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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 still unknown, it is now commonly accepted that they are responsible for a number of previously known but little-understood diseases generally classified under transmissible spongiform encephalopathy (TSEs) diseases, including scrapie (a disease of sheep), kuru (found in members of the cannibalistic Foré tribe in Papua New Guinea), 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 formed the word "prion" from a combination of the words "proteinaceous infectious particle".

Table of contents
1 Overview
2 Useful prions
3 How Prions Work
4 Other prion diseases
5 See also
6 External links


Prior to Prusiner's insight, all known pathogens (bacteria, viruseses, etc.) contained nucleic acids, which enable 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) but responded to agents that disrupt proteins. This hypothesis was originally 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 containing no DNA could reproduce itself was initially met with skepticism, but evidence has steadily accumulated in support of the 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 of a protein (without changing its amino acid sequence) can alter its biological properties. The actual reproduction of the protein is still carried out by the ribosome, while the infectious form of the prion protein only transfers the pathological conformation to the prions 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 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, several mutations that cause the variant shape have been identified and successfully cloned, and studies using genetically altered mice have bolstered the prion hypothesis. The evidence in support of the hypothesis is quite strong now, but not incontrovertible.

In Prusiner's second Scientific American article, he proposed a mechanism for prion propagation that does not require direct action of a prion protein on a normal protein. The suggestion there is that both N, the normal protein, and P, the prion protein, are a product of a post-translational metabolic pathway that forks, leading to either N or P. The presence of P has a negative feedback effect on the fork yielding N, so that P causes less and less N to be made, and more and more P. (For the Creutzfeld-Jakob prion PrP, N corresponds to PrPC, and P corresponds to PrPSC.)

Prions appear to be most infectious when in direct contact with affected tissues. For example, Creutzfeldt-Jakob disease has been transmitted to patients taking injections of growth hormone harvested from human pituitary glands, and from instruments used for brain surgery (prions can survive the "autoclave" sterilization process used for most surgical instruments). It is also believed that dietary consumption of affected animals can cause prions to accumulate slowly, especially when cannibalism or similar practices allow the proteins to accumulate over more than one generation. Laws in developed countries now proscribe the use of rendered ruminant proteins in ruminant feed as a precaution against the spread of prion infection in cattle and other ruminants.

The reason prions are not detected by the immune system is that their "safe" form is already present from birth in the body. The only distinction the "dangerous" prions have is that they are folded slightly differently. Prions infect the nerve lining of neural cells, forming an aggregate which ultimately destroys nerve cells. Depending on the area of the brain which they infect the symptoms can be different. For example, infecting the cerebellum causes impairment of movement. Infecting the cerebral cortex results in a decrease in memory and mental agility.

Useful prions

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 type 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, insuring that only related colonies obtain the benefit of sharing resources.

Since 1965, researchers working with the yeast Saccharomyces cerevisiae under the guidance of Brian S. Cox had been characterizing a genetic trait with a strange form of inheritance, which they referred to as the [PSI+] element. In 1994, Reed Wickner proposed that [PSI+] and another heritable element, [URE3], were both prions. 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. Researchers studied how the amino acid sequence contributed to the ability of the PSI protein (Sup35p) to convert between its prion and non-prion state. 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.

Prions may also be thought of as "'auto-chaperone" proteins. Chaperones are proteins that help fold other proteins into their functional conformations. Since prion proteins act on other molecules of their own kind, they can be considered as self-specific examples of a more general type of chaperone activity.

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

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

How Prions Work

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 (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. 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 protein (PrP) does not at all resemble the prion proteins of yeast in its 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.

Other prion diseases

See also

External links