prion

[PR(OTEINACEOUS) + I(NFECTIOUS) + -ON¹.]

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Prions (rhyming with aeons) is an acronym for ‘proteinaceous infectious particles’. The term was coined in 1982 by Stanley B. Prusiner, a neurologist at the University of California at San Francisco, who proposed that a new type of pathogen consisting solely of protein is responsible for a school of deadly neurodegenerative diseases called Transmissible Spongiform Encephalopathies (TSEs). These include scrapie in sheep, bovine spongiform encephalopathy (BSE or ‘mad cow disease’) in cattle and Creutzfeldt-Jakob Disease (CJD) in people.

Inheritance and infection

TSEs come in an array of strains and types, each causing a distinct pattern of brain damage and clinical signs. The ‘drowsy’ and ‘hyper’ lines of sheep scrapie first alerted researchers to such variations in the 1950s. In the late 1970s a type was discovered in North American captive elk that causes a wasting disease. In some human strains, such as CJD, symptoms progress from disturbances of balance and co-ordination to blindness and deep dementia. Others produce sleep disorders.

Some TSEs look like genetic conditions. For example, the very rare human TSE Gerstmann- Straussler-Scheinker Syndrome (GSS) appears to be strictly familial, striking distant cousins on opposite sides of the globe with eerie similarity. By contrast, other TSEs can clearly be the result of infection. Pioneering work by French veterinarians in the 1930s and 1940s illustrated that scrapie could be spread between sheep and goats by injection.

Among humans, the disease kuru, found in the south Pacific, was also shown to be transmissible. In the 1950s, it was the leading cause of death in the Fore-speaking tribe of the Eastern Highlands of Papua New Guinea, until an international team of researchers discovered that it was spread by funeral rites in which the dead were revered by eating or handling their organs. The West suffered cases of what experts came to dub ‘high tech cannibalism’: since the 1970s, corneal transplants, dural grafts and contaminated human growth hormone extracted from cadaveric pituitary glands have all been shown to be potential vectors for the spread of CJD.

Mechanism of infection

TSE infection has some very odd features. Victims mount no obvious immune response, and the agent responsible is extraordinarily resilient. The solvents used for the storage of pituitary glands for production of growth hormone should have killed all known pathogens. The infectivity of brain matter from scrapie-positive sheep survives exposure to formaldehyde and even ultraviolet radiation. The latter observation prompted a suggestion by British researchers that the scrapie agent, unlike viruses and bacteria, might not contain nucleic acid (DNA or RNA), since this would have been destroyed by ultraviolet radiation. Prusiner cited this evidence when he proposed the prion model in 1982.

Since then, Prusiner and supporters of his ideas around the world have tackled TSEs with a series of dramatic experiments using the latest molecular techniques. They have treated diseased brain tissue with detergents and centrifuges and harvested the encrusted, suspect prion. After several groups determined the genetic sequence of that protein, Prusiner realized that it was a fragment of a normal protein (prion protein or PrP), the function of which is still uncertain, which is found in healthy nerve cells. They have gone on to argue, but not to prove, that once mutated, this protein becomes an aberrant prion, e.g. PrP (Scrapie), which might then convert similar healthy protein to the diseased form through a domino-style process that Prusiner calls ‘conformation’. This conversion can be sparked, Prusiner speculates, in three different ways: a person can inherit ‘weak’ proteins genetically inclined to mutate; a person's natural prion protein can spontaneously mutate; or the mutated form can be transmitted through food, surgery, or drugs, seeding the transformation of the host animal's natural protein.

Continuing controversy

In 1997, Prusiner was awarded the Nobel Prize for Physiology or Medicine for elucidating an ‘entirely new genre of disease-causing agents’. However, for UK government scientists at the coalface of the British BSE crisis, and other TSE specialists in the United States, the award was premature.

Prions, they observed, had never been shown to cause disease. Only four days before Prusiner's Nobel Prize was announced, the prion scarcely merited a mention in an article in the journal Nature by the leading researcher Moira Bruce of the Neuropathogenesis Unit (NPU) in Edinburgh. Bruce described evidence that the same agent that had infected more than a million British cattle was responsible for the variant form of CJD (vCJD), which had started to strike young Britons. Two groups of test mice experimentally infected with either diseased cattle brain or human tissue from victims of vCJD, had very similar patterns of brain damage after very similar incubation times. In presenting her evidence, Bruce only once mentioned the word prion, and couched it in a distancing pair of quotation marks.

Bruce insists that the TSE agent ‘behaves exactly like a virus’, though her group thinks that it may be an unconventional sort, which they call a ‘virino’. The argument between the virus/virino and prion camps is built on styles of investigation that could scarcely be more different. Bruce's group is inheritor of a line of research founded on traditional biological observation. Much of what we know about the pathogenesis of these diseases comes from this group, and the Institute for Animal Health in Compton, Berkshire.

They inoculated mice with extracts of brain tissue from sheep with scrapie, then observed the emergence of infection over two years or more. They established that the strains of scrapie can be recognized by the incubation time and pattern of brain damage in such host mice. They detected the presence in the test mice of a gene that clearly affects incubation times, which they named Sinc, for ‘Scrapie Incubation’. It turns out that Sinc is the PrP gene.

They also discovered that the host animal must have a healthy immune system for infection to take hold. Infection somehow rides the organs of the immune system and eventually floods out into the central nervous system, proceeding up the spinal cord to the brain, causing holes and protein deposits (plaques).

In 1993, presenting her findings to the Royal Society in London, Bruce demonstrated that when another species (monkey, sheep, antelope, cat) has been infected with material from a cow with BSE, the infectious material from that new species still exhibits the characteristics of BSE in her strain-typing tests. The prion conformation model has yet to cope adequately with this finding. All the other species have very different natural prion proteins. The conformation and thus progression of the disease should logically vary according to the particular chemical composition of the victim's own prion protein, which is supposed to be transformed into an aberrant prion by the initial infection. To Bruce, the obvious explanation for the persistent properties of BSE in so many different species was that the BSE agent is a virus-like agent, possessing its own DNA or RNA, which, as in a viral infection, causes the production of more infectious agent just like itself.

To Prusiner, the failure of the opposition to isolate a virus or a nucleic acid is critical. He and his collaborators have shown that mice genetically engineered to stop them producing their own PrP cannot be infected with TSEs from other animals. To them, this is evidence that the protein is the agent. The virus camp sees PrP as a receptor for a foreign agent.

Prusiner and his supporters come back to the toughness of the aberrant protein and its resilience in the face of enzymes, radiation, formaldehyde, and heat. However, prion-sceptics point to work from 1991 indicating that TSE agents are probably not indestructible, just devilishly tricky to get at. And other viruses can survive formaldehyde. During rendering, autoclaving and hormone extraction, protein fragments toughen and aggregate. Whether it is this toughening, or native impenetrability, that protects the TSE agents, their inactivation remains a key challenge in agriculture and medicine.

The most important inroads paved so far by prionism have come in the field of molecular genetics. Prionists have found mutations in the PrP gene that point to genetic susceptibility to TSEs. Neurologist John Collinge, of Imperial College London, with Prusiner in the early 1990s, discovered the PrP mutation involved in the seemingly familial prion disease GSS.

It turns out that the natural prion protein usually carries two delicate tree-like carbohydrate structures, called glycoforms. Prusiner and collaborators in Oxford and Ohio have observed that glycoforms change during disease. Prionists construe the change as a destabilizing part of the protein conformation process. The viral camp sees it as a classic side-effect of a foreign agent getting inside a cell and disrupting protein glycosylation.

Whatever causes the change, pathologists around the world now use glycoform analysis to help them determine the strain of TSE they are seeing in patients. Not enough is known about the protein-sugar variation to determine whether or not it can serve as a stand-alone test to, say, distinguish scrapie from BSE.

The prionists even claim to have demonstrated the conformation process in a test tube, by mixing normal PrP with the aberrant scrapie version, although only limited amounts were converted before the process fizzled out.

Despite impressive progress for the prion model the scientific case is not proven. Bruce's group still believes that the tough protein revealed by Prusiner's research simply cloaks and protects an independent nucleic acid, making up a virino. The prionists, they argue, have not adequately accounted for strain variation in scrapie, or the persistence of a particular TSE's characteristics, whatever its host.

What began as an obscure argument over a rare class of neurological diseases, and continues as an intense scientific controversy, is now at the heart of a world-wide public health crisis. Estimates of the number of Britons likely to succumb to vCJD now swing from hundreds to hundreds of thousands. And the rest of Europe is now battling to stem BSE in its own herds. A current challenge is development of reliable tests that can quickly detect the difference between normal and diseased prions, for screening of food and blood.

— Emily Green, Colin Blakemore

Bibliography

• Collinge, J. (2000) Concise Oxford Textbook of Medicine Chapter 13.17 Oxford University Press, Oxford, 855.
• Farquhar, C. F., Somerville, R. A. & Bruce, M. E. (1998) Straining the prion hypothesis, Nature 391, 345-346
• Prusiner, S. B. (1982) Novel Proteinaceous Infectious Particles Cause Scrapie, Science, 216: 136-144

See also dementia; infection; microorganisms; virus.

The infective agent (s) responsible for Creutzfeld-Jacob disease, kuru and possibly other degenerative diseases of the brain in human beings, scrapie in sheep, and bovine spongiform encephalopathy (BSE). They are simple proteins, and unlike viruses do not contain any nucleic acid. Transmission occurs by ingestion of infected tissue.

Prions are infectious proteinaceous particles or, more simply, proteins that lack nucleic acid. They were discovered by Stanley Prusiner, who received the Nobel Prize in medicine in 1997 for his work on them. Prions are biologically unique, existing somewhere in the border zone between living things and nonliving matter. Although they show none of the characteristics associated with life, such as the need to metabolize and the capacity to reproduce, they are in some manner capable of replication in the body of a human or certain other mammals.

Prions apparently gain entry to the body mainly by ingestion, or else in contaminated human growth hormone, or, possibly, in contaminated blood or blood products. They selectively attack the central nervous system, causing a relentless and progressive destruction of neural tissue, leaving in its place microscopic vesicular globules. The pathological name for this is spongiform encephalopathy. Conditions in this category, all of them invariably fatal, are all transmissible. They include kuru, Creutzfeldt-Jakob disease, scrapie (a degenerative neural disease of sheep), bovine spongiform encephalopathy (mad cow disease), and variant Creutzfeldt-Jakob disease, which appears to be acquired by ingesting beef contaminated by the prions that cause mad cow disease.

As of September 2000, it remains unknown what other mammalian species are vulnerable to prions; in research laboratories they have been shown to infect rodents and primates. It is possible that all domestic farm animals are at risk, though so far only sheep, beef and dairy cattle, and wild ungulates such as deer and elk have been confirmed as vulnerable. There is no vaccine or serum to protect against infection, and no agent that can arrest or retard the progress of the spongiform degeneration once it begins.

(SEE ALSO: Transmissible Spongiform Encephalopathy)

— JOHN M. LAST

In 1997 Stanley Prusiner was awarded the Nobel Prize in physiology or medicine for a revolutionary theory about the mechanisms of infection. His theory, the "prion hypothesis," concerns an unusual protein, the prion, which occurs in the complete absence of DNA and RNA. According to Prusiner's theory, the prion differs from other well-known infections agents including bacteria and viruses. While the latter rely on nucleic acid for survival and replication, the prion is made of a protein and lacks nucleic acid. Both the existence of the prion and the underlying mode of infection are unprecedented in medical sciences. While several critical issues remain to be addressed, the prion hypothesis may furnish a plausible framework to understand the pathogenesis of several deadly brain diseases of the central nervous system.

A New Infectious Agent

Prion is an acronym for "proteinaceous infectious particle," a term coined by Prusiner in the early 1980s to describe the nature of the agent causing the fatal brain disorders known as transmissible spongiform encephalopathies (TSE), also called prion diseases. Well-known examples of prion diseases include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE, or "mad cow" disease) in cattle, and Creutzfeldt-Jakob disease (CJD) in humans. Prion diseases are infectious and can also be transmitted to healthy animals by inoculating them with extracts of diseased brain.

In the mid-1960s, Tikvah Alper and colleagues reported that nucleic acid was unlikely to be a component of the infectious agent that causes scrapie. In 1967 J. S. Griffith speculated that the scrapie agent might be a protein capable of "self replication" without nucleic acid. However, Prusiner was the first, in the early 1980s, to successfully purify the infectious agent and to show that it consisted mostly of protein (technically speaking it is a glycoprotein, because it has a sugar group attached). He chose to name the new agent "prion" to distinguish it from viruses or viroids.

The essential protein component of prion was later identified in 1984 as prion protein (PrP), which is encoded by a chromosome gene in the host genome. Researchers concluded that the prion is a new infectious agent that consists mostly of PrP. This view is often referred to as the "protein only" or prion hypothesis. Some scientists find this notion hard to accept and have argued that nucleic acid is needed to carry information necessary for infection. However, no one has been able to demonstrate that either DNA or RNA play a direct role in prion replication.

In 1992 Charles Weissmann and colleagues obtained conclusive evidence for the central role of PrP in the transmission of prion diseases, when they created transgenic mice devoid of the PrP gene. These so-called PrP knockout mice were found to be completely resistant to infection when inoculated with scrapie brain preparations. When the PrP gene was reintroduced into the knockout mice, they once again became susceptible to prion infection.

Role of Protein Conformation

How can a protein such as PrP made by a cellular gene become an infectious agent? Prusiner and associates had found that PrP could exist in two forms, a normal or cellular form (PrP^C) normally expressed at low levels in neurons and other cell types, and an abnormal or scrapie form (PrP^Sc) built up in diseased brain. PrP^C is a cell-surface glycoprotein, the function of which has yet to be established. PrP^C consists of a single polypeptide chain folded into predominantly spiral conformations known as α-helices. These structures give rise to a globular shape that is soluble and can be cleared from the cell by degrading enzymes called proteases.

In contrast, PrP^Sc that has been isolated from diseased brain is rich in an alternative conformation that resembles extended strands. These structures are known as β-sheets. The β-sheet rich PrP^Sc tends to aggregate and is resistant to heat and degradation by proteases. It is assumed that PrP^Sc can initiate the infection process by binding to predominantly-helical PrP^C and converting it into more stable PrP^Sc with β-sheet conformation. This will set off a chain reaction leading to accumulation of large amounts of PrP^Sc to levels that result in brain tissue damage. The conformational conversion from α-helices to β-sheets transforms the benign PrP^C into disease-causing PrP^Sc. This model of conformational conversion provides useful insights into the pathogenesis of prion diseases.

Prion Diseases

Historically, prion diseases have been given distinct names. Scrapie is a naturally occurring prion disease of sheep and goats that was first documented in Iceland during the eighteenth century. BSE or mad cow disease is a prion disease of cattle and is believed to be acquired through scrapie-contaminated foodstuffs. Kuru, a prion disease found among the Fore tribe of New Guinea, was shown by D. Carleton Gajdusek to be transmitted by the consumption of human tissue, particularly brain tissue, during funerary rituals. Gajdusek was awarded the 1976 Nobel Prize in physiology or medicine for this contribution. The early symptom of Kuru is a loss of coordination, followed by mental confusion and, ultimately, death. It has virtually disappeared since 1958, when the practice of eating human tissue was more or less eradicated in New Guinea.

CJD is the most common human prion disease, affecting about one in a million people. The main symptom is dementia, along with other neurological signs. There are three forms of CJD. Sporadic CJD, the cause of which has yet to be found, is a spontaneous disease that accounts for a majority of CJD cases. Familial CJD affects people who carry a mutation in the PrP gene on chromosome 20. The third form, called iatrogenic CJD, is the result of accidental transmission during medical treatments. A newly emerged CJD phenotype, commonly called variant CJD, has occurred in the United Kingdom since 1985. Variant CJD has a unique disease profile, and may result from the consumption of BSE-contaminated meat products. It has been diagnosed mostly in young people who initially seek treatment for psychiatric symptoms. Gertsmann-Sträussler-Scheinker (GSS) syndrome is a familial prion disease resulting from a mutation in the PrP gene. The main symptom of GSS is the loss of coordination and dementia. Fatal familial insomnia (FFI) is another a familial prion disease in which fatal dementia follows the loss of physiological sleep.

Although human prion diseases manifest as three etiologically different forms—spontaneously (sporadic CJD), through inheritance (familial CJD, GSS, and FFI), and by infection (iatrogenic CJD, kuru, and possibly the new variant CJD), they nonetheless share a common pathogenetic event. Within the framework of "protein only" hypothesis, they all involve the protein conformational change that converts PrP^C to pathogenic PrP^Sc. Such a structural change in PrP may be triggered by a rare spontaneous event leading to a sporadic disease, a mutation that causes a familial disease, or exposure to foreign PrP^Sc, leading to an acquired disease. The "protein only" hypothesis provides a plausible mechanism underlying the pathogenesis of all forms of prion diseases. Moreover, it also helps explain the tremendous variability in prion-associated disease phenotypes. Structurally distinct variants of PrP^Sc may accumulate in different regions of the brain and initiate pathogenic changes that may eventually lead to distinct pathology in different areas of the brain, and subsequently the particular disease symptoms.

The concept of the prion and the role of protein conformation in disease pathogenesis have renewed inquiry into the causes of other and more common neurodegenerative disorders, such as Alzheimer's disease, Hunt-ington's disease, and Parkinson's disease. A common hallmark of all these diseases, as in prion diseases, is the conversion of an otherwise soluble and functional neuronal protein into a β-sheet rich and protease-resistant protein that has a higher tendency to aggregate and is harmful to the brain. These common pathogenetic features raise the hope that therapeutic interventions based on the same principles may be effective in all these diseases.

Bibliography

Cohen, F. E., and S. B. Prusiner. "Pathologic Conformations of Prion Proteins."Annual Review in Biochemistry 67 (1998): 793-819.

Prusiner, S. B. "Molecular Biology of Prion Diseases." Science 252 (1991): 1515-1522.

———. "The Prion Diseases." Scientific American (1995): 48-57.

———. Prion Biology and Diseases. New York: Cold Spring Harbor Laboratory Press,1999.

—Pierluigi Gambetti and Shu G. Chen

Prions are abnormal forms of natural proteins. Current research indicates that a prion is composed of about 250 amino acids. Despite extensive and continuing investigations, no nucleic acid component has been found. Like viruses, prions are infectious agents.

A protein that not only folds into an unusual shape itself, but also seems to have the ability to cause other proteins to change their shape as well. For a long time, scientists were skeptical that prions existed, but now most accept them.

A small protein which is believed capable of infecting cells and causing itself to be replicated, even though it contains no nucleic acid, i.e. it is believed to induce transcription of the gene that codes for the prion protein. In some way the horizontally acquired prion also alters the folding of the expressed protein and it is the altered protein that polymerizes to form fibrils within neurons and causes the spongiform encephalopathy. Aspects of this prion theory remain controversial. Prions can be detected in tissues by infective bioassay, animal inoculation, or by Western blot or immunochemistry. Prions cause spongiform encephalopathies of humans and animals, such as Creutzfeldt–Jakob disease, kuru, scrapie, transmissible mink encephalopathy, feline spongiform encephalopathy, and bovine spongiform encephalopathy.

For the bird, see Prion (bird). For the theoretical subatomic particle, see Preon.

Prion Diseases (TSEs)
Classification and external resources
ICD-10	A81
ICD-9	046

A prion (pronounced /ˈpriː.ɒn/ ( listen)^[1]) is an infectious agent that is composed primarily of protein. To date, all such agents that have been discovered propagate by transmitting a mis-folded protein state; the protein itself does not self-replicate and the process is dependent on the presence of the polypeptide in the host organism.^[2] The mis-folded form of the prion protein has been implicated in a number of diseases in a variety of mammals, including bovine spongiform encephalopathy (BSE, also known as "mad cow disease") in cattle and Creutzfeldt-Jakob disease (CJD) in humans. All known prion diseases affect the structure of the brain or other neural tissue, and all are currently untreatable and are always fatal.^[3] In general usage, prion refers to the theoretical unit of infection. In scientific notation, PrP^C refers to the endogenous form of prion protein (PrP), which is found in a multitude of tissues, while PrP^Sc refers to the misfolded form of PrP, that is responsible for the formation of amyloid plaques and neurodegeneration.

Prions are hypothesized to infect and propagate by refolding abnormally into a structure which is able to convert normal molecules of the protein into the abnormally structured form. All known prions induce the formation of an amyloid fold, in which the protein polymerises into an aggregate consisting of tightly packed beta sheets. This altered structure is extremely stable and accumulates in infected tissue, causing tissue damage and cell death.^[4] This stability means that prions are resistant to denaturation by chemical and physical agents, making disposal and containment of these particles difficult.

Proteins showing prion-type behavior are also found in some fungi, which has been useful in helping to understand mammalian prions. Fungal prions, however, do not appear to cause disease in their hosts and may even confer an evolutionary advantage through a form of protein-based inheritance.^[5]

The word prion is a compound word derived from the initial and final letters of the words proteinaceous and infection.^[6]

Contents 1 Discovery 2 Structure 2.1 Isoforms 2.1.1 PrPC 2.1.2 PrPSc 3 Function 3.1 PrP and long-term memory 3.2 PrP and stem cell renewal 4 Prion disease 4.1 Transmission 4.2 Sterilization 4.3 Debate 4.3.1 Protein hypothesis 4.3.2 Genetics as a cause 4.3.3 Multi-component hypothesis 4.3.4 Heavy metal poisoning hypothesis 4.3.5 Viral hypothesis 5 Fungi 6 Potential treatments 7 See also 8 Further reading 9 References 10 External links

Discovery

The radiation biologist Tikvah Alper and the mathematician John Stanley Griffith developed the hypothesis during the 1960s that some transmissible spongiform encephalopathies are caused by an infectious agent consisting solely of proteins.^[7][8] This theory was developed to explain the discovery that the mysterious infectious agent causing the diseases scrapie and Creutzfeldt-Jakob Disease resisted ultraviolet radiation (UV radiation damages nucleic acids). Francis Crick recognized the potential importance of the Griffith protein-only hypothesis for scrapie propagation in the second edition of his "Central dogma of molecular biology".^[9] While asserting that the flow of sequence information from protein to protein, or from protein to RNA and DNA was "precluded" by this dogma, he noted that Griffith's hypothesis was a potential contradiction to this dogma (although it was not so promoted by Griffith). Since the revised "dogma" was formulated, in part, to accommodate the then-recent discovery of reverse transcription by Howard Temin and David Baltimore (who won the Nobel Prize in 1975), proof of the protein-only hypothesis might be seen as a "sure bet" for a future Nobel Prize.

Stanley B. Prusiner of the University of California, San Francisco announced in 1982 that his team had purified the hypothetical infectious prion, and that the infectious agent consisted mainly of a specific protein – though they did not manage to isolate the protein until two years after Prusiner's announcement.^[10]

Prusiner coined the word "prion" as a name for the infectious agent. While the infectious agent was named a prion, the specific protein that the prion was composed of is also known as the Prion Protein (PrP), though this protein may occur both in infectious and non-infectious forms. Prusiner was awarded the Nobel Prize in Physiology or Medicine in 1997 for his research into prions.^[11]

Structure

See also: PrP structure

Isoforms

The protein that prions are made of (PrP) is found throughout the body, even in healthy people and animals. However, PrP found in infectious material 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 PrP^C, while the infectious form is called PrP^Sc — the C refers to 'cellular' or 'common' PrP, while the Sc refers to 'scrapie', a prion disease occurring in sheep.^[12] While PrP^C is structurally well-defined, PrP^Sc is certainly polydisperse and defined at a relatively poor level. PrP can be induced to fold into other more-or-less well-defined isoforms in vitro, and their relationship to the form(s) that are pathogenic in vivo is not yet clear.

PrP^C

PrP^C is a normal protein found on the membranes of cells. It has 209 amino acids (in humans), one disulfide bond, a molecular weight of 35-36 kDa and a mainly alpha-helical structure. Several topological forms exist; one cell surface form anchored via glycolipid and two transmembrane forms.^[13] Its function is a complex issue that continues to be investigated. PrP^C binds copper (II) ions with high affinity.^[14] The significance of this finding is not clear, but it presumably relates to PrP structure or function. PrP^C is readily digested by proteinase K and can be liberated from the cell surface in vitro by the enzyme phosphoinositide phospholipase C (PI-PLC), which cleaves the glycophosphatidylinositol (GPI) glycolipid anchor.^[15] PrP has been reported to play important roles in cell-cell adhesion and intracellular signaling in vivo, and may therefore be involved in cell-cell communication in the brain.^[16]

PrP^Sc

The infectious isoform of PrP, known as PrP^Sc, is able to convert normal PrP^C proteins into the infectious isoform by changing their conformation, or shape; this, in turn, alters the way the proteins interconnect. Although the exact 3D structure of PrP^Sc is not known, it has a higher proportion of β-sheet structure in place of the normal α-helix structure.^[17] Aggregations of these abnormal isoforms form highly structured amyloid fibers, which accumulate to form plaques. The end of each fiber acts as a template onto which free protein molecules may attach, allowing the fiber to grow. Only PrP molecules with an identical amino acid sequence to the infectious PrP^Sc are incorporated into the growing fiber.^{[citation needed]}

Function

It has been proposed that neurodegeneration caused by prions may be related to abnormal function of PrP. However, the physiological function of the prion protein remains a controversial matter. 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.

PrP and long-term memory

There is evidence that PrP may have a normal function in maintenance of long term memory.^[18] Maglio and colleagues have shown that mice without the genes for normal cellular PrP protein have altered hippocampal long-term potentiation.^[19]

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 expressed PrP on their cell membrane and that hematopoietic tissues with PrP-null stem cells exhibited increased sensitivity to cell depletion.^[20]

Prion disease

Microscopic "holes" are characteristic in prion-affected tissue sections, causing the tissue to develop a "spongy" architecture

Main article: Transmissible spongiform encephalopathy

Prions cause neurodegenerative disease by aggregating extracellularly within the central nervous system to form plaques known as amyloid, 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.^[21] Other histological changes include astrogliosis and the absence of an inflammatory reaction.^[22] While the incubation period for prion diseases is generally quite long, once symptoms appear the disease progresses rapidly, leading to brain damage and death.^[23] Neurodegenerative symptoms can include convulsions, dementia, ataxia (balance and coordination dysfunction), and behavioural or personality changes.

All known prion diseases, collectively called transmissible spongiform encephalopathies (TSEs), are untreatable and fatal.^[24] A vaccine has been developed in mice, however, that may provide insight into providing a vaccine in humans to resist prion infections.^[25] Additionally, in 2006 scientists announced that they had genetically engineered cattle lacking a necessary gene for prion production – thus theoretically making them immune to BSE,^[26] building on research indicating that mice lacking normally-occurring prion protein are resistant to infection by scrapie prion protein.^[27]

Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all mammals.^[28] Due to small differences in PrP between different species it is unusual for a prion disease to be transmitted from one species to another. The human prion disease variant Creutzfeldt-Jakob disease, however, is believed to be caused by a prion which typically infects cattle, causing Bovine spongiform encephalopathy and is transmitted through infected meat.^[29]

The following diseases are caused by prions.

Affected animal(s)	Disease	Written shorthand	Disease name 2	Annotation
sheep	Scrapie[30]
goat
cattle	Bovine spongiform encephalopathy	BSE	mad cow disease[30]
mink[30]	Transmissible mink encephalopathy	TME
white-tailed deer	Chronic wasting disease	CWD
elk
mule deer
moose[30]
cat[30]	Feline spongiform encephalopathy	FSE
nyala	Exotic ungulate encephalopathy	EUE
oryx
greater kudu[30]
ostrich[31]	Spongiform encephalopathy			this has not been shown to be transmissible
human	Creutzfeldt-Jakob disease	CJD[30]
	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[30]
	Fatal familial insomnia	sFI[32]
	Kuru[30]

Transmission

Proposed mechanism of prion propagation

Although the identity and general properties of prions are now well understood, the mechanism of prion infection and propagation remains mysterious. 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 PrP^C to PrP^Sc by bringing a molecule of each of the two together into a complex.^[33]

Current research suggests that 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.^[34]

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 involves the denaturation of the protein to a state where the molecule is no longer able to induce the abnormal folding of normal proteins. Prions are generally quite resistant to proteases, heat, radiation, and formalin treatments,^[35] 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 bleach, caustic soda, and strong acidic detergents such as LpH^[36]. 134 degrees Celsius (274 degrees Fahrenheit) for 18 minutes in a pressurised steam autoclave may not be enough to deactivate the agent of disease.^[37][38] Ozone sterilization is currently being studied as a potential method for prion denature and deactivation.^[39] 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.^[40]

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 a pan containing 1N NaOH and heat 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 NaOH or 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 NaOH 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.^[41]

Debate

Whether prions are the agent which causes disease or merely a symptom caused by a different agent is still debated by a minority of researchers. The following sections describe several contending hypotheses.

Protein hypothesis

Prior to the discovery of prions, it was thought that all pathogens used nucleic acids to direct their replication. The "protein hypothesis" states that a protein structure can replicate without the use of nucleic acid. This was initially controversial as it contradicts the so-called "central dogma of molecular biology," which describes nucleic acid as the central form of replicative information.

Evidence in favor of a protein hypothesis includes:^[42]

• No virus particles, bacteria, or fungi have been conclusively associated with prion diseases
• No nucleic acid has been conclusively associated with infectivity; agent is resistant to degradation by nucleases
• No immune response to infection
• PrP^Sc experimentally transmitted between one species and another results in PrP^Sc with the amino-acid sequence of the recipient species, suggesting that replication of the donor agent does not occur
• PrP^Sc and PrP^C do not differ in amino-acid sequence, therefore a PrP^Sc-specific nucleic acid is a redundant concept
• Familial prion disease occurs in families with a mutation in the PrP gene, and mice with PrP mutations develop prion disease despite controlled conditions where transmission is prevented
• Animals lacking PrP^C do not contract prion disease.
• Infectious prions can be formed de novo from purified non-infectious components.^[43]

Genetics as a cause

A gene for the normal protein has been identified: the PRNP gene.^[44] In all inherited cases of prion disease, there is a mutation in the PRNP gene. Many different PRNP mutations have been identified and it is thought that the mutations somehow make PrP^C more likely to change spontaneously into the abnormal PrP^Sc form.^{[verification needed]} These mutations can occur throughout the gene. Some mutations involve expansion of the octapeptide repeat region at the N-terminal of PrP. Other mutations that have been identified as a cause of inherited prion disease occur at positions 102, 117 & 198 (GSS), 178, 200, 210 & 232 (CJD) and 178 (Fatal Familial Insomnia, FFI). The cause of prion disease can be sporadic, genetic, and infectious, or a combination of these factors.^{[verification needed]} For example, in order to have scrapie, both an infectious agent and a susceptible genotype need to be present.^[45]

Multi-component hypothesis

In 2007, biochemist Surachai Supattapone and his colleagues at Dartmouth College produced purified infectious prions de novo from defined components (PrP^C, co-purified lipids, and a synthetic polyanionic molecule).^[43] These researchers also showed that the polyanionic molecule required for prion formation was selectively incorporated into high-affinity complexes with PrP molecules, leading them to hypothesize that infectious prions may be composed of multiple host components, including PrP, lipid, and polyanionic molecules, rather than PrP^Sc alone.^[46]

Heavy metal poisoning hypothesis

Autoclavure destroys protein and genetic material, not the agent of disease.^[38] The protein that can become protease resistant amyloidosis may gain superoxide dismutase activity when bound to copper ions.^[47] Mark Purdey has provided epidemiology to support the idea that low concentrations of copper and high concentrations of manganese in the environment or animal feed lead to disease.

Recent reports suggest that imbalance of brain metal homeostasis is a significant cause of PrP^Sc-associated neurotoxicity, though the underlying mechanisms are difficult to explain based on existing information. Proposed hypotheses include a functional role for PrP^C in metal metabolism, and loss of this function due to aggregation to the disease associated PrP^Sc form as the cause of brain metal imbalance. Other views suggest gain of toxic function by PrP^Sc due to sequestration of PrP^C-associated metals within the aggregates, resulting in the generation of redox-active PrP^Sc complexes. The physiological implications of some PrP^C-metal interactions are known, while others are still unclear. The pathological implications of PrP^C-metal interaction include metal-induced oxidative damage, and in some instances conversion of PrP^C to a PrP^Sc-like form.^[48]

Viral hypothesis

The protein-only hypothesis has been criticised by those who feel that the simplest explanation of the evidence to date^[49] is viral. For more than a decade, Yale University neuropathologist Laura Manuelidis has been proposing that prion diseases are caused instead by an unidentified "slow" virus. In January 2007, she and her colleagues published an article reporting to have found a virus in 10%, or less, of their scrapie-infected cells in culture.^[50][51]

The virion hypothesis states that TSEs are caused by a replicable informational molecule (which is likely to be a nucleic acid) bound to PrP. Many TSEs, including scrapie and BSE, show strains with specific and distinct biological properties, a feature which supporters of the virion hypothesis feel is not explained by prions.

Evidence in favor of a viral hypothesis includes:^[42]

• Strain variation: differences in prion infectivity, incubation, symptomology and progression among species resembles that seen between viruses, especially RNA viruses
• The long incubation and rapid onset of symptoms resembles some viral infections, such as HIV-induced AIDS
• Viral-like particles that do not appear to be composed of PrP have been found in some of the cells of scrapie- or CJD-infected cell lines.^[51]

Recent studies propagating TSE infectivity in cell-free reactions^[52] and in purified component chemical reactions ^[43] strongly suggest against TSE viral nature.

Fungi

Fungal prion proteins were discovered in the yeast Saccharomyces cerevisiae by Reed Wickner in the early 1990s. Subsequently, a prion has also been found in the fungus Podospora anserina. These prions behave similarly to PrP, but are generally non-toxic to their hosts. Susan Lindquist's group at the Whitehead Institute has argued that 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 strong arguments demonstrating that fungal prions should be considered a diseased state^{[verification needed]}.

Research into fungal prions has given strong support to the protein-only hypothesis for mammalian prions, since it has been demonstrated that purified protein extracted from cells with a prion state can 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 mammalian prions may operate by an independent mechanism.

Potential treatments

Advancements in computer modeling have allowed for scientists to identify compounds which can serve as a treatment for prion caused diseases, such as one compound found to bind a cavity in the PrP^C and stabilize the conformation, reducing the amount of harmful PrP^Sc.^[53]

See also

• Protein folding
• Protein Misfolding Cyclic Amplification
• Proteopathy
• Tertiary structure

Further reading

• Deadly Feasts: The "Prion" Controversy and the Public's Health^[54], by Richard Rhodes
• The Pathological Protein: Mad Cow, Chronic Wasting, and Other Deadly Prion Diseases, Phillip Yam, 2003, Springer, ISBN 0387955089
• The Family That Couldn't Sleep by D. T. Max provides a history of prion diseases.
• The Prion Protein a special issue of the open-acccess journal Current Issues in Molecular Biology

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External links

Wikimedia Commons has media related to: Prions

The Wikibook General Biology has a page on the topic of Viruses

• Prion Animation (Flash required)
• CDC – USA Centers for Disease Control and Prevention – information on prion diseases
• World Health Organisation – WHO information on prion diseases
• The UK BSE Inquiry – Report of the UK public inquiry into BSE and variant CJD
• UK Spongiform Encephalopathy Advisory Committee (SEAC)
• Mammalian prion classification International Committee on Taxonomy of Viruses – ICTVdb
• Online Mendelian Inheritance in Man: Prion protein – PrP, inherited prion disease and transgenic animal models.
• The Surprising World of Prion Biology--A New Mechanism of Inheritance on-line lecture by Susan Lindquist
• UCSF Memory and Aging Center – medical center for diagnosis and care of people with prion disease and research into origin and treatment of prion diseases
  • UCSF Memory and Aging Center YouTube channel – films about CJD
• Institute for Neurodegenerative Diseases – labs studying prion diseases, run by Stanley B. Prusiner, MD
• Prion Disease Database (PDDB) - Comprehensive transcriptome resource for systems biology research in prion diseases.

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