The first glimpse came from virologist Patricia Merz in 1981 at the Institute for Basic Research in Developmental Disabilities at Staten Island, N.Y. who observed strange fibrils in scrapie-infected mouse brains. 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 "prion-related protein" (also "protease-resistant protein"). Prusiner received the Nobel Prize in Physiology or Medicine in 1997 for this research.}}

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.

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 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 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. 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 - a form of Lamarckian evolution.

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. 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.

Molecular properties of prions

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 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. These β sheets are thought to lead to amyloid aggregation.}

Dissent

Classification

References

External links

• 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
• ICTVdb 90.001.0.01. Mammalian Prions
• Official Mad Cow Disease Home Page.
• News & Views on Mad Cow Disease, Mad Deer Disease, Chronic Wasting Disease, and Bovine Spongiform Encephalopathy
• The BSE Inquiry, Statement No. 638, Dr. David Brown.

Biochemistry | Genetics | Proteins | Prions

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