Prion

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Prion Diseases (TSEs)
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ICD-10 A81
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ICD-9 046
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DiseasesDB {{{DiseasesDB}}}

A prion (IPA: [ˈpriːɒn].[1][2]) — short for proteinaceous infectious particle that lacks nucleic acid (by analogy to virion) — is a type of infectious agent made only of protein. Prions are believed 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, and they are generally quite resistant to denaturation by protease, heat, radiation, and formalin treatments,[3] although potency or infectivity can be reduced. The term does not, however, a priori preclude other mechanisms of transmission.

Although genetic research may shed light on prions, and there is a genetic component to many prion diseases, prion diseases are not exclusively genetic diseases and are grouped as transmissible spongiform encephalopathies. Diseases as varied as fatal familial insomnia and kuru (a laughing death that is translated into "to tremble with fear") are believed to be associated with prions. Other prion diseases include scrapie (a disease of sheep), chronic wasting disease, (in deer and elk), variant Creutzfeldt-Jakob disease (vCJD), and bovine spongiform encephalopathy (BSE or mad cow disease), all caused by similar proteins in different species.[4] It should be noted that the same gene is responsible for spongiform encephalopathies which are not known to be transmissible, as well as some non-neurological diseases. Some require a mutation for transmission to occur, and there are respective mutations which can prevent transmission for most of the TSEs. A non-disease function of the prion gene is not known but is an area of considerable active research.

All of these diseases affect the structure of the brain or other neural tissue, and all are untreatable and fatal. However, a vaccine has been developed in mice that may provide insight into providing a vaccine in humans to resist prion infections.[5]

Proteins showing prion behaviour are also found in some fungi. Some fungal prions may not be associated with any disease; it is unknown whether these prions represent an evolutionary advantage for their hosts. All known prions are believed to infect and propagate by formation of an amyloid fold, in which the protein polymerizes into a fiber with a core consisting of tightly packed beta sheets. Other mechanisms may exist in yet undiscovered infectious protein particles.

PrP and the prion hypothesis

Radiation biologist Tikvah Alper and physicist J.S. Griffith developed the theory in the 1960s that some TSEs are caused by an infectious agent made solely of protein.[6][7] This theory was developed to explain the discovery that the mysterious infectious agent causing the diseases scrapie and Creutzfeldt-Jakob Disease resisted ultraviolet radiation (which breaks down nucleic acids - present in viruses and all living things) yet responded to agents that disrupt proteins.[6]

A breakthrough occurred in 1982 when researchers led by Stanley B. Prusiner of the University of California, San Francisco purified infectious material and confirmed that the infectious agent consisted mainly of a specific protein. Prusiner coined the word "prion" as a name for the infectious agent, by combining the first two syllables of the words "proteinaceous" and "infectious." While the infectious agent was named a prion, the specific protein that the prion was made of was named PrP, an abbreviation for "protease-resistant protein". Prusiner received the Nobel Prize in Physiology or Medicine in 1997 for this research.[8]

File:Prion propagation.png
Proposed mechanism of prion propagation

Further research showed that the protein that prions are made of is found throughout the body, even in healthy people and animals. However, the prion protein 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' PrP, while the 'Sc' refers to 'scrapie,' a prion disease occurring in sheep. Normal prion protein(Common or cellular) is found on the membranes of cells, though its function has not been fully resolved. Since the original hypothesis was proposed, a gene for the normal protein has been isolated: the PRNP gene.[9]

Some prion diseases (TSEs) can be inherited, and in all inherited cases 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 spontaneously change into the PrPSc (disease) form. TSEs are the only known diseases that can be sporadic, genetic, or infectious; for more information see the article on TSEs.

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 (enlarge the diagram above for an illustration of this mechanism). 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.[10]

The prion hypothesis was initially highly controversial, because it seemed to contradict the so-called "central dogma of modern biology," which asserts that all living organisms use nucleic acids to reproduce. Prior to Alper's insight, all known pathogens (bacteria, viruses, etc.) used nucleic acids for their reproduction. The "protein-only hypothesis" – that a protein structure could reproduce itself in the absence of DNA – was initially met with skepticism.


Prions in yeast and other fungi

Prion-like proteins that behave in a similar way to PrP are found naturally in some fungi and non-mammalian animals. A group at the Whitehead Institute has argued that some of the fungal prions are not associated with any disease state and 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. Research into fungal prions has given strong support to the protein-only hypothesis for mammalian prions, as it has been demonstrated that seeds extracted from cells with the prion state, can convert the normal form of the protein into the infectious 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. Fungal prions have helped to suggest mechanisms of conversion that may apply to all prions.

Molecular properties

A great deal of our knowledge of how prions work at a molecular level comes from detailed biochemical analysis of yeast prion proteins. A typical yeast prion protein contains a region (protein domain) with many repeats of the amino acids glutamine (Q) and asparagine (N); these Q/N-rich domains form the core of the prion's structure. Ordinarily, yeast prion domains are flexible and lack a defined structure. When they convert to the prion state, several molecules of a particular protein come together to form a highly structured amyloid fiber. The end of the fiber acts as a template for the free protein molecules, causing the fiber to grow. Small differences in the amino acid sequence of prion-forming regions lead to distinct structural features on the surface of prion fibers. As a result, only free protein molecules that are identical in amino acid sequence to the prion protein can be recruited into the growing fiber. This "specificity" phenomenon may explain why transmission of prion diseases from one species to another, such as from sheep to cows or from cows to humans is a rare event.

File:Prion.gif
Molecular models of the structure of PrPC (left) and PrPSc (right)

The mammalian prion proteins do not resemble the prion proteins of yeast in their amino acid sequence. Nonetheless, the basic structural features (formation of amyloid fibers and a highly specific barrier to transmission between species) are shared between mammalian and yeast prions. The prion variant responsible for mad cow disease has the remarkable ability to bypass the species barrier to transmission.

The figure at right shows a model of two conformations of prion; on the left is the known, normal conformation of the structured C-terminal region of PrPC. (to explore/download see the RCSB Protein Databank). The N-terminal region is not shown here for having a flexible structure in aqueous solution. The structured domain shown is mainly made of three spirals called alpha helices (pink), with two short 'flat' regions of beta sheet (β sheet) structure (green). On the right is a proposed model of how the abnormal prion might look. Although the exact 3D structure of PrPSc is not known, there is increased β sheet content (green arrows) in the diseased form of the molecule.[11] These β sheets are thought to lead to amyloid aggregation.

Prions and long-term memory

There is evidence that prions may have a normal function in maintenance of memories over a long period of time.[12] Maglio and colleagues have shown that mice without the genes for normal cellular prion protein have altered hippocampal LTP.[13]

Other theories

Mark Purdey and Dr. David R. Brown have suggested that known metal ion interactions with prion protein might be relevant to progression of prion-mediated disease.[14] Purdey cited epidemiological studies of clusters of prion disease in locales with low soil concentrations of copper as evidence.


Brown's work claims to explain how protein tissue can be incinerated and remain "infectious", if that is the proper term for a theory that resembles heavy metal poisoning. Brown, whose primary professional affiliation is with the University of Bath in the United Kingdom, agrees that banning cannibalism in cows was a justifiable course of action.

Prion diseases

The following diseases are now believed to be caused by prions.

  • Scrapie in sheep
  • Bovine Spongiform Encephalopathy (BSE) in cows
  • Transmissible mink encephalopathy (TME) in mink
  • Chronic Wasting Disease (CWD) in elk and mule deer
  • Feline spongiform encephalopathy in cats
  • Exotic ungulate encephalopathy (EUE) in nyala, oryx and greater kudu
  • several varieties of Creutzfeldt-Jakob Disease (CJD), such as Iatrogenic Creutzfeldt-Jakob disease, Variant Creutzfeldt-Jakob disease, Familial Creutzfeldt-Jakob disease, and Sporadic Creutzfeldt-Jakob disease
  • Gerstmann-Sträussler-Scheinker syndrome (GSS)
  • Fatal Familial Insomnia (FFI)
  • Kuru
  • Alpers Syndrome

Genetic engineering research

On 31 December, 2006, Hematech, a biotechnology company based in Sioux Falls, South Dakota, announced that it had used genetic engineering and cloning technology to produce cattle that lacked a necessary gene for prion production - thus theoretically making them immune to BSE.[15]

Research with mice had previously indicated that animals lacking endogenous prion protein are resistant to infection by scrapie prion protein.[16]

See also

  • Transmissible spongiform encephalopathy

References
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  1. "prion". Oxford English Dictionary. Oxford University Press. 2nd ed. 1989.
  2. Pruisner, SB (1982), "Novel proteinaceous infectious particles cause scrapie", Science, vol. 216, no. 4542, p. 136-44 (pronounciation is explicitly defined as "pree-on" on page 141, third column)
  3. Qin, K. and O'Donnell, M., Zhao, R. Y. (2006-06-15). Doppel: More rival than double to prion. Neuroscience 141 (1): 1–8. PMID 16781817.
  4. (2001). Prion diseases of humans and animals: their causes and molecular basis. Annu Rev Neurosci 24: 519-50. PMID 11283320.
  5. (14 May 2005) Active Vaccine Prevents Mice From Developing Prion Disease. Science Daily.
  6. 6.0 6.1 (1967 May 20) Does the agent of scrapie replicate without nucleic acid?. Nature 214 (90): 764-6. PMID 4963878 Digital object identifier (DOI): 10.1038/214764a0.
  7. (1967 Sep 2) Self-replication and scrapie. Nature 215 (105): 1043-4. PMID 4964084 Digital object identifier (DOI): 10.1038/2151043a0.
  8. (1982 Apr 9) Novel proteinaceous infectious particles cause scrapie. Science 216 (4542): 136-44. PMID 6801762 Digital object identifier (DOI): 10.1126/science.278.5336.245.
  9. (1985 Apr) A cellular gene encodes PrP 27-30 protein. Cell 40 (4): 735-46. PMID 2859120.
  10. (1995 Oct 6) Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell 83 (1): 79-90. PMID 7553876.
  11. (1993 Dec 1)Conversion of alpha-helices into beta-sheets features in the formation of scrapie prion protein. PNAS USA 90 (23): 10962-6. PMID 7902575.
  12. (2005)Prions as adaptive conduits of memory and inheritance.. Nature Reviews Genetics 6: 435-450.
  13. (2004)Hippocampal synaptic plasticity in mice devoid of cellular prion protein. Molecular Brain Research 131 (1-2): 58-64.
  14. 2000-09-22, Normal Function of Prions, Statement to the BSE Inquiry
  15. Weiss, Rick, "Scientists Announce Mad Cow Breakthrough", The Washington Post, 2007-01-01. Retrieved 2007-01-01.
  16. Mice devoid of PrP are resistant to scrapie by H. Bueler, A. Aguzzi, A. Sailer, R. A. Greiner, P. Autenried, M. Aguet and C. Weissmann in Cell (1993) Volume 73 pages 1339-1347.

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