Prion

This article is about the infectious particles known as prions; for the bird, see Prion (bird).

A prion (pronounced "PREE-on") — short for proteinaceous infectious particle — is a unique type of infectious agent, as it is made only of protein. Prions are abnormally-structured forms of a host protein, which are able to convert normal molecules of the protein into the abnormal structure. Though the exact mechanisms of their actions and propagation are unknown, it is now commonly accepted that prions are responsible for a number of previously known but little-understood diseases generally classified under transmissible spongiform encephalopathy diseases (TSEs), including scrapie (a disease of sheep), kuru (found in members of the formerly cannibalistic Foré tribe in Papua New Guinea), Creutzfeldt-Jakob disease (CJD), Chronic Wasting Disease, Fatal Familial Insomnia (FFI), Gerstmann-Sträussler-Scheinker syndrome (GSS), and bovine spongiform encephalopathy (BSE or mad cow disease).^[1] These diseases affect the structure of brain tissue and all are fatal and untreatable.

So far all prions discovered are believed to infect and propagate by formation of an amyloid fold. However, since any infectious protein particle would be defined as a prion, other mechanisms may be possible.

The theory that TSEs are caused by an infectious agent made solely of protein has been around since the 1960s.^[2][3] This theory was developed to explain the discovery that the mysterious infectious agent causing 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.^[4] 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." Prusiner's intention was for the word 'prion' to be pronounced 'pree-on'. While the infectious agent was named a prion, the specific protein that the prion was made of was named PrP, an abbreviation for "prion-related protein". Prusiner was awarded the Nobel Prize in physiology or medicine in 1997 for this research.^[5]

Further research showed that PrP is found throughout the body, even in healthy people and animals. However, the PrP found in infectious material (i.e. the PrP that forms prions) 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. PrP^C is found on the membranes of cells, though its normal function has not been fully resolved. Since the original hypothesis was proposed, a gene for PrP has been isolated: the Prnp gene.^[6] 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 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 generally assumed that PrP^Sc directly interacts with PrP^C to cause the normal form of the protein to rearrange its structure (enlarge the diagram above for an illustration of this mechansism). 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.^[7]

Prior to Prusiner'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 (which, unlike DNA, has no obvious means of replication) could reproduce itself — was initially met with skepticism. However, evidence has steadily accumulated in support of this hypothesis, and it is now widely accepted. Rather than contradicting the central role of DNA, however, the prion hypothesis suggests a special case in which merely changing the shape, or conformation, of a protein (without changing its amino acid sequence) can alter its biological properties.

Prion-like proteins that behave in a similar way to PrP are found naturally in some fungi and non-mammalian animals. Some of these are not associated with any disease state and may have a useful role. Research into fungal prions has given strong support to the protein-only hypothesis for mammalian prions, as it shows that the prion form of a protein can directly convert the normal form of that protein. 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.

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.

The figure at right shows a model of two conformations of PrP; 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). Some of the protein (the N-terminal region) is not shown here as it does not have a fixed 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 structure (green). On the right is a proposed model of how the abnormal PrPSc form might look. Although the exact 3D structure of PrPSc is not known, there is increased β sheet content (green arrows) in the prion version of the molecule.[8] These β sheets are thought to lead to amyloid aggregation.}

The Wikibook [[wikibooks:|]] has a page on the topic of: Viruses, Prions, and Viroids (General Biology)

• Mad Cow Disease Information from the Center for Global Food Issues.
• Madcowering A BSE-TSE blog.
• 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.
• Prion Diseases (2003). Dr. Sean Heaphy, Leicester University.
• Prion Diseases and the BSE Crisis (1997). Article from Science magazine by Stanley Prusiner, discoverer of prions.
• Britannica Nobel: prion, 1997