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Prion Diseases (TSEs)
Classification and external resources

Microscopic "holes" are characteristic in prion-affected tissue sections, causing the tissue to develop a "spongy" architecture.
ICD-10 A81
ICD-9 046

A prion (pronounced /ˈpriː.ɒn/ ( listen)[1]) is an infectious agent that is composed primarily of protein.[2] To date, all such agents that have been discovered propagate by transmitting a mis-folded protein state; as with viruses the protein itself does not self-replicate, rather it induces existing polypeptides in the host organism to take on the rogue form.[3] The misfolded 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 universally fatal.[4] In general usage, prion refers to the theoretical unit of infection. In scientific notation, PrPC refers to the endogenous form of prion protein (PrP), which is found in a multitude of tissues, while PrPSc refers to the misfolded form of PrP, that is responsible for the formation of amyloid plaques[5] and neurodegeneration.[6] The precise composition of the prion is not known, though they can be formed by combining PrPC, polyadenylic acid, and lipids.[7]

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.[8] This structural stability means that prions are resistant to denaturation by chemical and physical agents, making disposal and containment of these particles difficult. Evolutionarily, prion replication has been shown to be subject to mutation and natural selection just like other forms of replication.[9]

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.[10]

The word prion is a portmanteau derived from the initial and final letters of the words proteinaceous and infection.[11]

Contents

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.[12][13] Their 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": 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).[14] 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 award.

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.[15] 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.[16]

Structure

Protein structure of the normal prion protein (PrP).

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 PrPC, while the infectious form is called PrPSc — the C refers to 'cellular' or 'common' PrP, while the Sc refers to 'scrapie', a prion disease occurring in sheep.[17] While PrPC is structurally well-defined, PrPSc 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.

PrPC

PrPC 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.[18] The normal protein is not sedimentable; meaning it cannot be separated by centrifuging techniques.[5] Its function is a complex issue that continues to be investigated. PrPC binds copper (II) ions with high affinity.[19] The significance of this finding is not clear, but it presumably relates to PrP structure or function. PrPC 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.[20] 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.[21]

PrPSc

The infectious isoform of PrP, known as PrPSc, is able to convert normal PrPC proteins into the infectious isoform by changing their conformation, or shape; this, in turn, alters the way the proteins interconnect. Although the exact 3D structure of PrPSc is not known, it has a higher proportion of β-sheet structure in place of the normal α-helix structure.[22] 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.[23] 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 PrPSc are incorporated into the growing fiber.[5]

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.[24]

PrP and long-term memory

There is evidence that PrP may have a normal function in maintenance of long-term memory.[25] Maglio and colleagues have shown that mice without the genes for normal cellular PrP protein have altered hippocampal long-term potentiation.[26]

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.[27]

Prion disease

Diseases caused by prions
Affected animal(s) Disease
sheep, goat Scrapie[28]
cattle Bovine spongiform encephalopathy (BSE), mad cow disease[28]
mink[28] Transmissible mink encephalopathy (TME)
white-tailed deer, elk, mule deer, moose[28] Chronic wasting disease (CWD)
cat[28] Feline spongiform encephalopathy (FSE)
nyala, oryx, greater kudu[28] Exotic ungulate encephalopathy (EUE)
ostrich[29] Spongiform encephalopathy
(Not been shown to be transmissible.)
human Creutzfeldt–Jakob disease (CJD)[28]
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)[28]
Fatal familial insomnia (sFI)[30]
Kuru[28]

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.[31] Other histological changes include astrogliosis and the absence of an inflammatory reaction.[32] While the incubation period for prion diseases is generally quite long, once symptoms appear the disease progresses rapidly, leading to brain damage and death.[33] 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.[34] A vaccine has been developed in mice, however, that may provide insight into providing a vaccine in humans to resist prion infections.[35] 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,[36] building on research indicating that mice lacking normally-occurring prion protein are resistant to infection by scrapie prion protein.[37]

Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all mammals.[38] 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.[39]

Transmission

Proposed mechanism of prion propagation

It has been recognized that prion diseases can arise in three different ways: acquired, familial, or sporadic.[40] It is often assumed that the diseased form directly interacts with the normal form to make it rearrange its structure. One idea, the "Protein X" hypothesis, is that an as-yet unidentified cellular protein (Protein X) enables the conversion of PrPC to PrPSc by bringing a molecule of each of the two together into a complex.[41]

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.[42]

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,[43] 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.[44] 134°C (274°F) for 18 minutes in a pressurized steam autoclave may not be enough to deactivate the agent of disease.[45][46] Ozone sterilization is currently being studied as a potential method for prion denature and deactivation.[47] 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.[48]

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.[49]

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 alternative 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:[50]

  • 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
  • PrPSc experimentally transmitted between one species and another results in PrPSc 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 PrPC 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.[7]

Genetic factors

A gene for the normal protein has been identified: the PRNP gene.[51] 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 PrPC more likely to change spontaneously into the abnormal PrPSc form.[52] 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.[53] For example, in order to have scrapie, both an infectious agent and a susceptible genotype need to be present.[52]

Multi-component hypothesis

In 2007, biochemist Surachai Supattapone and his colleagues at Dartmouth College produced purified infectious prions de novo from defined components (PrPC, co-purified lipids, and a synthetic polyanionic molecule).[7] 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 PrPSc alone.[54]

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.[55] This finding is in contrast to studies that found minimal infectious prions produced from recombinant PrP alone.[56][57]

Heavy metal poisoning hypothesis

Recent reports suggest that imbalance of brain metal homeostasis is a significant cause of PrPSc-associated neurotoxicity, though the underlying mechanisms are difficult to explain based on existing information. Proposed hypotheses include a functional role for PrPC in metal metabolism, and loss of this function due to aggregation to the disease associated PrPSc form as the cause of brain metal imbalance. Other views suggest gain of toxic function by PrPSc due to sequestration of PrPC-associated metals within the aggregates, resulting in the generation of redox-active PrPSc complexes. The physiological implications of some PrPC-metal interactions are known, while others are still unclear. The pathological implications of PrPC-metal interaction include metal-induced oxidative damage, and in some instances conversion of PrPC to a PrPSc-like form.[58]

Viral hypothesis

The protein-only hypothesis has been criticised by those who feel that the simplest explanation of the evidence to date is viral.[59] 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.[60][61]

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:[50]

  • 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.[61]

Recent studies propagating TSE infectivity in cell-free reactions[62] and in purified component chemical reactions [7] 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[55], casting further doubt on the viral hypothesis.

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.[63]

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 PrPC and stabilize the conformation, reducing the amount of harmful PrPSc.[64]

See also

Further reading

References

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Wikispecies

Up to date as of January 23, 2010

From Wikispecies

Taxonavigation

Regnum: not divided
Phylum: not divided
Classis: not divided
Ordo: not divided
Familia: Prion
Genera: Mammalian Prions - Fungal Prions

References


Simple English

File:Histology
Prions infect tissues and make them look spongy.

Prions ( listen (info • help)), short for "proteinaceous infectious particles (-ons)" are proteins that can make people sick. It is known to cause many forms of encephalitis, or brain disease, such as scrapie, Creutzfeldt-Jakob Disease, kuru, and Bovine Spongiform Encephalopathy, also known as Mad Cow Disease. Prions work by changing the shape of proteins in the living things it causes disease in. While normal proteins have lots of alpha helices, or twisted parts, changed proteins have lots of beta sheets, or flat parts. The word is pronounced pree-on.

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