"Prion." Wikipedia, The Free Encyclopedia. 11 Oct 2008, 16:26 UTC. 12 Oct 2008 <http://en.wikipedia.org/w/index.php?title=Prion&oldid=244590839>. Heavily edited for length by B.Rick.
A prion is thought to be an infectious agent that, according to current scientific consensus, is comprised entirely of a propagated, mis-folded protein. The mis-folded form of the prion protein has been implicated in a number of diseases in a variety of mammals, including bovine spongiform encephalopathy (BSE, also known as "mad cow disease") in cattle and Creutzfeldt-Jakob disease (CJD) in humans.
All hypothesized prion diseases affect the structure of the brain or other neural tissue, and all are currently untreatable and are always fatal. Scientifically speaking, PrPC refers to the endogenous prion protein, which is found in a multitude of tissues, while PrPSc refers to the misfolded form of PrPC, and is responsible for the formation of amyloid plaques that lead to neurodegeneration.
Prions are hypothesized to infect and propagate by refolding abnormally into a structure which is able to convert normal molecules of the protein into the abnormally structured form. All known prions induce the formation of an amyloid fold, in which the protein polymerises into an aggregate consisting of tightly packed beta sheets. This altered structure is extremely stable and accumulates in infected tissue, causing cell death and tissue damage. This stability means that prions are resistant to denaturation by chemical and physical agents, making disposal and containment of these particles difficult.
Proteins showing prion-type behavior are also found in some fungi and this has been quite important in helping to understand mammalian prions. However, fungal prions do not appear to cause disease in their hosts and may even confer an evolutionary advantage through a form of protein-based inheritance.
The radiation biologist Tikvah Alper and the mathematician John Stanley Griffith developed the hypothesis during the 1960s that some transmissible spongiform encephalopathies are caused by an infectious agent consisting solely of proteins.
Stanley B. Prusiner of the University of California, San Francisco announced in 1982 that his team had purified the hypothetical infectious prion, and that the infectious agent consisted mainly of a specific protein
The protein that prions are made of is found throughout the body, even in healthy people and animals. However, the prion protein found in infectious material has a different folding pattern and is resistant to proteases, the enzymes in the body that can normally break down proteins. The normal form of the protein is called PrPC, while the infectious form is called PrPSc — the C refers to 'cellular' or 'common' PrP, while the Sc refers to 'scrapie', a prion disease occurring in sheep PrPC
PrPC is a normal protein found on the membranes of cells. It has 209 amino acids (in humans), a molecular weight of 35-36kDa and a mainly alpha-helical structure. Several topological forms exist.
PrPSc, the infectious form of PrPC,is able to convert normal PrPC proteins into the infectious form by changing their conformation. Although the exact 3D structure of PrPSc is not known, there is increased β-sheet content in the diseased form of the molecule, replacing normal areas of α-helix. Aggregations of these abnormal forms may form highly structured amyloid fibers. The end of a fiber acts as a template for the free protein molecules, causing the fiber to grow.
It has now been conclusively proven that the prion protein's normal cellular role is as a copper dependent antioxidant. While a small number of researchers in the field pursue other possibilities, the majority of evidence from many researchers supports this finding. There is evidence that PrP may have a normal function in maintenance of long term memory.
Microscopic "holes" are characteristic in prion-affected tissue sections, causing the tissue to develop a "spongy" architecture.
Prions cause neurodegenerative disease by aggregating extracellularly within the central nervous system to form plaques known as amyloids, which disrupt the normal tissue structure. This disruption is characterized by "holes" in the tissue with resultant spongy architecture. While the incubation period for prion diseases is generally quite long, once symptoms appear the disease progresses rapidly, leading to brain damage and death. Neurodegenerative symptoms can include convulsions, dementia, balance and coordination dysfunction, and behavioural or personality changes.
All known prion diseases, collectively called transmissible spongiform encephalopathies (TSEs), are untreatable and fatal.
Prion diseases are the only known diseases that can be sporadic, genetic, or infectious.
Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all mammals. The following diseases are believed to be caused by prions:
- In animals:
- Scrapie in sheep and goats
- Bovine spongiform encephalopathy (BSE) in cattle (known as mad cow disease)
- Transmissible mink encephalopathy (TME) in mink
- Chronic wasting disease (CWD) in white-tailed deer, elk and mule deer
- Feline spongiform encephalopathy in cats
- Exotic ungulate encephalopathy (EUE) in nyala, oryx and greater kudu
- Spongiform encephalopathy of the ostrich
- In humans:
- Creutzfeldt-Jakob disease (CJD) and its varieties
- Gerstmann-Sträussler-Scheinker syndrome (GSS)
- Fatal familial insomnia (sFI)
Although the identity and general properties of prions are now well understood, the mechanism of prion infection and propagation remains mysterious. It is often assumed that the diseased form directly interacts with the normal form to make it rearrange its structure.
Current research suggests that the primary method of infection in animals is through ingestion. It is thought that prions may be deposited in the environment through the remains of dead animals and via urine, saliva, and other body fluids. They may then linger in the soil by binding to clay and other minerals.
Prions are generally quite resistant to denaturation by proteases, heat, radiation, and formalin treatments, although their infectivity can be reduced by such treatments.
Whether prions are the agent which causes disease or merely a symptom caused by a different agent is still under debate.
A gene for the normal protein has been isolated: the PRNP gene. Some prion diseases 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 PrPC more likely to spontaneously change into the abnormal PrPSc form.