Prion
A prion /ˈpriːɒn/ 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.
For the bird, see Prion (bird). For the theoretical subatomic particle, see Preon.
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).[10]
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".[11] Prions form abnormal aggregates of proteins called amyloids, which accumulate in infected tissue and are associated with tissue damage and cell death.[12] Amyloids are also associated with several other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.[13][14]
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.[15] 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.[16][17][18][19] Several yeast proteins have also been identified as having prionogenic properties,[20][21] as well as a protein involved in modification of synapses during the formation of memories[22][11] (see Eric Kandel § Molecular changes during learning). Prion replication is subject to epimutation and natural selection just as for other forms of replication, and their structure varies slightly between species.[23]
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.
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History[edit]
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][24] 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.[146]
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.[147][148]
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Etymology and pronunciation[edit]
The word prion, coined in 1982 by Stanley B. Prusiner, is derived from protein and infection, hence prion,[24] and is short for "proteinaceous infectious particle",[10] in reference to its ability to self-propagate and transmit its conformation to other proteins.[25] Its main pronunciation is /ˈpriːɒn/ ,[26][27][28] although /ˈpraɪɒn/, as the homographic name of the bird (prions or whalebirds) is pronounced,[28] is also heard.[29] In his 1982 paper introducing the term, Prusiner specified that it is "pronounced pree-on".[24]
Treatments[edit]
There are no effective treatments for prion diseases.[122] Clinical trials in humans have not met with success and have been hampered by the rarity of prion diseases.[122] Although some potential treatments have shown promise in the laboratory, none have been effective once the disease has commenced.[123]
Weaponization[edit]
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]
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