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A prion (/[invalid input: 'icon'][invalid input: 'Pronunciation prion.ogg']ˈpriː.ɒn/)^[1] is an infectious agent composed of protein in a misfolded form.^[2] This is in contrast to all other known infectious agents, which must contain nucleic acids (either DNA, RNA, or both). The word prion, coined in 1982 by Stanley B. Prusiner, is a portmanteau derived from the words protein and infection.^[3] Prions are responsible for the transmissible spongiform encephalopathies 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 universally fatal.^[4]

Prions propagate by transmitting a misfolded protein state. When a prion enters a healthy organism, the prion form of a protein induces existing, properly-folded protein to convert into the disease-associated, prion form; the prion acts as a template to guide the misfolding of more protein into prion form. These newly-formed prions can then go on to convert more proteins themselves, this triggers a chain reaction that produces large amounts of the prion form.^[5] 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 replicating 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.^[6] (Note that the propagation of the prion depends on the presence of normally-folded protein in which the prion can induce misfolding; animals which do not express the normal form of the prion protein cannot develop or transmit the disease.)

This altered structure is extremely stable and accumulates in infected tissue, causing tissue damage and cell death.^[7] This structural stability means that prions are resistant to denaturation by chemical and physical agents, making disposal and containment of these particles difficult. Prions come in different strains, each with a slightly different structure, and most of the time, strains breed true. Prion replication is nevertheless subject to occasional epimutation and then natural selection just like other forms of replication.^[8] However, the number of possible distinct prion strains is likely far smaller than the number of possible DNA sequences, so evolution takes place within a limited space.

All known mammalian prion diseases are caused by the so-called prion protein, PrP. The endogenous, properly-folded, form is denoted PrP^C (for common or cellular) while the disease-linked, misfolded form is denoted PrP^Sc (for Scrapie, after one of the diseases first linked to prions and neurodegeneration.)^[9]^[10] The precise structure of the prion is not known, though they can be formed by combining PrP^C, polyadenylic acid, and lipids in a Protein Misfolding Cyclic Amplification (PMCA) reaction.^[11]

Proteins showing prion-type behavior are also found in some fungi, which has been useful in helping to understand mammalian prions. Interestingly, fungal prions do not appear to cause disease in their hosts and may even confer an evolutionary advantage through a form of protein-based inheritance.^[12]

Discovery

Radiation biologist Tikvah Alper and 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.^[13]^[14] Their theory was developed to explain the discovery that the mysterious infectious agent causing the diseases scrapie and Creutzfeldt–Jakob disease resisted ionizing radiation. A single ionizing "hit" normally destroys an entire infectious particle, and the dose needed to hit half the particles depends on the size of the particles. The data suggested that the infectious agent was too small to be a virus.

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": 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).^[15] The revised hypothesis was later formulated, in part, to accommodate discovery of reverse transcription by Howard Temin and David Baltimore.

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.^[16] 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.^[17]

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.^[18] 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.^[19] The normal protein is not sedimentable; meaning it cannot be separated by centrifuging techniques.^[9] Its function is a complex issue that continues to be investigated. PrP^C binds copper (II) ions with high affinity.^[20] 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.^[21] 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.^[22]

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.^[23] Aggregations of these abnormal isoforms form highly structured amyloid fibers, which accumulate to form plaques. It is unclear if these aggregates are the cause of cell damage or are simply a side effect of the underlying disease process.^[24] 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.^[9] However, this property is not strictly shared by other proteins considered prions. The sup35p was shown to be able to be incorporated into existing aggregations even when three of the five oligopeptide repeats normally present were deleted. ^[25]

Prion replication mechanism

The first hypothesis that tried to explain how prions replicate in a protein-only manner was the heterodimer model.^[26] This model assumed that a single PrP^Sc molecule binds to a single PrP^C molecule and catalyzes its conversion into PrP^Sc. The two PrP^Sc molecules then come apart and can go on to convert more PrP^C. However, Manfred Eigen showed that since PrP^C has a very low rate of spontaneous conversion into PrP^Sc, the heterodimer model requires PrP^Sc to be an extraordinarily effective catalyst, increasing the rate of the conversion reaction by a factor of around 10¹⁵.^[27] What is more, despite considerable effort, infectious monomeric PrP^Sc has never been isolated. Theory and experiments both suggest that PrP^Sc exists only in aggregated forms such as amyloid, and that prion replication involves cooperativity.

File:Prion replication.png

Prion nucleation is rare, but can be bypassed by infection. Either nucleation or infection can initiate a replication cycle of fibril growth and breakage.

An alternative model assumes that PrP^Sc exists only as fibrils, and that fibril ends bind PrP^C and convert it into PrP^Sc. If this were all, then the quantity of prions would increase linearly, forming ever longer fibrils. But exponential growth of both PrP^Sc and of the quantity of infectious particles is observed during prion disease.^[28]^[29]^[30] This can be explained by taking into account fibril breakage.^[31] A mathematical solution for the exponential growth rate resulting from the combination of fibril growth and fibril breakage has been found.^[6] The exponential growth rate depends largely on the square root of the PrP^C concentration.^[6] The incubation period is determined by the exponential growth rate, and in vivo data on prion diseases in transgenic mice match this prediction.^[6] The same square root dependence is also seen in vitro in experiments with a variety of different amyloid proteins.^[32]

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.^[33]

PrP 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. In recent research done in mice, it was found that the cleavage of prions in peripheral nerves causes the activation of myelin repair in Schwann Cells and that the lack of prions caused demyelination in those cells.^[34]

PrP and long-term memory

There is evidence that PrP may have a normal function in maintenance of long-term memory.^[35] Maglio and colleagues have shown that mice without the genes for normal cellular PrP protein have altered hippocampal long-term potentiation.^[36]

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.^[37]

Prion disease

Diseases caused by prions
Affected animal(s)	Disease
sheep, goat	Scrapie^[38]
cattle	Bovine spongiform encephalopathy (BSE), mad cow disease^[38]
mink^[38]	Transmissible mink encephalopathy (TME)
white-tailed deer, elk, mule deer, moose^[38]	Chronic wasting disease (CWD)
cat^[38]	Feline spongiform encephalopathy (FSE)
nyala, oryx, greater kudu^[38]	Exotic ungulate encephalopathy (EUE)
ostrich^[39]	Spongiform encephalopathy (Not been shown to be transmissible.)
human	Creutzfeldt–Jakob disease (CJD)^[38]
	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)^[38]
	Fatal familial insomnia (FFI)^[40]
	Kuru^[38]

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.^[41] Other histological changes include astrogliosis and the absence of an inflammatory reaction.^[42] While the incubation period for prion diseases is generally quite long, once symptoms appear the disease progresses rapidly, leading to brain damage and death.^[43] 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.^[44] A vaccine has been developed in mice, however, that may provide insight into providing a vaccine in humans to resist prion infections.^[45] 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,^[46] building on research indicating that mice lacking normally occurring prion protein are resistant to infection by scrapie prion protein.^[47]

Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all mammals.^[48] 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.^[49]

Transmission

It has been recognized that prion diseases can arise in three different ways: acquired, familial, or sporadic.^[50] 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.^[51]

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.^[52]

A University of Californian research team, led by Nobel prize winner Stanley Prusiner, has proven that infection can occur from prions in manure.^{[citation needed]} 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. It was 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.^[53] 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.^[54]

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,^[55] 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.^[56] 134°C (274°F) for 18 minutes in a pressurized steam autoclave may not be enough to deactivate the agent of disease.^[57]^[58] Ozone sterilization is currently being studied as a potential method for prion denature and deactivation.^[59] 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.^[60]

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:

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.
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.
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.^[61]

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 hypotheses: some pertain to the composition of the infectious agent (protein-only, protein with other components, virus, or other), while others pertain to its mechanism of reproduction.

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:^[62]

No virus particles, bacteria, or fungi have been conclusively associated with prion diseases, although Saccharomyces cerevisiae has been known to be associated with infectious, yet non-lethal prions, such as Sup35p.
No nucleic acid has been conclusively associated with infectivity; agent is resistant to ultraviolet radiation
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
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, in the absence of gene-coding nucleic acids.^[11]

Genetic factors

A gene for the normal protein has been identified: the PRNP gene.^[63] 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.^[64] Although this discovery puts a hole in the general prion hypothesis, that prions can only aggregate proteins of identical amino acid make up. 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.^[65] For example, in order to have scrapie, both an infectious agent and a susceptible genotype need to be present.^[64]

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).^[11] 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.^[66]

In 2010, Jiyan Ma and colleagues at The Ohio State University produced infectious prions from a recipe of bacterially expressed recombinant PrP, POPG phospholipid, and RNA, further supporting the multi-component hypothesis.^[67] This finding is in contrast to studies that found minimal infectious prions produced from recombinant PrP alone.^[68]^[69]

Heavy metal poisoning hypothesis

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.^[70]

Viral hypothesis

The protein-only hypothesis has been criticised by those who feel that the simplest explanation of the evidence to date is viral.^[71] 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.^[72]^[73]

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:^[62]

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 lentiviruses, 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.^[73]

Recent studies propagating TSE infectivity in cell-free reactions^[74] and in purified component chemical reactions ^[11] strongly suggest against TSE viral nature. More recently, using a similar defined recipe of multiple components (PrP, POPG lipid, RNA), Jiyan Ma and colleagues generated infectious prions from recombinant PrP expressed from E. coli,^[67] casting further doubt on the viral hypothesis.

Fungi

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 the prion hypothesis, they were termed yeast prions. Subsequently, a prion has also been found in the fungus Podospora anserina. These prions behave similarly to PrP, but are generally 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 fungal prions could be considered a diseased state.^[75] Thus, the issue of whether fungal proteins are diseases, or have evolved for some specific functions, still remains unresolved.^[76]

As of 2010, there are eight known prion proteins in fungi, seven in Saccharomyces cerevisiae (Sup35, Rnq1, Ure2, Swi1, Mca1, Mot3, Cyc8) and one in Podospora anserina (HET-s).

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
Protein	Natural host	Normal function	Prion state	Prion phenotype	Year identified
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
Mca1	S. cerevisiae	Putative yeast caspase	[MCA+]	Unknown	2008
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

A putative prion protein, forming the [ISP+] element remains to be identified.

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.^[77]

Recently, antiprion antibodies capable of crossing the blood-brain-barrier and targeting cytosolic prion protein (an otherwise major obstacle in prion therapeutics) have been described.^[78]

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^ "BSE proteins may cause fatal insomnia". BBC News. 1999-05-28. Retrieved 2010-02-28.
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^ http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0009804
^ Deadly Feasts: The "Prion" Controversy and the Public's Health, Richard Rhodes, 1998, Touchstone, ISBN 0-684-84425-7

External links

General

CDC – USA Centers for Disease Control and Prevention – information on prion diseases
World Health Organisation – WHO information on prion diseases
Prion Animation (Flash required)

Reports and committees

The UK BSE Inquiry – Report of the UK public inquiry into BSE and variant CJD
UK Spongiform Encephalopathy Advisory Committee (SEAC)

Genetics

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

Research

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.

Other

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. (YouTube channel)

Template:Link GA

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@@ Line 11: / Line 11: @@
 A '''prion''' ({{IPAc-en|icon|Pronunciation prion.ogg|ˈ|p|r|iː|.|ɒ|n}})<ref>{{OED|Prion}}</ref> is an [[infectious agent]] composed of [[protein]] in a [[Protein_folding|misfolded]] form.<ref name=Sherris>{{cite book | editors = Ryan KJ, Ray CG, ''et al'' | title = Sherris Medical Microbiology | edition = 4th | publisher = McGraw Hill | year = 2004 | isbn = 0-8385-8529-9 | pages=624–8}}</ref> This is in contrast to all other known infectious agents, which must contain [[nucleic acid]]s (either [[DNA]], [[RNA]], or both).  The word '''prion,''' coined in 1982 by [[Stanley B. Prusiner]], is a [[portmanteau]] derived from the words ''protein'' and ''infection''.<ref name="Nobel">{{cite web | url=http://nobelprize.org/nobel_prizes/medicine/laureates/1997/prusiner-autobio.html | title=Stanley B. Prusiner - Autobiography | publisher=NobelPrize.org | accessdate=2007-01-02}}</ref> Prions are responsible for the [[transmissible spongiform encephalopathy|transmissible spongiform encephalopathies]] in a variety of [[mammal]]s, 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 [[neuron|neural]] tissue and all are currently untreatable and universally fatal.<ref>{{cite journal |author=Prusiner SB |title=Prions |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=95 |issue=23 |pages=13363–83 |year=1998 |month=November |pmid=9811807 |pmc=33918 |doi=10.1073/pnas.95.23.13363|url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9811807 |accessdate=2010-02-28}}</ref>
-Prions propagate by transmitting a [[protein folding|misfolded protein]] state.  When a prion enters a healthy organism, the prion form of a protein induces existing, properly-folded protein to convert into the disease-associated, prion form; the prion acts as a template to guide the misfolding of more protein into prion form.  These newly-formed prions can then go on to convert more proteins themselves, this triggers a chain reaction that produces large amounts of the prion form.<ref>{{cite journal |author=Aguzzi A |title=Unraveling prion strains with cell biology and organic chemistry |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=105 |issue=1 |pages=11–2 |year=2008 |month=January |pmid=18172195 |pmc=2224168 |doi=10.1073/pnas.0710824105 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=18172195 |accessdate=2010-02-28}}</ref> All known prions induce the formation of an [[amyloid]] fold, in which the protein polymerises into an aggregate consisting of tightly packed [[beta sheet]]s. Amyloid aggregates are fibrils, growing at their ends, and replicating 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.<ref name="Masel 99">{{cite journal |doi=10.1016/S0301-4622(99)00016-2 |author=Masel J, Jansen VAA, Nowak MA |title=Quantifying the kinetic parameters of prion replication |journal=Biophysical Chemistry |volume=77 |issue=2-3 |pages=139–152 |year=1999 |month=March|pmid=10326247}}</ref>  (Note that the propagation of the prion depends on the presence of normally-folded protein in which the prion can induce misfolding; animals which do not express the normal form of the prion protein cannot develop or transmit the disease.)
+Prions propagate by transmitting a [[protein folding|misfolded protein]] state.  When a prion enters a healthy organism, the prion form of a protein induces existing, properly-folded protein to convert into the disease-associated, prion form; the prion acts as a template to guide the misfolding of more protein into prion form.  These newly-formed prions can then go on to convert more proteins themselves, this triggers a chain reaction that produces large amounts of the prion form.<ref>{{cite journal |author=Aguzzi A |title=Unraveling prion strains with cell biology and organic chemistry |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=105 |issue=1 |pages=11–2 |year=2008 |month=January |pmid=18172195 |pmc=2224168 |doi=10.1073/pnas.0710824105 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=18172195 |accessdate=2010-02-28}}</ref> All known prions induce the formation of an [[amyloid]] fold, in which the protein polymerises into an aggregate consisting of tightly packed [[beta sheet]]s. Amyloid aggregates are fibrils, growing at their ends, and replicating 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.<ref name="Masel 99">{{cite journal |doi=10.1016/S0301-4622(99)00016-2 |author=Masel J, Jansen VAA, Nowak MA |title=Quantifying the kinetic parameters of prion replication |journal=Biophysical Chemistry |volume=77 |issue=2–3 |pages=139–152 |year=1999 |month=March|pmid=10326247}}</ref>  (Note that the propagation of the prion depends on the presence of normally-folded protein in which the prion can induce misfolding; animals which do not express the normal form of the prion protein cannot develop or transmit the disease.)
 This altered structure is extremely stable and accumulates in infected tissue, causing tissue damage and cell death.<ref>{{cite journal |author=Dobson CM |title=The structural basis of protein folding and its links with human disease |journal=Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences |volume=356 |issue=1406 |pages=133–45 |year=2001 |month=February |pmid=11260793 |pmc=1088418 |doi=10.1098/rstb.2000.0758 |url=http://rstb.royalsocietypublishing.org/cgi/pmidlookup?view=long&pmid=11260793 |accessdate=2010-02-28}} {{Dead link|date=September 2010|bot=H3llBot}}</ref> This structural stability means that prions are resistant to [[denaturation (biochemistry)|denaturation]] by chemical and physical agents, making disposal and containment of these particles difficult. Prions come in different strains, each with a slightly different structure, and most of the time, strains breed true. Prion replication is nevertheless subject to occasional [[epimutation]] and then [[natural selection]] just like other forms of replication.<ref>{{cite journal |author=Li J, Browning S, Mahal SP, Oelschlegel AM, Weissmann C |title=Darwinian evolution of prions in cell culture |journal=Science |volume=327 |issue=5967 |pages=869–72 |year=2010 |month=February |pmid=20044542 |pmc=2848070 |doi=10.1126/science.1183218 |url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=20044542 |accessdate=2010-02-28 |laysummary=http://news.bbc.co.uk/2/hi/health/8435320.stm}}</ref> However, the number of possible distinct prion strains is likely far smaller than the number of possible DNA sequences, so evolution takes place within a limited space.
@@ Line 36: / Line 36: @@
 ==== PrP<sup>C</sup> ====
-PrP<sup>C</sup> is a normal protein found on the [[cell membrane|membranes]] of [[cell (biology)|cells]]. It has 209 [[amino acid]]s (in humans), one [[disulfide bond]], a molecular weight of 35-36 [[Atomic mass unit|kDa]] and a mainly [[alpha helix|alpha-helical]] structure. Several [[Membrane topology|topological]] forms exist; one cell surface form anchored via [[glycolipid]] and two [[transmembrane]] forms.<ref>{{cite journal |author=Hegde RS, Mastrianni JA, Scott MR, ''et al.'' |title=A transmembrane form of the prion protein in neurodegenerative disease |journal=Science |volume=279 |issue=5352 |pages=827–34 |year=1998 |month=February |pmid=9452375 |doi=10.1126/science.279.5352.827 |url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=9452375 |accessdate=2010-02-28}}</ref> The normal protein is not sedimentable; meaning it cannot be separated by centrifuging techniques.<ref name=Krull>{{cite book |author=Krull, Ira S.; Brian K. Nunnally |title=Prions and mad cow disease |publisher=Marcel Dekker |location=New York, N.Y |year=2004 |pages=6 |isbn=0-8247-4083-1 |url=http://books.google.com/?id=WjeuaHopV5UC&pg=PA6&dq=Prions+and+mad+cow+disease+sedimentable&cd=1#v=onepage&q= |accessdate=2010-02-28}}</ref> Its function is a complex issue that continues to be investigated. PrP<sup>C</sup> binds [[copper]] (II) [[ion]]s with high affinity.<ref>{{cite journal |author=Brown DR, Qin K, Herms JW, ''et al.'' |title=The cellular prion protein binds copper in vivo |journal=Nature |volume=390 |issue=6661 |pages=684–7 |year=1997 |pmid=9414160 |doi=10.1038/37783 |accessdate=2010-02-28}}</ref> The significance of this finding is not clear, but it presumably relates to PrP structure or function. PrP<sup>C</sup> is readily digested by [[proteinase K]] and can be liberated from the cell surface in vitro by the enzyme [[phospholipase C|phosphoinositide phospholipase C]] (PI-PLC), which cleaves the [[glycophosphatidylinositol]] (GPI) glycolipid anchor.<ref name="weissmann">{{cite journal |author=Weissmann C |title=The state of the prion |journal=Nature Reviews. Microbiology |volume=2 |issue=11 |pages=861–71 |year=2004 |month=November |pmid=15494743 |doi=10.1038/nrmicro1025 |accessdate=2010-02-28}}</ref>  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.<ref>{{cite journal |author=Málaga-Trillo E, Solis GP, Schrock Y, ''et al.'' |title=Regulation of embryonic cell adhesion by the prion protein |journal=Plos Biology |volume=7 |issue=3 |pages=e55 |year=2009 |month=March |pmid=19278297 |pmc=2653553 |doi=10.1371/journal.pbio.1000055 |url=http://dx.plos.org/10.1371/journal.pbio.1000055 |accessdate=2010-02-28}}</ref>
+PrP<sup>C</sup> is a normal protein found on the [[cell membrane|membranes]] of [[cell (biology)|cells]]. It has 209 [[amino acid]]s (in humans), one [[disulfide bond]], a molecular weight of 35-36 [[Atomic mass unit|kDa]] and a mainly [[alpha helix|alpha-helical]] structure. Several [[Membrane topology|topological]] forms exist; one cell surface form anchored via [[glycolipid]] and two [[transmembrane]] forms.<ref>{{cite journal |author=Hegde RS, Mastrianni JA, Scott MR, ''et al.'' |title=A transmembrane form of the prion protein in neurodegenerative disease |journal=Science |volume=279 |issue=5352 |pages=827–34 |year=1998 |month=February |pmid=9452375 |doi=10.1126/science.279.5352.827 |url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=9452375 |accessdate=2010-02-28}}</ref> The normal protein is not sedimentable; meaning it cannot be separated by centrifuging techniques.<ref name=Krull>{{cite book |author=Krull, Ira S.; Brian K. Nunnally |title=Prions and mad cow disease |publisher=Marcel Dekker |location=New York, N.Y |year=2004 |pages=6 |isbn=0-8247-4083-1 |url=http://books.google.com/?id=WjeuaHopV5UC&pg=PA6&dq=Prions+and+mad+cow+disease+sedimentable&cd=1#v=onepage&q= |accessdate=2010-02-28}}</ref> Its function is a complex issue that continues to be investigated. PrP<sup>C</sup> binds [[copper]] (II) [[ion]]s with high affinity.<ref>{{cite journal |author=Brown DR, Qin K, Herms JW, ''et al.'' |title=The cellular prion protein binds copper in vivo |journal=Nature |volume=390 |issue=6661 |pages=684–7 |year=1997 |pmid=9414160 |doi=10.1038/37783 |accessdate=2010-02-28}}</ref> The significance of this finding is not clear, but it presumably relates to PrP structure or function. PrP<sup>C</sup> is readily digested by [[proteinase K]] and can be liberated from the cell surface in vitro by the enzyme [[phospholipase C|phosphoinositide phospholipase C]] (PI-PLC), which cleaves the [[glycophosphatidylinositol]] (GPI) glycolipid anchor.<ref name="weissmann">{{cite journal |author=Weissmann C |title=The state of the prion |journal=Nature Reviews. Microbiology |volume=2 |issue=11 |pages=861–71 |year=2004 |month=November |pmid=15494743 |doi=10.1038/nrmicro1025 |accessdate=2010-02-28}}</ref>  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.<ref>{{cite journal |author=Málaga-Trillo E, Solis GP, Schrock Y, ''et al.'' |title=Regulation of embryonic cell adhesion by the prion protein |journal=Plos Biology |volume=7 |issue=3 |pages=e55 |year=2009 |month=March |pmid=19278297 |pmc=2653553 |doi=10.1371/journal.pbio.1000055 |url=http://dx.plos.org/10.1371/journal.pbio.1000055 |accessdate=2010-02-28 |editor1-last=Weissmann |editor1-first=Charles}}</ref>
 ==== PrP<sup>Sc</sup> ====
@@ Line 51: / Line 51: @@
 [[File:Prion replication.png|thumb|left|Prion nucleation is rare, but can be bypassed by infection. Either nucleation or infection can initiate a replication cycle of fibril growth and breakage.]]
-An alternative model assumes that PrP<sup>Sc</sup> exists only as fibrils, and that fibril ends bind PrP<sup>C</sup> and convert it into PrP<sup>Sc</sup>. If this were all, then the quantity of prions would increase [[linear function|linearly]], forming ever longer fibrils. But [[exponential growth]] of both PrP<sup>Sc</sup> and of the [[Median lethal dose|quantity of infectious particles]] is observed during prion disease.<ref>{{cite journal |doi=10.1099/0022-1317-72-12-2905 |author=Bolton DC, Rudelli RD, Currie JR, Bendheim PE |title=Copurification of sp33-37 and scrapie agent from hamster brain prior to detectable histopathology and clinical-disease |journal=Journal of General Virology| volume=72 | pages=2905–2913 |year=1991 |pmid=1684986}}</ref><ref>{{cite journal |author=Jendroska K, Heinzel FP, Torchia M, Stowring L, Kretzschmar HA, Kon A, Stern A, Prusiner SB, DeArmond SJ |title=Proteinase-resistant prion protein accumulation in syrian-hamster brain correlates with regional pathology and scrapie infectivity |journal=Neurology| volume=41 |issue=9 | pages=1482–1490 |year=1991| url=http://www.neurology.org/cgi/content/abstract/41/9/1482?ck=nck |pmid=1679911}}</ref><ref>{{cite journal |doi=10.1099/0022-1317-77-8-1925 |author=Beekes M, Baldauf E, Diringer H |title=Sequential appearance and accumulation of pathognomonic markers in the central nervous system of hamsters orally infected with scrapie |journal=Journal of General Virology| volume=77 | pages=1925–1934 |year=1996 |pmid=8760444}}</ref> This can be explained by taking into account fibril breakage.<ref>{{cite journal |author=Bamborough P, Wille H, Telling GC, Yehiely F, Prusiner SB, Cohen FE |title=Prion protein structure and scrapie replication: theoretical, spectroscopic, and genetic investigations |journal=Cold Spring Harbor Symposium on Quantitative Biology| volume=61 | pages=495–509 |year=1996| pmid=9246476}}</ref> A mathematical solution for the [[exponential growth]] rate resulting from the combination of fibril growth and fibril breakage has been found.<ref name="Masel 99" /> The [[exponential growth]] rate depends largely on the [[square root]] of the PrP<sup>C</sup> concentration.<ref name="Masel 99" /> The [[incubation period]] is determined by the [[exponential growth]] rate, and [[in vivo]] data on prion diseases in [[transgenic mice]] match this prediction.<ref name="Masel 99" /> The same square root dependence is also seen [[in vitro]] in experiments with a variety of different [[amyloid|amyloid proteins]].<ref>{{cite journal |doi=10.1126/science.1178250 |author=Knowles TPJ, Waudby CA, Devlin GL, Cohen SIA, Aguzzi A, Vendruscolo M, Terentjev EM, Welland ME, Dobson CM |title=An Analytical Solution to the Kinetics of Breakable Filament Assembly |journal=Science| volume=326 |issue=5959 | pages=1533–1537 |year=2009 |pmid=20007899}}</ref>
+An alternative model assumes that PrP<sup>Sc</sup> exists only as fibrils, and that fibril ends bind PrP<sup>C</sup> and convert it into PrP<sup>Sc</sup>. If this were all, then the quantity of prions would increase [[linear function|linearly]], forming ever longer fibrils. But [[exponential growth]] of both PrP<sup>Sc</sup> and of the [[Median lethal dose|quantity of infectious particles]] is observed during prion disease.<ref>{{cite journal |doi=10.1099/0022-1317-72-12-2905 |author=Bolton DC, Rudelli RD, Currie JR, Bendheim PE |title=Copurification of sp33-37 and scrapie agent from hamster brain prior to detectable histopathology and clinical-disease |journal=Journal of General Virology| volume=72 | pages=2905–2913 |year=1991 |pmid=1684986 |issue=12}}</ref><ref>{{cite journal |author=Jendroska K, Heinzel FP, Torchia M, Stowring L, Kretzschmar HA, Kon A, Stern A, Prusiner SB, DeArmond SJ |title=Proteinase-resistant prion protein accumulation in syrian-hamster brain correlates with regional pathology and scrapie infectivity |journal=Neurology| volume=41 |issue=9 | pages=1482–1490 |year=1991| url=http://www.neurology.org/cgi/content/abstract/41/9/1482?ck=nck |pmid=1679911}}</ref><ref>{{cite journal |doi=10.1099/0022-1317-77-8-1925 |author=Beekes M, Baldauf E, Diringer H |title=Sequential appearance and accumulation of pathognomonic markers in the central nervous system of hamsters orally infected with scrapie |journal=Journal of General Virology| volume=77 | pages=1925–1934 |year=1996 |pmid=8760444 |issue=8}}</ref> This can be explained by taking into account fibril breakage.<ref>{{cite journal |author=Bamborough P, Wille H, Telling GC, Yehiely F, Prusiner SB, Cohen FE |title=Prion protein structure and scrapie replication: theoretical, spectroscopic, and genetic investigations |journal=Cold Spring Harbor Symposium on Quantitative Biology| volume=61 | pages=495–509 |year=1996| pmid=9246476}}</ref> A mathematical solution for the [[exponential growth]] rate resulting from the combination of fibril growth and fibril breakage has been found.<ref name="Masel 99" /> The [[exponential growth]] rate depends largely on the [[square root]] of the PrP<sup>C</sup> concentration.<ref name="Masel 99" /> The [[incubation period]] is determined by the [[exponential growth]] rate, and [[in vivo]] data on prion diseases in [[transgenic mice]] match this prediction.<ref name="Masel 99" /> The same square root dependence is also seen [[in vitro]] in experiments with a variety of different [[amyloid|amyloid proteins]].<ref>{{cite journal |doi=10.1126/science.1178250 |author=Knowles TPJ, Waudby CA, Devlin GL, Cohen SIA, Aguzzi A, Vendruscolo M, Terentjev EM, Welland ME, Dobson CM |title=An Analytical Solution to the Kinetics of Breakable Filament Assembly |journal=Science| volume=326 |issue=5959 | pages=1533–1537 |year=2009 |pmid=20007899}}</ref>
-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.<ref>{{cite journal |author=Masel J, Jansen VAA |title=Designing drugs to stop the formation of prions and other amyloids | journal=Biophysical Chemistry| volume=88 |issue=1-3 | pages=47–59 |year=2000 |pmid=11152275 |doi= 10.1016/S0301-4622(00)00197-6 |url=http://linkinghub.elsevier.com/retrieve/pii/S0301462200001976}}</ref>
+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.<ref>{{cite journal |author=Masel J, Jansen VAA |title=Designing drugs to stop the formation of prions and other amyloids | journal=Biophysical Chemistry| volume=88 |issue=1–3 | pages=47–59 |year=2000 |pmid=11152275 |doi= 10.1016/S0301-4622(00)00197-6 |url=http://linkinghub.elsevier.com/retrieve/pii/S0301462200001976}}</ref>
 == PrP function ==
@@ Line 61: / Line 61: @@
 === PrP and long-term memory ===
-There is evidence that PrP may have a normal function in maintenance of [[long-term memory]].<ref>{{cite journal |author=Shorter J, Lindquist S |title=Prions as adaptive conduits of memory and inheritance |journal=Nature Reviews. Genetics |volume=6 |issue=6 |pages=435–50 |year=2005 |month=June |pmid=15931169 |doi=10.1038/nrg1616 |accessdate=2010-02-28}}</ref> Maglio and colleagues have shown that mice without the genes for normal cellular PrP protein have altered [[hippocampus|hippocampal]] [[long-term potentiation]].<ref>{{cite journal |author=Maglio LE, Perez MF, Martins VR, Brentani RR, Ramirez OA |title=Hippocampal synaptic plasticity in mice devoid of cellular prion protein |journal=Brain Research. Molecular Brain Research |volume=131 |issue=1-2 |pages=58–64 |year=2004 |month=November |pmid=15530652 |doi=10.1016/j.molbrainres.2004.08.004 |url=http://linkinghub.elsevier.com/retrieve/pii/S0169-328X(04)00399-7 |accessdate=2010-02-28}}</ref>
+There is evidence that PrP may have a normal function in maintenance of [[long-term memory]].<ref>{{cite journal |author=Shorter J, Lindquist S |title=Prions as adaptive conduits of memory and inheritance |journal=Nature Reviews. Genetics |volume=6 |issue=6 |pages=435–50 |year=2005 |month=June |pmid=15931169 |doi=10.1038/nrg1616 |accessdate=2010-02-28}}</ref> Maglio and colleagues have shown that mice without the genes for normal cellular PrP protein have altered [[hippocampus|hippocampal]] [[long-term potentiation]].<ref>{{cite journal |author=Maglio LE, Perez MF, Martins VR, Brentani RR, Ramirez OA |title=Hippocampal synaptic plasticity in mice devoid of cellular prion protein |journal=Brain Research. Molecular Brain Research |volume=131 |issue=1–2 |pages=58–64 |year=2004 |month=November |pmid=15530652 |doi=10.1016/j.molbrainres.2004.08.004 |url=http://linkinghub.elsevier.com/retrieve/pii/S0169-328X(04)00399-7 |accessdate=2010-02-28}}</ref>
 === PrP and stem cell renewal ===
@@ Line 92: / Line 92: @@
 |[[Exotic ungulate encephalopathy]] (EUE)
 |-
-|[[ostrich]]<ref name="hussein2004">{{cite journal | author= Hussein MF, Al-Mufarrej SI | year= 2004 | url=http://www3.kfu.edu.sa/sjournal/eng/pdffiles/b526.pdf | format=pdf | title=Prion Diseases: A Review; II. Prion Diseases in Man and Animals. | journal=Scientific Journal of King Faisal University (Basic and Applied Sciences) | issue= 2 | pages=139 | accessdate=2010-02-28 | volume=5}}</ref>
+|[[ostrich]]<ref name="hussein2004">{{cite journal | author= Hussein MF, Al-Mufarrej SI | year= 2004 | url=http://www3.kfu.edu.sa/sjournal/eng/pdffiles/b526.pdf | format=pdf | title=Prion Diseases: A Review; II. Prion Diseases in Man and Animals | journal=Scientific Journal of King Faisal University (Basic and Applied Sciences) | issue= 2 | pages=139 | accessdate=2010-02-28 | volume=5}}</ref>
 |Spongiform encephalopathy<br>(Not been shown to be transmissible.)
 |-
@@ Line 134: / Line 134: @@
  |url=http://dx.plos.org/10.1371/journal.ppat.0030093 |accessdate=2010-02-28 }}</ref>
-A University of Californian research team, led by Nobel prize winner Stanley Prusiner, has proven that infection can occur from prions in manure.{{citation needed|date=December 2010}}  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.  It was 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]].<ref>{{Citation |last=MacKenzie |first=Debora
+A University of Californian research team, led by Nobel prize winner Stanley Prusiner, has proven that infection can occur from prions in manure.{{citation needed|date=December 2010}}  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.  It was 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]].<ref>{{Cite news |last=MacKenzie |first=Debora
  |date=13 January 2011 |title=Prion disease can spread through air |periodical=New Scientist
  |publisher=New Science Publications |at=Health |oclc=60637733 |accessdate=3 April 2011
- |url=http://www.newscientist.com/article/dn19971-prion-disease-can-spread-through-air.html }}</ref>  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.<ref>{{Citation
+ |url=http://www.newscientist.com/article/dn19971-prion-disease-can-spread-through-air.html |postscript=<!-- Bot inserted parameter. Either remove it; or change its value to "." for the cite to end in a ".", as necessary. -->{{inconsistent citations}} }}</ref>  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.<ref>{{Cite news
  |last=Dorsselaer |first=Alain Van |display-authors=3 |last9=Cashman |first9=Neil R.
  |last2=Carapito |first2=Christine |last3=Delalande |first3=François |last4=Schaeffer-Reiss |first4=Christine
@@ Line 145: / Line 145: @@
  |periodical=PLoS One |publisher=Public Library of Science |volume=6 |issue=3 |page=e17815
  |url=http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0017815
- |issn=1932-6203 |pmid=21448279 |pmc=3063168 |doi=10.1371/journal.pone.0017815 |oclc=70662135 }}</ref>
+ |issn=1932-6203 |pmid=21448279 |pmc=3063168 |doi=10.1371/journal.pone.0017815 |oclc=70662135
+ |editor1-last=Darlix
+ |editor1-first=Jean-Luc
+ |postscript=<!-- Bot inserted parameter. Either remove it; or change its value to "." for the cite to end in a ".", as necessary. -->{{inconsistent citations}} }}</ref>
 === 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 (biochemistry)|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 [[protease]]s, [[heat]], [[radiation]], and [[formalin]] treatments,<ref>{{cite journal |author=Qin K, O'Donnell M, Zhao RY |title=Doppel: more rival than double to prion |journal=Neuroscience |volume=141 |issue=1 |pages=1–8 |year=2006 |month=August |pmid=16781817 |doi=10.1016/j.neuroscience.2006.04.057 |url=http://linkinghub.elsevier.com/retrieve/pii/S0306-4522(06)00510-0 |accessdate=2010-02-28}}</ref> 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.<ref>{{cite journal |author=Race RE, Raymond GJ |title=Inactivation of transmissible spongiform encephalopathy (prion) agents by environ LpH |journal=Journal of Virology |volume=78 |issue=4 |pages=2164–5 |year=2004 |month=February |pmid=14747583 |pmc=369477 |doi=10.1128/JVI.78.4.2164-2165.2004 |url=http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=14747583 |accessdate=2010-02-28}}</ref> 134°C (274°F) for 18 minutes in a pressurized steam [[autoclave]] may not be enough to deactivate the agent of disease.<ref>{{cite journal |author=Collins SJ, Lawson VA, Masters CL |title=Transmissible spongiform encephalopathies |journal=Lancet |volume=363 |issue=9402 |pages=51–61 |year=2004 |pmid=14723996 |doi=10.1016/S0140-6736(03)15171-9}}</ref><ref name="pmid10716712">{{cite journal |author=Brown P, Rau EH, Johnson BK, Bacote AE, Gibbs CJ, Gajdusek DC |title=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 |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=97 |issue=7 |pages=3418–21 |year=2000 |month=March |pmid=10716712 |pmc=16254 |doi=10.1073/pnas.050566797 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=10716712 |accessdate=2010-02-28}}</ref> Ozone sterilization is currently being studied as a potential method for prion denature and deactivation.<ref>{{cite web | url=http://www.hpa.org.uk/hpa/news/articles/press_releases/2005/050414_ozone_sterilizer.htm  | title=Ozone Sterilization | date=2005-04-14 | publisher=UK Health Protection Agency | accessdate=2010-02-28 |archiveurl = http://web.archive.org/web/20080522065033/http://www.hpa.org.uk/hpa/news/articles/press_releases/2005/050414_ozone_sterilizer.htm |archivedate = 2008-05-22}}</ref> 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.<ref>{{cite journal |author=Weissmann C, Enari M, Klöhn PC, Rossi D, Flechsig E |title=Transmission of prions |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=99 Suppl 4 |issue= |pages=16378–83 |year=2002 |month=December |pmid=12181490 |pmc=139897 |doi=10.1073/pnas.172403799 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=12181490 |accessdate=2010-02-28}}</ref>
+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 (biochemistry)|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 [[protease]]s, [[heat]], [[radiation]], and [[formalin]] treatments,<ref>{{cite journal |author=Qin K, O'Donnell M, Zhao RY |title=Doppel: more rival than double to prion |journal=Neuroscience |volume=141 |issue=1 |pages=1–8 |year=2006 |month=August |pmid=16781817 |doi=10.1016/j.neuroscience.2006.04.057 |url=http://linkinghub.elsevier.com/retrieve/pii/S0306-4522(06)00510-0 |accessdate=2010-02-28}}</ref> 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.<ref>{{cite journal |author=Race RE, Raymond GJ |title=Inactivation of transmissible spongiform encephalopathy (prion) agents by environ LpH |journal=Journal of Virology |volume=78 |issue=4 |pages=2164–5 |year=2004 |month=February |pmid=14747583 |pmc=369477 |doi=10.1128/JVI.78.4.2164-2165.2004 |url=http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=14747583 |accessdate=2010-02-28}}</ref> 134°C (274°F) for 18 minutes in a pressurized steam [[autoclave]] may not be enough to deactivate the agent of disease.<ref>{{cite journal |author=Collins SJ, Lawson VA, Masters CL |title=Transmissible spongiform encephalopathies |journal=Lancet |volume=363 |issue=9402 |pages=51–61 |year=2004 |pmid=14723996 |doi=10.1016/S0140-6736(03)15171-9}}</ref><ref name="pmid10716712">{{cite journal |author=Brown P, Rau EH, Johnson BK, Bacote AE, Gibbs CJ, Gajdusek DC |title=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 |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=97 |issue=7 |pages=3418–21 |year=2000 |month=March |pmid=10716712 |pmc=16254 |doi=10.1073/pnas.050566797 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=10716712 |accessdate=2010-02-28}}</ref> Ozone sterilization is currently being studied as a potential method for prion denature and deactivation.<ref>{{cite web | url=http://www.hpa.org.uk/hpa/news/articles/press_releases/2005/050414_ozone_sterilizer.htm  | title=Ozone Sterilization | date=2005-04-14 | publisher=UK Health Protection Agency | accessdate=2010-02-28 |archiveurl = http://web.archive.org/web/20080522065033/http://www.hpa.org.uk/hpa/news/articles/press_releases/2005/050414_ozone_sterilizer.htm |archivedate = 2008-05-22}}</ref> 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.<ref>{{cite journal |author=Weissmann C, Enari M, Klöhn PC, Rossi D, Flechsig E |title=Transmission of prions |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=99 Suppl 4 |issue= 90004|pages=16378–83 |year=2002 |month=December |pmid=12181490 |pmc=139897 |doi=10.1073/pnas.172403799 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=12181490 |accessdate=2010-02-28}}</ref>
 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:
@@ Line 179: / Line 182: @@
 ==== Multi-component hypothesis ====
-In 2007, biochemist Surachai Supattapone and his colleagues at [[Dartmouth College]] produced purified infectious prions ''de novo'' from defined components (PrP<sup>C</sup>, co-purified lipids, and a synthetic polyanionic molecule).<ref name="minimal prion">{{cite journal |author=Deleault NR, Harris BT, Rees JR, Supattapone S |title=Formation of native prions from minimal components in vitro |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=104 |issue=23 |pages=9741–6 |year=2007 |month=June |pmid=17535913 |pmc=1887554 |doi=10.1073/pnas.0702662104 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=17535913 |accessdate=2010-02-28}}</ref>  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<sup>Sc</sup> alone.<ref>{{cite journal |author=Geoghegan JC, Valdes PA, Orem NR, ''et al.'' |title=Selective incorporation of polyanionic molecules into hamster prions |journal=The Journal of Biological Chemistry |volume=282 |issue=50 |pages=36341–53 |year=2007 |month=December |pmid=17940287 |doi=10.1074/jbc.M704447200 |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=17940287 |accessdate=2010-02-28}}</ref>
+In 2007, biochemist Surachai Supattapone and his colleagues at [[Dartmouth College]] produced purified infectious prions ''de novo'' from defined components (PrP<sup>C</sup>, co-purified lipids, and a synthetic polyanionic molecule).<ref name="minimal prion">{{cite journal |author=Deleault NR, Harris BT, Rees JR, Supattapone S |title=Formation of native prions from minimal components in vitro |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=104 |issue=23 |pages=9741–6 |year=2007 |month=June |pmid=17535913 |pmc=1887554 |doi=10.1073/pnas.0702662104 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=17535913 |accessdate=2010-02-28}}</ref>  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<sup>Sc</sup> alone.<ref>{{cite journal |author=Geoghegan JC, Valdes PA, Orem NR, ''et al.'' |title=Selective incorporation of polyanionic molecules into hamster prions |journal=The Journal of Biological Chemistry |volume=282 |issue=50 |pages=36341–53 |year=2007 |month=December |pmid=17940287 |doi=10.1074/jbc.M704447200 |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=17940287 |accessdate=2010-02-28 |pmc=3091164}}</ref>
 In 2010, Jiyan Ma and colleagues at The Ohio State University produced infectious prions from a recipe of bacterially expressed recombinant PrP, POPG phospholipid, and RNA, further supporting the multi-component hypothesis.<ref name="recombinant prion">{{cite journal |author=Wang F, Wang X, Yuan CG, Ma J |title=Generating a prion with bacterially expressed recombinant prion protein |journal=Science |volume=327 |issue=5969 |pages=1132–5 |year=2010 |month=February |pmid=20110469 |pmc=2893558 |doi=10.1126/science.1183748 |url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=20110469 |accessdate=2010-02-28}}</ref>  This finding is in contrast to studies that found minimal infectious prions produced from recombinant PrP alone.<ref>{{cite journal |author=Legname G, Baskakov IV, Nguyen HO, ''et al.'' |title=Synthetic mammalian prions |journal=Science |volume=305 |issue=5684 |pages=673–6 |year=2004 |month=July |pmid=15286374 |doi=10.1126/science.1100195 |url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=15286374 |accessdate=2010-02-28}}</ref><ref>{{cite journal |author=Makarava N, Kovacs GG, Bocharova O, ''et al.'' |title=Recombinant prion protein induces a new transmissible prion disease in wild-type animals |journal=Acta Neuropathologica |volume=119 |issue=2 |pages=177–87 |year=2010 |month=February |pmid=20052481 |pmc=2808531 |doi=10.1007/s00401-009-0633-x |accessdate=2010-02-28}}</ref>

Prion: Difference between revisions

Revision as of 20:21, 17 May 2011

Discovery

Structure

Isoforms

PrP^C

PrP^Sc

Prion replication mechanism

PrP function

PrP and long-term memory

PrP and stem cell renewal

Prion disease

Transmission

Sterilization

Debate

Protein hypothesis

Genetic factors

Multi-component hypothesis

Heavy metal poisoning hypothesis

Viral hypothesis

Fungi

Potential treatments

See also

Further reading

References

External links

General

Reports and committees

Genetics

Research

Other

Revision as of 20:21, 17 May 2011

Discovery

Structure

Isoforms

PrPC

PrPSc

Prion replication mechanism

PrP function

PrP and long-term memory

PrP and stem cell renewal

Prion disease

Transmission

Sterilization

Debate

Protein hypothesis

Genetic factors

Multi-component hypothesis

Heavy metal poisoning hypothesis

Viral hypothesis

Fungi

Potential treatments

See also

Further reading

References

External links

General

Reports and committees

Genetics

Research

Other

PrP^C

PrP^Sc