Difference between revisions of "Prion" - New World Encyclopedia

From New World Encyclopedia
 
(20 intermediate revisions by 6 users not shown)
Line 1: Line 1:
{{for|the bird|Prion (bird)}}
+
{{Paid}}{{Approved}}{{Images OK}}{{Submitted}}{{Copyedited}}
{{DiseaseDisorder infobox |
+
 
  Name       = Prion Diseases (TSEs)|
+
{{Infobox disease
  ICD10       = A81 |
+
| Name = Prion Diseases (TSEs)
  ICD9       = {{ICD9|046}} |
+
| Image = Histology bse.jpg
 +
| Caption = Microscopic "holes" are characteristic in prion-affected tissue sections, causing the tissue to develop a "spongy" architecture.
 +
| ICD10 = {{ICD10|A|81||a|81}}
 +
| ICD9 = {{ICD9|046}}
 +
| MeshID =
 
}}
 
}}
A '''prion''' ({{IPA2|ˈpriːɒn}}.<ref>{{OED|prion}}</ref><ref>{{Harvard reference | Surname=Pruisner | Given=SB | Authorlink=Stanley Prusiner | Title=Novel proteinaceous infectious particles cause scrapie | Journal=Science | Volume=216 | Issue=4542 | Year=1982 | Page=136-44 (pronounciation is explicitly defined as "pree-on" on page 141, third column) | URL=http://www.sciencemag.org/cgi/reprint/216/4542/136}}</ref>{{Audio|Pronunciation prion.ogg|listen}}) &mdash; short for '''pr'''oteinaceous '''i'''nfectious particle that lacks nucleic acid (by analogy to [[virion]]) &mdash; is a type of [[infectious disease|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 [[molecule]]s of the protein into the abnormally structured form, and they are generally quite resistant to [[denaturation (biochemistry)|denaturation]] by [[protease]], [[heat]], [[radiation]], and [[formalin]] treatments,<ref name=Qin_2006>{{cite journal|last=Qin|first=K.|coauthors=O'Donnell, M., Zhao, R. Y.|date=2006-06-15|title=Doppel: More rival than double to prion|journal=Neuroscience|volume=141|issue=1|pages=1–8|doi=10.1016/j.neuroscience.2006.04.057|id=PMID 16781817|url=http://www.ncbi.nlm.nih.gov/entrez/utils/lofref.fcgi?itool=Abstract-def&PrId=3048&uid=16781817&db=pubmed&url=http://linkinghub.elsevier.com/retrieve/pii/S0306-4522(06)00510-0|accessdate=2006-07-12}} </ref> although potency or infectivity can be reduced. The term does not, however, ''a priori'' preclude other mechanisms of transmission.
+
'''Prion''' ({{IPA2|ˈpriːɒn}}; 'prē,än<ref>The Oxford American College Dictionary (New York: G. P. Putnam's Sons, 2002).</ref>; "pree-on"<ref> S. B. Pruisner, "Novel proteinaceous infectious particles cause scrapie," ''Science'' 216(4542) (1982): 136–44. Pronunciation is explicitly defined as "pree-on" on page 141, third column.</ref>) is short for '''pr'''oteinaceous '''i'''nfectious particle that lacks [[nucleic acid]] (analogous to virion, a single [[infection|infectious]] [[virus|viral]] particule) and is a type of infectious agent made only of [[protein]]. At the most basic level, the lack of nucleic acids distinguishes prions from viruses (genetic material contained within a protective protein shell) and viroids ([[nucleotide]]s of [[RNA]] without protein coat).
 +
 
 +
The functionality of a protein is dependent upon its ability to fold into a precise three-dimensional shape. Revealing the complexity and harmony of the universe, proteins rapidly fold into the correct shape despite the innumerable possible configurations. It is believed that prions disrupt this harmony and cause [[disease]] by refolding abnormally and converting normal proteins into their configuration.
 +
{{toc}}
 +
Prion diseases are transmissible neurodegenerative conditions that affect the [[brain]] and neural tissue of [[animal]]s and [[human|people]]. Although there is a [[gene|genetic]] component to many prion diseases, prion diseases are not exclusively genetic diseases. They are grouped as “transmissible spongiform encephalopathies” (TSEs). Prion diseases include [[scrapie]] (a disease of [[sheep]]), [[chronic wasting disease]] (in deer and elk), variant [[Creutzfeldt-Jakob disease]] (vCJD) in humans, and [[bovine spongiform encephalopathy]] (BSE or ''mad cow disease''), all caused by similar proteins in different [[species]].<ref>J. Collinge, "Prion diseases of humans and animals: Their causes and molecular basis," ''Annu. Rev. Neurosci.'' 24: 519–50.</ref> 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.  All of these disease are untreatable and fatal.
 +
 
 +
==Overview==
 +
 
 +
Prions are believed to infect and propagate by refolding abnormally into a structure that is able to convert normal [[molecule]]s of the protein into the abnormally structured form. Prions have the same [[amino acid]] makeup as naturally occurring proteins in the body, but essentially become deadly by changing shape, and they can force normal proteins to adopt their configuration.<ref>New York University Medical Center and School of Medicine, [http://www.sciencedaily.com/releases/2005/05/050514111648.htm Active vaccine prevents mice from developing prion disease]. ''Science Daily'' (2005). Retrieved February 6, 2007.</ref> These misfolded proteins can aggregate in toxic clumps and affect the structure of the [[brain]] or other [[neurons|neural]] tissue. They can easily infect the animals because they do not elicit an [[immune system|immune]] response.<ref>New York University Medical Center and School of Medicine, [http://www.sciencedaily.com/releases/2005/05/050514111648.htm Active vaccine prevents mice from developing prion disease]. ''Science Daily'' (2005). Retrieved February 6, 2007.</ref> They are generally quite resistant to [[denaturation (biochemistry)|denaturation]] by [[protease]], [[heat]], [[radiation]], and [[formalin]] treatments,<ref>K. Qin, M. O'Donnell, and R. Y. Zhao, "Doppel: More rival than double to prion," ''Neuroscience'' 141(1) (2006): 1–8.</ref> although potency or infectivity can be reduced.  
 +
 
 +
It should be noted that the same gene is responsible for spongiform encephalopathies that 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.
 +
 
 +
While prion diseases are untreatable and fatal, a vaccine has been developed in [[mouse|mice]] that may provide insight into providing a [[vaccine]] in humans to resist prion infections.<ref>New York University Medical Center and School of Medicine, [http://www.sciencedaily.com/releases/2005/05/050514111648.htm Active vaccine prevents mice from developing prion disease]. ''Science Daily'' (2005). Retrieved February 6, 2007.</ref>
 +
 
 +
Proteins showing prion behavior are also found in some [[fungus|fungi]]. Some [[fungal prions]] may not be associated with any disease.  
  
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 (disease)|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.<ref>{{cite journal|title=Prion diseases of humans and animals: their causes and molecular basis|journal=Annu Rev Neurosci|year=2001|volume=24|pages=519-50|id=PMID 11283320}}</ref> 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 diseasesSome 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 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 sheet]]sOther mechanisms may exist in yet undiscovered infectious protein particles.
  
All of these diseases affect the structure of the [[brain]] or other [[neurons|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.<ref>(14 May 2005) [http://www.sciencedaily.com/releases/2005/05/050514111648.htm Active Vaccine Prevents Mice From Developing Prion Disease]. ''Science Daily''.</ref>
+
==History==
 +
Radiation biologist Tikvah Alper and physicist J. S. Griffith developed the theory in the 1960s that some transmissible spongiform encephalopathies (TSEs) are caused by an infectious agent made solely of [[protein]].<ref>T. Alper, W. A. Cramp, D. A. Haig, and M. C. Clarke, "Does the agent of scrapie replicate without nucleic acid?" ''Nature'' 214(90) (1967): 764–6.</ref><ref>J. S. Griffith, "Self-replication and scrapie," ''Nature'' 215(105) (1967): 1043–4.</ref>
 +
This theory was developed to explain the discovery that the mysterious infectious agent causing the diseases [[scrapie]] and [[Creutzfeldt-Jakob disease|Creutzfeldt-Jakob Disease]] resisted [[ultraviolet]] radiation (which breaks down [[nucleic acid]]s&mdash;present in viruses and all living things) yet responded to agents that disrupt proteins.
  
Proteins showing prion behaviour are also found in some [[fungus|fungi]]. Some [[fungal prions]] may not be associated with any disease; it is unknown whether these prions represent an [[evolution|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 sheet]]s. Other mechanisms may exist in yet undiscovered infectious protein particles.
+
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]].<ref>S. B. Prusiner, "Novel proteinaceous infectious particles cause scrapie," ''Science'' 216(4542) (1982): 136–44.</ref>
 +
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.
  
==PrP and the prion hypothesis==
+
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 [[enzyme]]s in the body that can normally break down proteins. The normal form of the protein is called PrP<sup>C</sup>, while the infectious form is called PrP<sup>Sc</sup>&mdash;the "C" refers to "cellular" PrP, while the "Sc" refers to "[[scrapie]]," the prion disease occurring in sheep. Normal prion protein (common or cellular) is found on the [[cell membrane|membranes]] of [[cell (biology)|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.<ref>B. Oesch, D. Westaway, M. Wälchli, M. McKinley, S. Kent, R. Aebersold, R. Barry, P. Tempst, D. Teplow, and L. Hood, "A cellular gene encodes scrapie PrP 27-30 protein," ''Cell'' 40(4) (1985): 735–46. PMID 2859120. Retrieved February 26, 2008.</ref>  
Radiation biologist Tikvah Alper and physicist J.S. Griffith developed the theory in the 1960s that some [[transmissible spongiform encephalopathy|TSEs]] are caused by an infectious agent made solely of [[protein]].<ref name=Nature90>{{cite journal|title=Does the agent of scrapie replicate without nucleic acid?|journal=Nature|date=1967 May 20|volume=214|issue=90|pages=764-6|id=PMID 4963878 {{doi|10.1038/214764a0}}}}</ref><ref>{{cite journal|title=Self-replication and scrapie|journal=Nature|date=1967 Sep 2|volume=215|issue=105|pages=1043-4|id=PMID 4964084 {{doi|10.1038/2151043a0}}}}</ref>
 
This theory was developed to explain the discovery that the mysterious infectious agent causing the diseases [[scrapie]] and [[Creutzfeldt-Jakob disease|Creutzfeldt-Jakob Disease]] resisted [[ultraviolet]] radiation (which breaks down [[nucleic acid]]s - present in viruses and all living things) yet responded to agents that disrupt proteins.<ref name=Nature90/>  
 
  
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.<ref>{{cite journal|title=Novel proteinaceous infectious particles cause scrapie|journal=Science|date=1982 Apr 9|volume=216|issue=4542|pages=136-44|id=PMID 6801762 {{doi|10.1126/science.278.5336.245}}}}</ref>
+
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<sup>C</sup> more likely to spontaneously change into the PrP<sup>Sc</sup> (disease) form. TSEs are the only known diseases that can be sporadic, [[genetic]], or infectious.
  
[[Image:Prion_propagation.png|thumb|0px|right|Proposed mechanism of prion propagation]]
+
Although the identity and general properties of prions are now well-understood, the mechanism of prion infection and propagation remains mysterious. It is often assumed that the diseased form directly interacts with the normal form to make it rearrange its structure (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<sup>C</sup> to  PrP<sup>Sc</sup> by bringing a molecule of each of the two together into a complex.<ref>G. Telling, M. Scott, J. Mastrianni, R. Gabizon, M. Torchia, F. Cohen, S. DeArmond, and S. Prusiner, "Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein," ''Cell'' 83(1) (1995): 79–90. PMID 7553876. Retrieved February 26, 2008.</ref>
  
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 PrP<sup>C</sup>, while the infectious form is called PrP<sup>Sc</sup>— 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 [[cell membrane|membranes]] of [[cell (biology)|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.<ref>{{cite journal|title=A cellular gene encodes PrP 27-30 protein|journal=Cell|date=1985 Apr|volume=40|issue=4|pages=735-46|id=PMID 2859120}}</ref>  
+
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 [[pathogen]]s ([[bacterium|bacteria]], [[virus]]es, etc.) used [[nucleic acid]]s for their reproduction. The "protein-only hypothesis"&mdash;that a protein structure could reproduce itself in the absence of [[DNA]]&mdash;was initially met with skepticism and still has critics. Yale University neuropathologist Laura Manuelidis has challenged this explanation for the disease. In January 2007, she and her colleagues published an article in the ''Proceedings of the National Academy of Science'' asserting that they've found a virus responsible for the diseases.<ref>Yale University Office of Public Affairs, [http://www.yale.edu/opa/newsr/07-01-30-02.all.html Press release (January 29, 2007): Potentially pathogenic virus found in Mad Cow cells]. ''Yale'' (2007). Retrieved February 2, 2007.</ref>
  
Some [[transmissible spongiform encephalopathy|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<sup>C</sup> more likely to spontaneously change into the PrP<sup>Sc</sup> (disease) form. TSEs are the only known diseases that can be [[wikt:sporadic|sporadic]], [[genetic disease|genetic]], or [[infectious disease|infectious]]; for more information see the article on [[Transmissible spongiform encephalopathy|TSEs]].
+
==Prions in human disease==
 +
There are four principal [[disease]] syndromes associated with prions in [[human]]s: [[Creutzfeld-Jakob disease|Creutzfeld-Jakob Disease]] (CJD), variant Creutzfeld-Jakob Disease (vCJD), [[Kuru (disease)|Kuru]], and [[Fatal Familial Insomnia]]. Of these, only Kuru and vCJD are transmissible, the other two being either heritable or ''sporadic'' (i.e., caused by some unknown event, possibly a mutation, that occurs during the life of the affected individual).
  
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<sup>C</sup> to  PrP<sup>Sc</sup> by bringing a molecule of each of the two together into a complex.<ref>{{cite journal|title=Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein|journal=Cell|date=1995 Oct 6|volume=83|issue=1|pages=79-90|id=PMID 7553876}}</ref>
+
[[Kuru (disease)|Kuru]] and vCJD are known to be transmitted to humans who have eaten the meat or brains of infected animals (or, in the case of Kuru, infected humans).
  
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 [[pathogen]]s ([[bacterium|bacteria]], [[virus]]es, etc.) used [[nucleic acid]]s for their reproduction. The "protein-only hypothesis" – that a protein structure could reproduce itself in the absence of [[DNA]] – was initially met with skepticism.
+
This raises the question: How can prions, which are merely proteins, make their way through the gut and into the [[brain]], where they cause the dreaded "spongiform encephalitis"? Proteins normally are digested down to [[amino acid]]s in the gut, and transported through the gut epithelium by amino acid transporters. If that was the case for prions, they would no longer be prions by the time they were absorbed through the gut wall, and would no longer be infectious.  
  
 +
Some recent research, reviewed by Aguzzi and Heikenwalder (2006),<ref>A. Aguzzi and M. Heikenwalder, "Prion diseases: Cannibals and garbage piles," ''Nature Reviews: Microbiology'' 4(2007): 765.</ref> sheds light on this question.
  
 +
First of all, prions resist digestion in the gut. They remain intact proteins and are known to accumulate in the distal ileum. They resist digestion because they are extremely resistant to all forms of degradation. They also resist destruction by high-temperature autoclave and by formaldehyde, and in fact, by most means tested so far. In fact, cases of vCJD have been known to be contracted from properly sterilized surgical instruments.
  
 +
But, even if prions are not digested, they should not be absorbed across the intestinal wall. In fact, they circumvent the normal process of intestinal absorption by passing into the the Gut-Associated Lymphoid Tissue (GALT). Related to this, it seems that chronic inflammation predisposes to prion infectivity, e.g., in rheumatoid arthritis, type-I [[diabetes]], or Crohn’s disease.
  
 
==Prions in yeast and other fungi==
 
==Prions in yeast and other fungi==
{{main|Fungal prions}}
 
  
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.
+
Prion-like proteins that behave in a similar way to PrP are found naturally in some [[fungus|fungi]] and non-[[mammal]]ian 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 National Institutes of Health 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 ==
 
== Molecular properties ==
  
A great deal of our knowledge of how prions work at a molecular level comes from detailed biochemical analysis of [[fungal prions|yeast prion]] proteins. A typical yeast prion protein contains a region ([[protein domain]]) with many repeats of the [[amino acid]]s [[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. <!--What happened to "more easily than viruses"? —>
+
A great deal of our knowledge of how prions work at a [[molecule|molecular]] level comes from detailed [[biochemistry|biochemical]] analysis of [[yeast]] prion proteins. A typical yeast prion protein contains a region (protein domain) with many repeats of the [[amino acid]]s [[glutamine]] (Q) and [[asparagine]] (N). These Q/N-rich domains form the core of the prion's structure.  
  
[[Image:Prion.gif|right|thumb|400px|Molecular models of the structure of PrP<sup>C</sup> (left) and PrP<sup>Sc</sup> (right)]]
+
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.  
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 [[mammal]]ian 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<sup>C</sup>. (to explore/download see the [http://www.rcsb.org/pdb/cgi/explore.cgi?pid=257211117306887&page=0&pdbId=1AG2 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 helix|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<sup>Sc</sup> is not known, there is increased
+
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 [[mammal]]ian and yeast prions. The prion variant responsible for mad cow disease has the remarkable ability to bypass the species barrier to transmission.
β sheet content (green arrows) in the diseased form of the molecule.<ref>{{cite journal|title=Conversion of alpha-helices into beta-sheets features in the formation of scrapie prion protein|journal=PNAS USA|date=1993 Dec 1|volume=90|issue=23|pages=10962-6|url=http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=7902575|id=PMID 7902575}}</ref> These β sheets are thought to lead to [[amyloid]] aggregation.
 
  
 
== Prions and long-term memory ==
 
== Prions and long-term memory ==
  
There is evidence that prions may have a normal function in maintenance of [[long term memory|memories]] over a long period of time.<ref>{{cite journal|title=Prions as adaptive conduits of memory and inheritance.|journal=Nature Reviews Genetics|date=2005 |volume=6|pages=435-450|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15931169&query_hl=6&itool=pubmed_DocSum}}</ref>  
+
There is evidence that prions may have a normal function in maintenance of [[memory|memories]] over a long period of time.<ref>J. Shorter J. and S. Lindquist, "Prions as adaptive conduits of memory and inheritance," ''Nat. Rev. Genet.'' 6 (2005): 435–50. PMID 15931169. Retrieved February 26, 2008.</ref> Maglio and colleagues have shown that mice without the genes for normal cellular prion protein have altered [[hippocampus|hippocampal]] Long-term potentiation (LTP).<ref>L. Maglio, M. Perez, V. Martins, R. Brentani, and O. Ramirez, "Hippocampal synaptic plasticity in mice devoid of cellular prion protein," ''Brain Res. Mol. Brain Res.'' 131(1–2) (2004): 58–64. PMID 15530652. Retrieved February 26, 2008.</ref>
Maglio and colleagues have shown that mice without the genes for normal cellular prion protein have altered [[hippocampus|hippocampal]] [[Long-term_potentiation|LTP]].<ref>{{cite journal|title=Hippocampal synaptic plasticity in mice devoid of cellular prion protein|journal= Molecular Brain Research|date=2004 |volume=131|issue=1-2|pages=58-64|url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T07-4DB5DY6-1&_user=10&_coverDate=11%2F24%2F2004&_rdoc=7&_fmt=summary&_orig=browse&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=b42f725910f75f85e6555b9555c141ee}}</ref>
 
 
 
==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.<ref>[http://www.bseinquiry.gov.uk/files/ws/s638.pdf 2000-09-22, Normal Function of Prions, Statement to the BSE Inquiry]</ref> Purdey cited epidemiological studies of clusters of prion disease in locales with low soil concentrations of copper as evidence.
 
 
 
<!-- Please mention the exact section where he says anything like this,
 
"Nevertheless David Brown actually suggests that the infectious prion particles may influence the course of the disease by altering ionic homeostasis in the brain."<ref>[http://www.bseinquiry.gov.uk/files/ws/s638.pdf 2000-09-22, Normal Function of Prions, Statement to the BSE Inquiry]</ref>{{fact}}<!-- If I can find it, I will leave this alone,
 
and I suspect that Brown's work only _allows_ this to be said. —>
 
 
 
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 [[Manganism|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==
 
==Prion diseases==
Line 66: Line 77:
 
* In [[animal]]s:
 
* In [[animal]]s:
 
:* [[Scrapie]] in [[sheep]]
 
:* [[Scrapie]] in [[sheep]]
:* [[Bovine Spongiform Encephalopathy]] (BSE) in [[cow]]s
+
:* [[Bovine Spongiform Encephalopathy]] (BSE) in [[cattle]]
 
:* [[Transmissible mink encephalopathy]] (TME) in [[mink]]
 
:* [[Transmissible mink encephalopathy]] (TME) in [[mink]]
:* [[Chronic Wasting Disease]] (CWD) in [[elk]] and [[mule deer]]
+
:* [[Chronic Wasting Disease]] (CWD) in [[elk]] and mule [[deer]]
:* [[Feline spongiform encephalopathy]] in [[cats]]
+
:* Feline spongiform encephalopathy in [[cat]]s
:* [[Exotic ungulate encephalopathy]] (EUE) in [[nyala]], [[oryx]] and [[greater kudu]]
+
:* Exotic [[ungulate]] encephalopathy (EUE) in nyala, oryx, and greater kudu
 
* In [[human]]s:
 
* In [[human]]s:
:* 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
+
:* 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)
+
:* Gerstmann-Sträussler-Scheinker syndrome (GSS)
 
:* [[Fatal Familial Insomnia]] (FFI)
 
:* [[Fatal Familial Insomnia]] (FFI)
 
:* [[Kuru (disease)|Kuru]]
 
:* [[Kuru (disease)|Kuru]]
:* [[Alpers' disease|Alpers Syndrome]]
+
:* Alpers Syndrome
  
==Genetic engineering research==
+
==Notes==
 
+
{{Reflist}}
On [[31 December]], [[2006]], [http://www.hematech.com/ Hematech], a biotechnology company based in [[Sioux Falls, South Dakota|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.<ref>{{cite news |first= Rick|last=Weiss |title=Scientists Announce Mad Cow Breakthrough|url=http://www.washingtonpost.com/wp-dyn/content/article/2006/12/31/AR2006123100672.html|publisher=The [[Washington Post]]|date=[[2007-01-01]]|accessdate=2007-01-01}}</ref>
 
 
 
Research with mice had previously indicated that animals lacking endogenous prion protein are resistant to infection by scrapie prion protein.<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=8100741 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 (journal)|Cell]] (1993) Volume 73 pages 1339-1347.</ref>
 
 
 
==See also==
 
* [[Transmissible spongiform encephalopathy]]
 
  
 
==References==
 
==References==
{{Wikibookspar||General Biology/Classification of Living Things/Viruses, Prions, and Viroids}}
+
* Pan, K. M., M. Baldwin, J. Nguyen, M. Gasset, A. Serban, D. Groth, I. Mehlhorn, Z. Huang, R. J. Fletterick, F. E. Cohen, et al. 1993. [http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=7902575 Conversion of alpha-helices into beta-sheets features in the formation of scrapie prion protein]. ''Proc. Nat'l. Acad. Sci. USA'' 90(23): 10962–10966. PMID 7902575. Retrieved February 26, 2008.
<div class="references-small">
 
<references/>
 
</div>
 
  
 
==External links==
 
==External links==
*[http://www.mad-cow-facts.com Mad Cow Disease] Information from the Center for Global Food Issues.
+
All links retrieved November 30, 2022.
*[http://www.madcowering.com Madcowering] A BSE-TSE blog.
+
 
*[http://thepathologicalprotein.com/ The Pathological Protein - Mad Cow, Chronic Wasting, and Other Deadly Prion Diseases] (2003, updated online 2005). Philip Yam, [[Scientific American]] magazine writer and News Editor.
+
*[http://www.mad-cow.org/ Official Mad Cow Disease Home Page].  
*[http://www-micro.msb.le.ac.uk/3035/prions.html Prion Diseases] (2003). Dr. Sean Heaphy, Leicester University.
+
*[http://www.sciencedaily.com/releases/2003/09/030917074003.htm Science Daily article on transmission of prions through soil].
*[http://www.sciencemag.org/feature/data/prusiner/245.shl Prion Diseases and the BSE Crisis] (1997). Article from Science magazine by Stanley Prusiner.
+
*[http://www.scq.ubc.ca/?p=435 A good overview of prion biology from the Science Creative Quarterly].
*[http://www.britannica.com/nobel/micro/481_90.html Britannica Nobel: prion, 1997]
 
*ICTVdb [http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/90.001.0.01.htm 90.001.0.01. Mammalian Prions]
 
*[http://www.mad-cow.org/ Official Mad Cow Disease Home Page.]
 
*[http://organicconsumers.org/madcow.htm News & Views on Mad Cow Disease, Mad Deer Disease, Chronic Wasting Disease, and Bovine Spongiform Encephalopathy]
 
*[http://nobelprize.org/nobel_prizes/medicine/laureates/1997/prusiner-autobio.html Biography of Dr Prusiner]
 
*[http://www.sciencedaily.com/releases/2003/09/030917074003.htm Science Daily article on transmission of prions through soil]
 
*[http://www.scq.ubc.ca/?p=435 A good overview of prion biology from the Science Creative Quarterly]
 
  
 
[[Category:Life sciences]]
 
[[Category:Life sciences]]
 +
[[Category:Molecular biology]]
 
{{credit|102634122}}
 
{{credit|102634122}}

Latest revision as of 23:00, 30 November 2022


Prion Diseases (TSEs)

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

ICD-10A81
ICD-9046

Prion (IPA: [ˈpriːɒn]; 'prē,än[1]; "pree-on"[2]) is short for proteinaceous infectious particle that lacks nucleic acid (analogous to virion, a single infectious viral particule) and is a type of infectious agent made only of protein. At the most basic level, the lack of nucleic acids distinguishes prions from viruses (genetic material contained within a protective protein shell) and viroids (nucleotides of RNA without protein coat).

The functionality of a protein is dependent upon its ability to fold into a precise three-dimensional shape. Revealing the complexity and harmony of the universe, proteins rapidly fold into the correct shape despite the innumerable possible configurations. It is believed that prions disrupt this harmony and cause disease by refolding abnormally and converting normal proteins into their configuration.

Prion diseases are transmissible neurodegenerative conditions that affect the brain and neural tissue of animals and people. Although there is a genetic component to many prion diseases, prion diseases are not exclusively genetic diseases. They are grouped as “transmissible spongiform encephalopathies” (TSEs). Prion diseases include scrapie (a disease of sheep), chronic wasting disease (in deer and elk), variant Creutzfeldt-Jakob disease (vCJD) in humans, and bovine spongiform encephalopathy (BSE or mad cow disease), all caused by similar proteins in different species.[3] 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. All of these disease are untreatable and fatal.

Overview

Prions are believed to infect and propagate by refolding abnormally into a structure that is able to convert normal molecules of the protein into the abnormally structured form. Prions have the same amino acid makeup as naturally occurring proteins in the body, but essentially become deadly by changing shape, and they can force normal proteins to adopt their configuration.[4] These misfolded proteins can aggregate in toxic clumps and affect the structure of the brain or other neural tissue. They can easily infect the animals because they do not elicit an immune response.[5] They are generally quite resistant to denaturation by protease, heat, radiation, and formalin treatments,[6] although potency or infectivity can be reduced.

It should be noted that the same gene is responsible for spongiform encephalopathies that 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.

While prion diseases are untreatable and fatal, a vaccine has been developed in mice that may provide insight into providing a vaccine in humans to resist prion infections.[7]

Proteins showing prion behavior are also found in some fungi. Some fungal prions may not be associated with any disease.

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.

History

Radiation biologist Tikvah Alper and physicist J. S. Griffith developed the theory in the 1960s that some transmissible spongiform encephalopathies (TSEs) are caused by an infectious agent made solely of protein.[8][9] 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.

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.[10] 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.

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," the 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.[11]

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.

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.[12]

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 and still has critics. Yale University neuropathologist Laura Manuelidis has challenged this explanation for the disease. In January 2007, she and her colleagues published an article in the Proceedings of the National Academy of Science asserting that they've found a virus responsible for the diseases.[13]

Prions in human disease

There are four principal disease syndromes associated with prions in humans: Creutzfeld-Jakob Disease (CJD), variant Creutzfeld-Jakob Disease (vCJD), Kuru, and Fatal Familial Insomnia. Of these, only Kuru and vCJD are transmissible, the other two being either heritable or sporadic (i.e., caused by some unknown event, possibly a mutation, that occurs during the life of the affected individual).

Kuru and vCJD are known to be transmitted to humans who have eaten the meat or brains of infected animals (or, in the case of Kuru, infected humans).

This raises the question: How can prions, which are merely proteins, make their way through the gut and into the brain, where they cause the dreaded "spongiform encephalitis"? Proteins normally are digested down to amino acids in the gut, and transported through the gut epithelium by amino acid transporters. If that was the case for prions, they would no longer be prions by the time they were absorbed through the gut wall, and would no longer be infectious.

Some recent research, reviewed by Aguzzi and Heikenwalder (2006),[14] sheds light on this question.

First of all, prions resist digestion in the gut. They remain intact proteins and are known to accumulate in the distal ileum. They resist digestion because they are extremely resistant to all forms of degradation. They also resist destruction by high-temperature autoclave and by formaldehyde, and in fact, by most means tested so far. In fact, cases of vCJD have been known to be contracted from properly sterilized surgical instruments.

But, even if prions are not digested, they should not be absorbed across the intestinal wall. In fact, they circumvent the normal process of intestinal absorption by passing into the the Gut-Associated Lymphoid Tissue (GALT). Related to this, it seems that chronic inflammation predisposes to prion infectivity, e.g., in rheumatoid arthritis, type-I diabetes, or Crohn’s disease.

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 National Institutes of Health 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.

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.

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.[15] Maglio and colleagues have shown that mice without the genes for normal cellular prion protein have altered hippocampal Long-term potentiation (LTP).[16]

Prion diseases

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

  • Scrapie in sheep
  • Bovine Spongiform Encephalopathy (BSE) in cattle
  • 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

Notes

  1. The Oxford American College Dictionary (New York: G. P. Putnam's Sons, 2002).
  2. S. B. Pruisner, "Novel proteinaceous infectious particles cause scrapie," Science 216(4542) (1982): 136–44. Pronunciation is explicitly defined as "pree-on" on page 141, third column.
  3. J. Collinge, "Prion diseases of humans and animals: Their causes and molecular basis," Annu. Rev. Neurosci. 24: 519–50.
  4. New York University Medical Center and School of Medicine, Active vaccine prevents mice from developing prion disease. Science Daily (2005). Retrieved February 6, 2007.
  5. New York University Medical Center and School of Medicine, Active vaccine prevents mice from developing prion disease. Science Daily (2005). Retrieved February 6, 2007.
  6. K. Qin, M. O'Donnell, and R. Y. Zhao, "Doppel: More rival than double to prion," Neuroscience 141(1) (2006): 1–8.
  7. New York University Medical Center and School of Medicine, Active vaccine prevents mice from developing prion disease. Science Daily (2005). Retrieved February 6, 2007.
  8. T. Alper, W. A. Cramp, D. A. Haig, and M. C. Clarke, "Does the agent of scrapie replicate without nucleic acid?" Nature 214(90) (1967): 764–6.
  9. J. S. Griffith, "Self-replication and scrapie," Nature 215(105) (1967): 1043–4.
  10. S. B. Prusiner, "Novel proteinaceous infectious particles cause scrapie," Science 216(4542) (1982): 136–44.
  11. B. Oesch, D. Westaway, M. Wälchli, M. McKinley, S. Kent, R. Aebersold, R. Barry, P. Tempst, D. Teplow, and L. Hood, "A cellular gene encodes scrapie PrP 27-30 protein," Cell 40(4) (1985): 735–46. PMID 2859120. Retrieved February 26, 2008.
  12. G. Telling, M. Scott, J. Mastrianni, R. Gabizon, M. Torchia, F. Cohen, S. DeArmond, and S. Prusiner, "Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein," Cell 83(1) (1995): 79–90. PMID 7553876. Retrieved February 26, 2008.
  13. Yale University Office of Public Affairs, Press release (January 29, 2007): Potentially pathogenic virus found in Mad Cow cells. Yale (2007). Retrieved February 2, 2007.
  14. A. Aguzzi and M. Heikenwalder, "Prion diseases: Cannibals and garbage piles," Nature Reviews: Microbiology 4(2007): 765.
  15. J. Shorter J. and S. Lindquist, "Prions as adaptive conduits of memory and inheritance," Nat. Rev. Genet. 6 (2005): 435–50. PMID 15931169. Retrieved February 26, 2008.
  16. L. Maglio, M. Perez, V. Martins, R. Brentani, and O. Ramirez, "Hippocampal synaptic plasticity in mice devoid of cellular prion protein," Brain Res. Mol. Brain Res. 131(1–2) (2004): 58–64. PMID 15530652. Retrieved February 26, 2008.

References
ISBN links support NWE through referral fees

External links

All links retrieved November 30, 2022.

Credits

New World Encyclopedia writers and editors rewrote and completed the Wikipedia article in accordance with New World Encyclopedia standards. This article abides by terms of the Creative Commons CC-by-sa 3.0 License (CC-by-sa), which may be used and disseminated with proper attribution. Credit is due under the terms of this license that can reference both the New World Encyclopedia contributors and the selfless volunteer contributors of the Wikimedia Foundation. To cite this article click here for a list of acceptable citing formats.The history of earlier contributions by wikipedians is accessible to researchers here:

The history of this article since it was imported to New World Encyclopedia:

Note: Some restrictions may apply to use of individual images which are separately licensed.