Sometimes taking more than 30 years to display symptoms, the diseases slowly attack brain tissue, often leaving spongelike holes. They are characterized by accumulations of abnormal forms of a protein, called prion protein, which, unlike viruses or bacteria, contain no genetic material and have no known ability to reproduce themselves. Normal prion proteins occur naturally in brain tissue. The abnormal form differs in shape from the normal prions and is not susceptible to enzymes that normally break down proteins. In the brain, abnormal prions appear to increase their number by directly converting normal prions.
Prion diseases have both infectious and hereditary components. The gene that codes for prions can mutate and be passed on to the next generation. Most of the diseases also can be acquired directly by infection, but unlike other infectious agents, prions provoke no immune response. Most prion diseases, however, are not highly transmissable; chronic wasting disease is the exception because infected deer that have not developed the disease shed prions from lymph tissue in their intestines, contaminating the soil and plants on which other deer graze with the prions in their feces.
An epidemic of BSE in Great Britain that was diagnosed in 1986 and infected some 178,000 cows appears to have been caused by a protein feed supplement that contained rendered remains of scrapie-infected sheep brains. In 1996 a suspicion that BSE had been transmitted to humans who died of a variant of CJD in Britain caused a scientific and economic furor as the European Union imposed a ban (1996) on the export of British beef, which was partially lifted in 1999 and fully lifted in 2006. The U.S. Dept. of Agriculture banned the import of cattle and many cattle byproducts from most European nations because of BSE. Instances of BSE in cattle have also occurred in many other European countries, Canada, the United States, and Japan, but the vast majority of cases occurred in Britain in the 1980s. There is now compelling evidence that BSE is the same disease as variant CJD (vCJD), which has killed less than 200 people, but it is not yet known exactly how the disease is passed from animals to humans.
The idea of disease-causing protein particles was first put forward in 1981 by Stanley B. Prusiner, the neurologist who coined the term prion (from proteinaceous infectious particle). The prion theory has been controversial from the beginning, and although scientific evidence for the existence of such infectious particles has increased, an exact causal link between prions and the diseases they are believed to cause remains to be established. Critics believe that these diseases are caused by unidentified viruses.
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. In general usage, prion refers to the theoretical unit of infection. 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 word prion is a portmanteau developed by combining the first two syllables of the words proteinaceous and infectious (-on by analogy to virion).
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 - though they did not manage to satisfactorily isolate the protein until two years after Prusiner's announcement. Prusiner coined the word "prion" as a name for the infectious agent, by combining the first two syllables of the words proteinaceous and infectious (-on by analogy to virion). While the infectious agent was named a prion, the specific protein that the prion was made of was named PrP, an abbreviation for "protease resistant protein". Prusiner was awarded the Nobel Prize in Physiology or Medicine in 1997 for his research into prions.
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 due to the vacuole formation in the neurons. Other histological changes include astrogliosis and the absence of an inflammatory reaction. 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, ataxia (balance and coordination dysfunction), and behavioural or personality changes.
All known prion diseases, collectively called transmissible spongiform encephalopathies (TSEs), are untreatable and fatal. However, a vaccine has been developed in mice that may provide insight into providing a vaccine in humans to resist prion infections. Additionally, in 2006 scientists announced that they had genetically engineered cattle lacking a necessary gene for prion production - thus theoretically making them immune to BSE, building on research indicating that mice lacking normally-occurring prion protein are resistant to infection by scrapie prion protein.
Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all mammals. Due to small differences in PrP between different species, it is unusual for a prion disease to be transmitted from one species to another (but recent laboratory experiments show that this is possible). However, the human prion disease variant Creutzfeldt-Jakob disease is believed to be caused by a prion which typically infects cattle and is transmitted through infected meat.
Some researchers have suggested that metal ion interactions with prion proteins might be relevant to the progression of prion-mediated disease, based on epidemiological studies of clusters of prion disease in locales with low soil concentrations of copper.
The following diseases are believed to be caused by prions.
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. 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.
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.
The World Health Organization recommends any of the following three procedures for the sterilization of all heat-resistant surgical instruments that are potentially contaminated with prions:
Another method for decomposing and disposing of any organic compound is burning it at high temperatures in an oxygen-rich atmosphere. This method is used for the disposal of deadly chemical weapons such as nerve gasses and mustard gas. This reduces it all to simple gaseous compounds, including water vapor, that are safe to release into the environment.
Evidence in favor of a protein-only hypothesis include:
In 2007, biochemist Surachai Supattapone and his colleagues at Dartmouth College produced purified infectious prions de novo from defined components (PrPC, co-purified lipids, and a synthetic polyanionic molecule) . These researchers also showed that the polyanionic molecule required for prion formation was selectively incorporated into high-affinity complexes with PrP molecules, leading them to hypothesize that infectious prions may be composed of multiple host components, including PrP, lipid, and polyanionic molecules, rather than PrPSc alone .
The virion hypothesis states that TSEs are caused by a replicable informational molecule (which is likely to be a nucleic acid) bound to PrP. Many TSEs, including scrapie and BSE, show strains with specific and distinct biological properties, a feature which supporters of the virion hypothesis feel is not explained by prions. The presence of a nucleic acid bound to the protein would explain the strains observed. It has also been shown that TSEs including BSE retain their host-specific properties after passage through many different species.
Evidence in favor of a viral hypothesis include:
Evidence favouring a pollutant cause:
Research into fungal prions has given strong support to the protein-only hypothesis for mammalian prions, since it has been demonstrated that purified protein extracted from cells with the prion state can convert the normal form of the protein into the infectious form in vitro, and in the process, preserve the information corresponding to different strains of the prion state. It has also shed some light on prion domains, which are regions in a protein that promote the conversion into a prion. Fungal prions have helped to suggest mechanisms of conversion that may apply to all prions.
The Pathological Protein: Mad Cow, Chronic Wasting, and Other Deadly Prion Diseases covers the science of TSE diseases in greater depth than Deadly Feasts but is not so thorough on policy issues. The Family That Couldn't Sleep by D. T. Max provides a history of prion diseases for a popular audience.