From Academic Kids

For the bird called a "prion", see Prion (bird)

Prions — short for proteinaceous infectious particle — are infectious self-reproducing protein structures. Though their exact mechanisms of action and reproduction 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 cannibalistic For tribe in Papua New Guinea), Creutzfeldt-Jakob disease (CJD), Chronic Wasting Disease, Fatal Familial Insomnia (FFI), Gerstmann-Strussler-Scheinker syndrome (GSS), and bovine spongiform encephalopathy (mad cow disease) (Collinge, 2001). These diseases affect the structure of brain tissue and are all fatal and untreatable.


The Prion Hypothesis

The theory that TSEs are caused by an infectious agent made solely of protein has been around since the 1960s (Alper, 1967; Griffith, 1967). However it was not until 1982 that the prion protein itself was discovered, by Stanley B. Prusiner of UCSF, who was awarded the Nobel Prize in physiology or medicine in 1997 for this discovery (Prusiner, 1982). Prusiner coined the word "prion" by combining the first two syllables of the words "proteinaceous" and "infectious". It should be noted that Prusiner intended the word 'prion' to be pronounced 'pree-on'.

Prior to Prusiner's insight, all known pathogens (bacteria, viruses, etc.) contained nucleic acids that are necessary for reproduction. The prion hypothesis was developed to explain the discovery that the mysterious infectious agent causing Creutzfeldt-Jakob disease resisted ultraviolet radiation (which breaks down nucleic acids), yet responded to agents that disrupt proteins (Alper, 1967). Initially, this hypothesis was highly controversial, because it seemed to contradict the "central dogma of modern biology", which asserts that 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. The actual synthesis of the prion protein is still carried out by the ribosome, while the infectious form of the prion protein only transfers the pathological conformation to the proteins synthesized by the cell.

A breakthrough occurred when researchers discovered that the infectious agent consisted mainly of a specific protein, which Prusiner called PrP, an abbreviation for "prion-related protein". This protein is found in the membranes of normal cells (its precise function is not known), but an altered shape distinguished the infectious agent. The normal one is called PrPC, while the infectious one is called PrPSc (the 'C' refers to 'cellular' PrP, while the 'Sc' refers to 'scrapie', a prion disease occurring in sheep) (Oesch, 1985). It is hypothesized that the distorted protein somehow induces normal PrP structure to also become distorted, producing a chain reaction that both propagates the disease and generates new infectious material. Since the original hypothesis was proposed, a gene for the PrP protein has been isolated (the Prnp gene) (Oesch, 1985), several mutations that cause the variant shape have been identified and successfully cloned, and studies using genetically altered mice have bolstered the prion hypothesis.

Although the identity and general properties of prions are now well-understood, the mechanism of prion infection and replication remains mysterious. It is generally assumed that PrPSc directly interacts with PrPC to cause the normal form of the protein to rearrange its structure. 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 (Telling, 1995).

The degenerative diseases caused by prions are known collectively as "transmissible spongiform encephalopathies" or TSEs (Collinge, 2001).

Useful Prions in Yeast and Fungi

Not all prions are dangerous; in fact, prion-like proteins are found naturally in many (perhaps all) plants and animals. Because of this, scientists reasoned that such proteins could give some sort of evolutionary advantage to their host. This was suggested to be the case in a species of fungus Podospora anserina. Genetically compatible colonies of this fungus can merge together and share cellular contents such as nutrients and cytoplasm. A natural system of protective "incompatibility" proteins exists to prevent promiscuous sharing between unrelated colonies. One such protein, called HET-S, adopts a prion-like form in order to function properly (Coustou, 1997). The prion form of HET-S spreads rapidly throughout the cellular network of a colony and can convert the non-prion form of the protein to a prion state after compatible colonies have merged (Maddelein, 2002). However, when an incompatible colony tries to merge with a prion-containing colony, the prion causes the "invader" cells to die, ensuring that only related colonies obtain the benefit of sharing resources .

In 1965, Brian Cox, a geneticist working with the yeast Saccharomyces cerevisiae, described a genetic trait (termed [PSI+]) with an unusual pattern of inheritance. Despite many years of effort, Cox could not identify a conventional mutation that was responsible for the [PSI+] trait. In 1994, yeast geneticist Reed Wickner correctly hypothesized that [PSI+] as well as another mysterious heritable trait, [URE3], resulted from prion forms of certain normal cellular proteins (Wickner, 1994). It was soon noticed that heat shock proteins (which help other proteins fold properly) were intimately tied to the inheritance and transmission of [PSI+] and other yeast prions. Since then, researchers have unravelled how the proteins that code for [PSI+] and [URE3] can convert between prion and non-prion forms, as well as the consequences of having intracellular prions. In certain situations, cells infected with [PSI+] actually fare better than their prion-free siblings; this finding suggests that, in some proteins, the ability to adopt a prion form may result from positive evolutionary selection (Harrison, 2002).

As of 2003, the following proteins in Saccharomyces cerevisiae had been identified or postulated as prions:

  • Sup35p, forming the [PSI+] element;
  • Ure2p, forming the [URE3] element;
  • Rnq1p, forming the [RNQ+] element (also known as [PIN+]);
  • New1p, forming the [NU+] element.

Prions have also been speculatively linked to memory [1] ( and cellular differentiation, the process by which stem cells take on specialized functions (such as muscle or blood cells).

Molecular Properties of Prions

A great deal of our knowledge of how prions work at a molecular level comes from detailed biochemical analysis of yeast prion proteins.

Missing image
Atomic force micrograph of Sup35p prion domain amyloids

A typical yeast prion proteins contain 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, 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 (see figure at left). 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.

 Molecular Model of PrP Structure

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, alpha helical PrPC structure (to explore/download see the RSCB Protein Databank (, while 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 (Pan, 1993). These β sheets can lead to amyloid aggregation.


Mammalian prions, agents of spongiform encephalopathies
Disease name Natural host Prion name PrP isoform
ScrapieSheep and goatsScrapie prionOvPrPSc
Transmissible mink encephalopathy (TME)MinkTME prionMkPrPSc
Chronic wasting disease (CWD)Mule deer and elkCWD prionMDePrPSc
Bovine spongiform encephalopathy (BSE)CattleBSE prionBovPrPSc
Feline spongiform encephalopathy (FSE)CatsFSE prionFePrPSc
Exotic ungulate encephalopathy (EUE)Nyala and greater kuduEUE prionNyaPrPSc
KuruHumansKuru prionHuPrPSc
Creutzfeldt-Jakob disease (CJD)HumansCJD prionHuPrPSc
(New) Variant Creutzfeldt-Jakob disease (vCJD, nvCJD)HumansBSE prion*BovPrPSc*
Gerstmann-Strussler-Scheinker syndrome (GSS)HumansGSS prionHuPrPSc
Fatal familial insomnia (FFI)HumansFFI prionHuPrPSc
* or variant
Fungal prion
Protein Natural host Prion name
Ure2pSaccharomyces cerevisiae[URE2+] prion
Sup35pSaccharomyces cerevisiae[PSI+] prion
Rnq1pSaccharomyces cerevisiae[PIN+] prion (also known as [RNQ+])
HET-SPodospora anserina[Het-s] prion

See also


  • Alper T, Cramp WA, Haig DA, Clarke MC (1967). Does the agent of scrapie replicate without nucleic acid? Nature 214 (90), 764-766
  • Collinge J (2001). Prion diseases of humans and animals: their causes and molecular basis. Ann. Rev. Neurosci. 24, 519-550 [2] (
  • Coustou, V et al (1997). The protein product of the het-s heterokaryon incompatibility gene of the fungus Podospora anserina behaves as a prion analog. Proc. Natl. Acad. Sci. USA 94 (18), 9773-78 [3] (
  • Griffith JS (1967). Self-replication and scrapie. Nature 215, 1043-1044
  • Harrison P et al (2002). A small reservoir of disabled ORFs in the yeast genome and its implications for the dynamics of proteome evolution. J. Mol. Biol. 316 (3), 409-419 [4] (
  • Maddelein, ML et al (2002). Amyloid aggregates of the HET-S prionprotein are infectious. Proc. Natl. Acad. Sci. USA 99 (11), 7402-7 [5] (
  • Oesch B, et al (1985). A cellular gene encodes PrP 27-30 protein. Cell 40 (4), 735-746 [6] (
  • Pan, KM et al (1993). Conversion of alpha-helices into beta-sheets features in the formation of scrapie prion protein. Proc. Natl. Acad. Sci. USA 90 (23), 10962-66 [7] (
  • Prusiner SB (1982). Novel proteinaceous infectious particles cause scrapie. Science 216 (4542), 136-144 [8] (
  • Telling GC, et al (1995). Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell 83 (1), 79-90 [9] (
  • Wickner, RB (1994). [URE3] as an altered URE2 protein: evidence for a prion analog in Saccharomces cerevisiae. Science 264 (5158), 566-569. [10] (

External links

  • Prion Diseases and the BSE Crisis ( (1997). Article from Science magazine by Stanley Prusiner, discoverer of prions.
  • The Prion Diseases ( (1995). Article from Scientific American magazine by Stanley Prusiner.
  • Prion Diseases ( (2003). Dr. Sean Heaphy, Leicester University.
  • Madcowering ( A BSE-TSE blog.
  • Mad Cow Disease ( Information from the Center for Global Food Issues.cs:Prion

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