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Prion

2007 Schools Wikipedia Selection. Related subjects: Health and medicine

   CAPTION: Prion Diseases (TSEs)
   Classifications and external resources

   ICD- 10 A81
   ICD- 9  046

   A prion ( IPA: [ˈpriːɒn] . listen ) — short for proteinaceous
   infectious particle (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, 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. Diseases as varied as fatal familial
   insomnia and kuru (laughing death) 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. 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. (see external links below, Science
   Daily article on vaccine).

   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
   fibre 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. This theory was developed to explain the
   discovery that the mysterious infectious agent causing the diseases
   scrapie and Creutzfeldt-Jakob Disease, which resisted ultraviolet
   radiation (which breaks down nucleic acids - present in viruses and all
   living things), yet responded to agents that disrupt proteins.

   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.
   Proposed mechanism of prion propagation
   Enlarge
   Proposed mechanism of prion propagation

   Further research showed that prions are found throughout the body, even
   in healthy people and animals. However, the prion 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' PrP, while the 'Sc' refers
   to ' scrapie,' a prion disease occurring in sheep. Normal prion (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.

   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
   PrP^C more likely to spontaneously change into the PrP^Sc (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 PrP^C to PrP^Sc
   by bringing a molecule of each of the two together into a complex.

   Prior to Alper's insight, all known pathogens (bacteria, viruses, etc.)
   contained nucleic acids that are necessary for reproduction. The prion
   hypothesis was highly controversial, because it seemed to contradict
   the so-called " central dogma of modern biology" that asserts all
   living organisms use nucleic acids to reproduce. The "protein-only
   hypothesis" — that a protein structure (which, unlike DNA, has no
   obvious means of replication) could reproduce itself — was initially
   met with skepticism. Scientists were skeptical of the idea that a
   protein structure could reproduce itself without DNA. It does not
   contradict the central role of DNA. The prion hypothesis proposes a
   means of spreading the shape of a protein.

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 fibre. 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.
   Molecular models of the structure of PrPC (left) and PrPSc (right)
   Enlarge
   Molecular models of the structure of PrP^C (left) and PrP^Sc (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 PrP^C. (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 PrP^Sc is not known, there is increased β sheet content
   (green arrows) in the diseased form of the molecule. These β sheets are
   thought to lead to amyloid aggregation.

Dissent

   Mark Purdy and Doctor David R. Brown have suggested that metal ion
   interactions with prion protein might be relevant to progression of
   prion-mediated disease. Purdy cites epidemiological studies of clusters
   of prion disease in locales with low soil concentrations of copper as
   evidence.

   Brown's work explains how protein tissue can be incinerated and remain
   "infectious", if that is the proper term for a theory that resembles
   heavy metal poisoning. Brown, of Oxford, agrees that banning
   cannibalism in cows was correct.

Therapeutic strategies

   Recently Japanese scientists at the Obihiro University of Agriculture
   and Veterinary Medicine developed one of the first strategies to
   delaying the onset of disease. They found that sulfated
   glycosaminoglycans (GAGs) and sulfated glycans inhibit formation of
   protease resistant protein in cells and prolong the incubation time of
   scrapie-infected animals. Among the glycopyranosides and their polymers
   examined, monomeric 4-sulfo-N-acetyl-glucosamine (4SGN), and two
   glycopolymers, poly-4SGN and poly-6-sulfo-N-acetyl-glucosamine
   (poly-6SGN), inhibited PrPSc formation with 50% effective doses below
   20 microg/ml, and their inhibitory effect became more evident with
   consecutive treatments. Structural comparisons suggested that a
   combination of an N-acetyl group at C-2 and an M-sulfate group at
   either O-4 or O-6 on glucopyranoside might be involved in the
   inhibition of PrPSc formation. Furthermore, polymeric but not monomeric
   6SGN inhibited PrPSc formation, suggesting the importance of a
   polyvalent configuration in its effect. These results indicate that the
   synthetic sulfated glycosides are useful not only for the analysis of
   structure-activity relationship of GAGs but also for the development of
   therapeutics for prion diseases.

Prion Diseases

   The following diseases are now believed to be caused by prions.
     * In animals:

          + 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

     * In humans:

          + 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

   Retrieved from " http://en.wikipedia.org/wiki/Prion"
   This reference article is mainly selected from the English Wikipedia
   with only minor checks and changes (see www.wikipedia.org for details
   of authors and sources) and is available under the GNU Free
   Documentation License. See also our Disclaimer.
