Prions — short for proteinaceous infectious particle — are infectious self-reproducing protein structures. Though their exact mechanisms of action and reproduction are still 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, and bovine spongiform encephalopathy (mad cow disease). These diseases affect the structure of brain tissue and are all fatal and untreatable.
Prions were first hypothesized in 1982 by Stanley B. Prusiner of UCSF, who was awarded the Nobel Prize in physiology or medicine in 1997 for the discovery. Prusiner coined the word "prion" by combining the first two syllables of the words "proteinaceous" and "infectious".
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 why the mysterious infectious agent causing Creutzfeldt-Jakob disease resisted ultraviolet radiation (which breaks down nucleic acids), yet responded to agents that disrupt proteins. 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. Prusiner's idea — 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 and possibly exceptional 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 creation 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 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). 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), several mutations that cause the variant shape have been identified and successfully cloned, and studies using genetically altered mice have bolstered the prion hypothesis. In 2004, researchers succeeded in infecting mice with artifical prions composed entirely of synthetic PrPSC protein, confirming the "protein only" model for prion disease.
Although the identity and general properties of prions are now well-understood, the mechanism of prion infection and replication remains mysterious. One idea (the "Protein X" hypothesis) is that an as-yet unidentified cellular enzyme (Protein X) catalyzes the conversion of PrPC to PrPSC by bringing a molecule of each of the two together into a complex. An alternative idea is that prion propagation does not require direct action of a prion protein on a normal protein, but rather results from a positive feedback loop during the biosynthesis of PrP. In this view, the presence of PrPSC somehow alters the way in which PrP is synthesized, shunting it down an alternative metabolic pathway that results in the formation of more PrPSC instead of the normal PrPC form.
The degenerative diseases caused by prions are known collectively as "transmissible spongiform encephalopathies" or TSEs.
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. 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. 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. 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.
As of 2003, the following proteins in Saccharomyces cerevisiae had been identified or postulated as 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 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 addition of 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 normal, alpha helical form, while on the right is the prion form. Note the increased sheet content (green arrows) in the prion version of the molecule. These sheets create an electric dipole and can lead to amyloid aggregation.
|Mammalian prions, agents of spongiform encephalopathies|
|Disease name||Natural host||Prion name||PrP isoform|
|Scrapie||Sheep and goats||Scrapie prion||OvPrPSc|
|Transmissible mink encephalopathy (TME)||Mink||TME prion||MkPrPSc|
|Chronic wasting disease (CWD)||Mule deer and elk||CWD prion||MDePrPSc|
|Bovine spongiform encephalopathy (BSE)||Cattle||BSE prion||BovPrPSc|
|Feline spongiform encephalopathy (FSE)||Cats||FSE prion||FePrPSc|
|Exotic ungulate encephalopathy (EUE)||Nyala and greater kudu||EUE prion||NyaPrPSc|
|Creutzfeldt-Jakob disease (CJD)||Humans||CJD prion||HuPrPSc|
|(New) Variant Creutzfeldt-Jakob disease (vCJD, nvCJD)||Humans||BSE prion*||BovPrPSc*|
|Gerstmann-Strussler-Scheinker syndrome (GSS)||Humans||GSS prion||HuPrPSc|
|Fatal familial insomnia (FFI)||Humans||FFI prion||HuPrPSc|
|* or variant|
|Protein||Natural host||Prion name|
|Ure2p||Saccharomyces cerevisiae||[URE2+] prion|
|Sup35p||Saccharomyces cerevisiae||[PSI+] prion|
|Rnq1p||Saccharomyces cerevisiae||[PIN+] prion (also known as [RNQ+])|
|HET-S||Podospora anserina||[Het-s] prion|