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), and Bovine Spongiform Encephalopathy ("Mad Cow Disease"). These diseases affect the structure of brain tissue and are both 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".
Prions are the hypothetical (and initially discounted) infectious agents consisting only of protein, with no nucleic acids. All pathogens known prior to that time (bacteria, viruses, etc.) contain 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.
A breakthrough occurred when researchers discovered that the infectious agent consisted mainly of a protein called PRP. This protein is found in the membranes of normal cells (its precise function is not known), but an altered shape distinguished the infectious agent. 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, the mutation that causes the variant shape has 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.
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. Though the risk is not yet proven, modern farming practices now disallow the use of rendered ruminant proteins in ruminant feed as a precaution.
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 symptons 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.
Not all prions are dangerous; in fact they are found naturally in many (perhaps all) plants and animals. Because of this, scientists reasoned that the deformed proteins must give some sort of evolutionary advantage to their host. This was proved to be the case when studying a specific type of moss covering forest floors. Normally viruses can travel from an infected moss section to an uninfected moss section when the areas grow close enough for the outer cells to touch. However prions were discovered in the infected moss, which appeared to travel part way into the sides of the uninfected moss. This caused cells on the edges of the moss to die, creating a barrier of dead cells which viruses are unable to cross, preventing contamination.
Since 1965, researchers working with the yeast Saccharomyces cerevisiae under the guidance of Brian Cox[?] had been characterizing a strange form of inheritance, which they referred to as the [PSI+] element. In 1994, Reed Wickner[?] proposed that [PSI+] and another heritable element were both prions. It was soon noticed that heat shock proteins[?] (which help other proteins fold properly) were able to reduce the effects of [PSI+]. 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. This research led Susan Lindquist to propose that prionic conversion might be advantageous in some situations, leading to their evolutionary conservation.