PRION

A 'prion' (^[1]) — short for 'pr'oteinaceous 'i'nfectious particle (-'on' by analogy to virion) — is an infectious agent composed only of protein. They cause a number of diseases in a variety of animals, including BSE in cattle and CJD in humans. All known prion diseases affect the structure of the brain or other neural tissue, and all are currently untreatable and fatal. Mice genetically modified to avoid the symptoms are important models of study.^[2] In general usage, 'prion' can refer to both the theoretical unit of infection or the specific protein (i.e. PrP) which is thought to be the infective agent, whether or not it is in an infective state. Normal prion protein is essential for synaptic function. ^[3]
Prions are believed 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. However, the term in itself does not preclude other mechanisms of transmission. All known prions induce the formation of an amyloid fold, in which the protein polymerizes into a fiber with a core consisting of tightly packed beta sheets. Other mechanisms may exist in yet undiscovered infectious protein particles. This altered structure renders them quite resistant to denaturation by chemical and physical agents, although infectivity can be reduced by these treatments, making disposal and containment of these particles difficult.
Proteins showing prion behaviour are also found in some fungi. Some fungal prions may not be associated with any disease; it is unknown whether these prions represent an evolutionary advantage for their hosts.

Contents

Discovery

Structure

Isoforms

PrPC

PrPSc

Function

PrP and long-term memory

Prion disease

Transmission

Sterilization

Debate

Protein-only hypothesis

Viral hypothesis

Heavy Metal Poisoning hypothesis

Genetics

Prions in yeast and other fungi

See also

References

External links

Discovery

Radiation biologist Tikvah Alper and physicist J.S. Griffith developed the theory in the 1960s that some transmissible spongiform encephalopathies are caused by an infectious agent made solely of protein.^[4][5] This theory was developed to explain the discovery that the mysterious infectious agent causing the diseases scrapie and Creutzfeldt-Jakob Disease resisted ultraviolet radiation (which breaks down nucleic acids - present in viruses and all living things) yet responded to agents that disrupt proteins.
Francis Crick recognized the potential importance of the Griffith protein-only hypothesis for scrapie propagation in the second edition of his famous "Central dogma of molecular biology" (Nature. 1970 Aug 8;227(5258):561-3). While asserting that the flow of sequence information from protein to protein, or from protein to RNA and DNA was "precluded" by the dogma, he noted that Griffith's hypothesis was a potential difficulty (although it was not so promoted by Griffith). As the revised "dogma" was formulated, in part, to accommodate the then recent discovery of reverse transcription by Howard Temin and David Baltimore (Nobel Prize, 1975), proof of the protein-only hypothesis might have been seen as a sure bet for a future Prize.
Stanley B. Prusiner of the University of California, San Francisco announced in 1982 that his team had purified infectious material and that the infectious agent consisted mainly of a specific protein, although they had not managed to satisfactorily isolate the protein until two years after making his announcement.^[1]
Prusiner coined the word "prion" as a name for the infectious agent, by combining the first two syllables of the words ''proteinaceous'' and ''infectious''.^[7] 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.^[8]

Structure

Isoforms

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 structure and is resistant to proteases, the enzymes in the body that can normally break down proteins. The normal form of the protein is called 'PrP^C', while the infectious form is called 'PrP^Sc' — the ''C'' refers to 'cellular' or 'common' PrP, while the ''Sc'' refers to 'scrapie', a prion disease occurring in sheep. While 'PrP^C' is structurally well-defined, 'PrP^Sc' is certainly polydisperse and defined at a relatively poor level. PrP can be induced to fold into other more-or-less well-defined isoforms in vitro, and their relationship to the form(s) that are pathogenic in vivo is not yet clear.

PrP^C

PrP^C is a normal protein found on the membranes of cells. Several topological forms of it exist; one cell surface form anchored via glycolipid and two transmembrane forms,^[9] however its function has not been fully resolved.^[10] PrP^C is readily digested by proteinase K and can be liberated from the cell surface by the enzyme ''phosphatidyl inositol-specific phospholipase C'', which cleaves the ''phosphatidyl inositol'' glycolipid anchor.^[11] A typical yeast prion protein contains a core region (domain) with many repeats of the amino acids glutamine and asparagine. Normal yeast prion domains are flexible and lack a defined structure. ^[12]

PrP^Sc

The infectious isoform of PrP^C, known as PrP^Sc, is able to catalyse the formation of other normal PrP^C proteins into the infectious isoform by changing their conformation.
Although the exact 3D structure of PrP^Sc is not known, there is increased β-sheet content in the diseased form of the molecule, replacing normal areas of α-helix.^[13] Aggregations of these abnormal isoforms forms a highly structured amyloid fiber. The end of the fiber acts as a template for the 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. The mammalian prion proteins do not resemble the prion proteins of yeast in their amino acid sequence, however, they are still known as PrP^C and PrP^Sc and share basic structural features.

Function

PrP and long-term memory

There is evidence that PrP may have a normal function in maintenance of long term memory.^[14] Maglio and colleagues have shown that mice without the genes for normal cellular PrP protein have altered hippocampal LTP.^[15]

Prion disease

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 characterised by "holes" in the tissue with resultant spongy architecture due to the vacuole formation in the neurons.^[16] Other histological changes include astrogliosis and the absence of an inflammatory reaction.^[17] While the incubation period for prion diseases is generally quite long, once symptoms appear the disease progresses rapidly, leading to brain damage and death.^[18] 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.^[19] However, a vaccine has been developed in mice that may provide insight into providing a vaccine in humans to resist prion infections.^[20] 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,^[21] building on research indicating that mice lacking normally-occurring prion protein are resistant to infection by scrapie prion protein.^[22]
Prions are able to affect a variety of different species, however the prions involved are somewhat species-specific: they are similar but not identical.^[23] However overlap may occur; 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. Variant Creutzfeldt-Jakob disease: risk of transmission by blood transfusion and blood therapies, Ironside, JW, , , Haemophilia, 2006
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.^[24]
The following diseases are believed to be caused by prions.

★ In 'animals':

★
★ , genetic, or infectious.
It should be noted that the same gene is responsible for spongiform encephalopathies which are not known to be transmissible, as well as some non-neurological diseases. Some require a mutation for transmission to occur, and there are respective mutations which can prevent or protect against transmission for most of the TSEs (eg. mutations leading to total absence of the PRNP gene or heterozygosity at codon 129 of the same gene). The normal role of the prion gene has yet to be found, and so it is an area of considerable active research. Indeed gene knockout mice lacking the prion gene only exhibit subtle differences and seem to be incapable of acquiring spongiforme encephalopathy.

Prions in yeast and other fungi

Prion-like proteins that behave in a similar way to PrP are found naturally in some fungi and non-mammalian animals. A group at the Whitehead Institute has argued that some of the fungal prions are not associated with any disease state and may have a useful role; however, researchers at the NIH have also provided strong arguments demonstrating that fungal prions should be considered a diseased state. Research into fungal prions has given strong support to the protein-only hypothesis for mammalian prions, as it has been demonstrated that seeds 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. Fungal prions have helped to suggest mechanisms of conversion that may apply to all prions.

See also

★ Protein folding

★ Proteopathy

★ Tertiary structure

References

1.
2. Targeting Cellular Prion Protein Reverses Early Cognitive Deficits and Neurophysiological Dysfunction in Prion-Infected Mice, Giovanna R. Mallucci, , , Neuron, 2007
3. Prion protein is necessary for normal synaptic function Letters to Nature, ''Nature'' 370, 295 - 297 (28 July 1994); doi:10.1038/370295a0
4. Does the agent of scrapie replicate without nucleic acid?, Alper T, Cramp W, Haig D, Clarke M, , , Nature, 1967
5. Self-replication and scrapie, Griffith J, , , Nature, 1967
6.
7. Novel proteinaceous infectious particles cause scrapie, Prusiner, SB, , , Science, 1982
8.
9. Contact-Induced Structure Transformation in Transmembrane Prion Propagation, DM Ou, CC Chen, CM Chen, , , Biophysical Journal, 2007
10. A glycolipid-anchored prion protein is endocytosed via clathrin-coated pits., Shyng SL, Heuser JE, Harris DA, , , J Cell Biol., 1994
11. The State of the Prion, Weissmann, C, , , Nature Reviews Microbiology, 2004
12. Stability, Folding, Dimerization, and Assembly Properties of the Yeast Prion Ure2p ''Biochemistry'' 2001, 40, 1764-1773
13. Conversion of alpha-helices into beta-sheets features in the formation of scrapie prion protein, , , , PNAS USA,
14. Prions as adaptive conduits of memory and inheritance, Shorter J, Lindquist S, , , Nat Rev Genet, 2005
15. Hippocampal synaptic plasticity in mice devoid of cellular prion protein, Maglio L, Perez M, Martins V, Brentani R, Ramirez O, , , Brain Res Mol Brain Res, 2004
16. Robbins Pathologic Basis of Disease, , , Cotran, W.B Saunders Company, , 0-7216-7335-X
17. Transmissible Spongiform Encephalopathies in Humans, Belay E., , , Annu. Rev. Microbiol., 1999
18.
19. Intracellular re-routing of prion protein prevents propagation of PrPSc and delays onset of prion disease, Gilch, Sabine, ''et al.'', , , The EMBO Journal, 2001
20. Active Vaccine Prevents Mice From Developing Prion Disease New York University Medical Center and School of Medicine
21. Scientists Announce Mad Cow Breakthrough Rick Weiss
22.

External links

★ Biography of Dr Prusiner

★ Mammalian prions - 90.001.0.01 ICTVdb

★ MicrobiologyBytes: Prion Diseases

★ Prion Diseases and the BSE Crisis (1997). Article from ''Science'' magazine by Stanley Prusiner.

★ Overview of prion biology from the Science Creative Quarterly

★ Science Daily article on transmission of prions through soil

★ The Pathological Protein - Mad Cow, Chronic Wasting, and Other Deadly Prion Diseases] (2003, updated online 2005). Philip Yam, Scientific American writer and news editor.