derived human menopausal gonadotropin, administered for the treatment of infertility, was published in 2011.
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:
Heating at for 18 minutes in a pressurized steam autoclave has been found to be somewhat effective in deactivating prions. Ozone sterilization has been studied as a potential method for prion denaturation and deactivation. Other approaches being developed include thiourea-urea treatment, guanidinium chloride treatment, and special heat-resistant subtilisin combined with heat and detergent. A number of decontamination reagents have been commercially manufactured with significant differences in efficacy among methods. A method sufficient for sterilizing prions on one material may fail on another.
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.
In addition, keratinase from B. licheniformis, alkaline serine protease from Streptomyces sp, subtilisin-like pernisine from Aeropyrum pernix, alkaline protease from Nocardiopsis sp, nattokinase from B. subtilis, engineered subtilisins from B. lentus and serine protease from three lichen species have been found to degrade PrPSc.
Fungal proteins that exhibit templated structural 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 . 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 that some fungal prions are not associated with any disease state, but they may have a useful role; however, researchers at the NIH have also provided arguments suggesting that fungal prions could be considered a diseased state. There is evidence that fungal prions have evolved specific functions that are beneficial to the microorganism that enhance their ability to adapt to their diverse environments. Further, within yeasts, prions can act as vectors of Epigenetics inheritance, transferring traits to offspring without any Genome change.
Research into 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 to be distinct from infectious mammalian prions in that they lack a cofactor required for propagation. The characteristic prion domains may vary among species – e.g., characteristic fungal prion domains are not found in mammalian prions.
| + Fungal prions | |||||
| Ure2p | Saccharomyces cerevisiae | Nitrogen catabolite repressor | URE3 | Growth on poor nitrogen sources | 1994 |
| Sup35p | S. cerevisiae | Translation termination factor | PSI+ | Increased levels of nonsense suppression | 1994 |
| HET-S | Podospora anserina | Regulates heterokaryon incompatibility | Het-s | Heterokaryon formation between incompatible strains | |
| Rnq1p | S. cerevisiae | Protein template factor | RNQ+, PIN+ | Promotes aggregation of other prions | |
| Swi1 | S. cerevisiae | Chromatin remodeling | SWI+ | Poor growth on some carbon sources | 2008 |
| Cyc8 | S. cerevisiae | Transcriptional repressor | OCT+ | Transcriptional derepression of multiple genes | 2009 |
| Mot3 | S. cerevisiae | Nuclear transcription factor | MOT3+ | Transcriptional derepression of anaerobic genes | 2009 |
| Sfp1 | S. cerevisiae | Putative transcription factor | ISP+ | Antisuppression | 2010 |
Many possible treatments work in the test-tube but not in lab animals. One treatment that prolongs the incubation period in lab mice has failed in human patients diagnosed with definite or probable Variant Creutzfeldt–Jakob disease. Another treatment that works in mice was tried in 6 human patients, all of whom died, before it went out of stock. There was no significant increase in lifespan, but autopsy suggests that the drug was safe and reached "encouraging" concentrations in the brain and cerebrospinal fluid.
While there is no known way to extend the life of a patient with prion disease, some drugs can be prescribed to control specific symptoms of the disease and accommodations can be given to improve quality of life.
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. 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.
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.
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. 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. 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. Griffith proposed three ways in which a protein could be a pathogen:
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.
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). The central dogma was later revised, in part, to accommodate reverse transcription (which both Howard Temin and David Baltimore discovered in 1970).
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. 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.
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. Prusiner was awarded the Nobel Prize in Physiology or Medicine in 1997 for his research into prions.
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. 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. The involvement of abnormal proteins in all of these diseases 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.
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. 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.
TDP-43
Specifically, aggregation of TARDBP, 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.
RNPA2B1, RNPA1
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.
Aβ
Alzheimer's disease is a form of dementia that is characterized by the buildup of two abnormal proteins in the brain: Aβ protein in amyloid plaques and tau protein in neurofibrillary tangles. Cumulative evidence indicates that abnormalities of Abeta are the earliest pathology sign of Alzheimer's. In experimental animals, scientists found that Aβ can be induced to aggregate to form Aβ plaques and cerebral amyloid angiopathy by a mechanism that is similar to that underlying prion diseases. Under highly unusual circumstances, Aβ deposition also can be stimulated in humans by the iatrogenic introduction of abeta 'seeds' (sometimes referred to as 'Aβ prions') into the body. Specifically, researchers analyzed people who had been treated with biological materials (such as growth hormone or dura mater patches) that had been collected from deceased human donors; they found that some of the recipients developed prion disease, but also that some of them had Aβ plaques and cerebral amyloid angiopathy in the brain. This finding suggests that some batches of the biologic agents were contaminated with Aβ seeds, probably because some of the donors had Alzheimer's disease at the time of death. When a very long time had passed following exposure to the contaminated biologic material (30 years or more), some of the affected individuals showed other signs of Alzheimer's disease, including tauopathy. Researchers emphasize that Alzheimer's is not a contagious disease; rather, the findings in humans support the theory that abnormal Aβ initiates Alzheimer's disease by a 'prion-like' mechanism that originates within the body.
Alpha-synuclein
Both multiple system atrophy (MSA) and Parkinson's disease (PD) are associated with misfolded alpha-synuclein. In 2015, it was found that mice engineered to have a susceptible human version of alpha-synuclein become sick with MSA when injected in the brain with the brain homogenate of human MSA patients, but they do not get PD when injected with the brain homogenate of human PD patients. This suggests that the two diseases are different, with MSA being more transmissible. Misfolded alpha-synuclein from either Parkinson's disease or MSA can be detected by protein misfolding cyclic amplification (PMCA). The two forms, after PMCA, show different levels of fluorescence when bound to thioflavin T. This allows for distinguishing between the two diseases.
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". 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.
(2004). 9780203912973, Marcel Dekker. ISBN 9780203912973
See also
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