Prion
Encyclopedia
A prion is an infectious agent composed of protein
in a misfolded
form. This is in contrast to all other known infectious agents (virus
/bacteria
/fungus
/parasite) which must contain nucleic acid
s (either DNA
, RNA
, or both). The word prion, coined in 1982 by Stanley B. Prusiner
, is a portmanteau derived from the words protein and infection. Prions are responsible for the transmissible spongiform encephalopathies
in a variety of mammal
s, including bovine spongiform encephalopathy
(BSE, also known as "mad cow disease") in cattle
and Creutzfeldt–Jakob disease (CJD) in humans. All known prion diseases affect the structure of the brain
or other neural
tissue and all are currently untreatable and universally fatal.
Prions propagate by transmitting a misfolded protein
state. When a prion enters a healthy organism, it induces existing, properly folded proteins to convert into the disease-associated, prion form; the prion acts as a template to guide the misfolding of more protein into prion form. These newly formed prions can then go on to convert more proteins themselves; this triggers a chain reaction that produces large amounts of the prion form. All known prions induce the formation of an amyloid
fold, in which the protein polymerises into an aggregate consisting of tightly packed beta sheet
s. Amyloid aggregates are fibrils, growing at their ends, and replicating when breakage causes two growing ends to become four growing ends. The incubation period
of prion diseases is determined by the exponential growth
rate associated with prion replication, which is a balance between the linear growth and the breakage of aggregates. (Note that the propagation of the prion depends on the presence of normally folded protein in which the prion can induce misfolding; animals which do not express the normal form of the prion protein cannot develop or transmit the disease.)
This altered structure is extremely stable and accumulates in infected tissue, causing tissue damage and cell death. This structural stability means that prions are resistant to denaturation
by chemical and physical agents, making disposal and containment of these particles difficult. Prions come in different strains, each with a slightly different structure, and most of the time, strains breed true. Prion replication is nevertheless subject to occasional epimutation and then natural selection
just like other forms of replication. However, the number of possible distinct prion strains is likely far smaller than the number of possible DNA sequences, so evolution takes place within a limited space.
All known mammalian prion diseases are caused by the so-called prion protein, PrP
. The endogenous, properly folded, form is denoted PrPC (for common or cellular) while the disease-linked, misfolded form is denoted PrPSc (for Scrapie
, after one of the diseases first linked to prions and neurodegeneration.) The precise structure of the prion is not known, though they can be formed by combining PrPC, polyadenylic acid, and lipids in a Protein Misfolding Cyclic Amplification
(PMCA) reaction.
Proteins showing prion-type behavior are also found in some fungi
, which has been useful in helping to understand mammalian prions. Interestingly, fungal prions
do not appear to cause disease in their hosts.
are caused by an infectious agent consisting solely of proteins. Their theory was developed to explain the discovery that the mysterious infectious agent causing the diseases scrapie
and Creutzfeldt–Jakob disease resisted ionizing radiation
. A single ionizing "hit" normally destroys an entire infectious particle, and the dose needed to hit half the particles depends on the size of the particles. The data suggested that the infectious agent was too small to be a virus.
Francis Crick
recognized the potential importance of the Griffith protein-only hypothesis for scrapie propagation in the second edition of his "Central dogma of molecular biology
": while asserting that the flow of sequence information from protein to protein, or from protein to RNA and DNA was "precluded", he noted that Griffith's hypothesis was a potential contradiction (although it was not so promoted by Griffith). The revised hypothesis was later formulated, in part, to accommodate discovery of reverse transcription by Howard Temin
and David Baltimore
.
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 isolate the protein until two years after Prusiner's announcement. Prusiner coined the word "prion" as a name for the infectious agent. While the infectious agent was named a prion, the specific protein that the prion was composed of is also known as the Prion Protein (PrP), though this protein may occur both in infectious and non-infectious forms. Prusiner was awarded the Nobel Prize in Physiology or Medicine
in 1997 for his research into prions, albeit not without controversy.
s, 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. While PrPC is structurally well-defined, PrPSc 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.
of cells
. It has 209 amino acid
s (in humans), one disulfide bond
, a molecular weight of 35-36 kDa
and a mainly alpha-helical
structure. Several topological
forms exist; one cell surface form anchored via glycolipid
and two transmembrane forms. The normal protein is not sedimentable; meaning it cannot be separated by centrifuging techniques. Its function is a complex issue that continues to be investigated. PrPC binds copper
(II) ion
s with high affinity. The significance of this finding is not clear, but it presumably relates to PrP structure or function. PrPC is readily digested by proteinase K
and can be liberated from the cell surface in vitro by the enzyme phosphoinositide phospholipase C
(PI-PLC), which cleaves the glycophosphatidylinositol
(GPI) glycolipid anchor. PrP has been reported to play important roles in cell-cell adhesion and intracellular signaling in vivo, and may therefore be involved in cell-cell communication in the brain.
, or shape; this, in turn, alters the way the proteins interconnect. Although the exact 3D structure of PrPSc is not known, it has a higher proportion of β-sheet
structure in place of the normal α-helix
structure. Aggregations of these abnormal isoforms form highly structured amyloid
fibers, which accumulate to form plaques. It is unclear if these aggregates are the cause of cell damage or are simply a side effect of the underlying disease process. The end of each fiber acts as a template onto which free protein molecules may attach, allowing the fiber to grow. Only PrP molecules with an identical amino acid sequence to the infectious PrPSc are incorporated into the growing fiber. However, this property is not strictly shared by other proteins considered prions. The sup35p
was shown to be able to be incorporated into existing aggregations even when three of the five oligopeptide repeats normally present were deleted.
The first hypothesis that tried to explain how prions replicate in a protein-only manner was the heterodimer model. This model assumed that a single PrPSc molecule binds to a single PrPC molecule and catalyzes
its conversion into PrPSc. The two PrPSc molecules then come apart and can go on to convert more PrPC. However, Manfred Eigen
showed that since PrPC has a very low rate of spontaneous conversion into PrPSc, the heterodimer model requires PrPSc to be an extraordinarily effective catalyst
, increasing the rate of the conversion reaction by a factor of around 1015. What is more, despite considerable effort, infectious monomeric PrPSc has never been isolated. Theory and experiments both suggest that PrPSc exists only in aggregated forms such as amyloid
, and that prion replication involves cooperativity
.
An alternative model assumes that PrPSc exists only as fibrils, and that fibril ends bind PrPC and convert it into PrPSc. If this were all, then the quantity of prions would increase linearly
, forming ever longer fibrils. But exponential growth
of both PrPSc and of the quantity of infectious particles is observed during prion disease. This can be explained by taking into account fibril breakage. A mathematical solution for the exponential growth rate resulting from the combination of fibril growth and fibril breakage has been found. The exponential growth rate depends largely on the square root
of the PrPC concentration. The incubation period
is determined by the exponential growth rate, and in vivo
data on prion diseases in transgenic mice match this prediction. The same square root dependence is also seen in vitro
in experiments with a variety of different amyloid proteins
.
The mechanism of prion replication has implications for designing drugs. Since the incubation period of prion diseases is so long, an effective drug does not need to eliminate all prions, but simply needs to slow down the rate of exponential growth. Models predict that the most effective way to achieve this, using a drug with the lowest possible dose, is to find a drug that binds to fibril ends and blocks them from growing any further.
repair in Schwann Cells and that the lack of prions caused demyelination in those cells.
. As well, a 2004 study found that mice lacking genes for normal cellular PrP protein show altered hippocampal
long-term potentiation
.
. The study showed that all long-term hematopoietic stem cells expressed PrP on their cell membrane and that hematopoietic tissues with PrP-null stem cells exhibited increased sensitivity to cell depletion.
Prions cause neurodegenerative disease by aggregating extracellularly within the central nervous system
to form plaques known as amyloid
, 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 convulsion
s, 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. A vaccine has been developed in mice, however, 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. The human prion disease variant Creutzfeldt-Jakob disease, however, is believed to be caused by a prion which typically infects cattle, causing Bovine spongiform encephalopathy
and is transmitted through infected meat.
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.
A University of California research team, led by Nobel prize winner Stanley Prusiner, has proven that infection can occur from prions in manure. And since manure is present in many areas surrounding water reservoirs, as well as used on many crop fields, it raises the possibility of widespread transmission. It was reported in January 2011 that researchers had discovered prions spreading through airborne transmission on aerosol
particles, in an animal testing
experiment focusing on scrapie
infection in laboratory mice. Preliminary evidence supporting the notion that prions can be transmitted through use of urine-derived human menopausal gonadotropin, administered for the treatment of infertility
, was published in 2011.
of the protein to a state where the molecule is no longer able to induce the abnormal folding of normal proteins. Prions are generally quite resistant to protease
s, heat
, radiation
, and formalin treatments, although their infectivity can be reduced by such treatments. Effective prion decontamination relies upon protein hydrolysis or reduction or destruction of protein tertiary structure. Examples include bleach
, caustic soda, and strongly acidic detergents such as LpH. 134°C (274°F) for 18 minutes in a pressurized steam autoclave
may not be enough to deactivate the agent of disease. Ozone sterilization is currently being studied as a potential method for prion denature and deactivation. Renaturation of a completely denatured prion to infectious status has not yet been achieved; however, partially denatured prions can be renatured to an infective status under certain artificial conditions.
The World Health Organization
recommends any of the following three procedures for the sterilization of all heat-resistant surgical instruments to ensure that they are not contaminated with prions:
s used nucleic acid
s to direct their replication. The "protein hypothesis" states that a protein structure can replicate without the use of nucleic acid. This was initially controversial as it contradicts the so-called "central dogma of molecular biology
", which describes nucleic acid as the central form of replicative information.
Evidence in favor of a protein hypothesis includes:
for the normal protein has been identified: the PRNP
gene. In all inherited cases of prion disease, 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 change spontaneously into the abnormal PrPSc form. Although this discovery puts a hole in the general prion hypothesis, that prions can only aggregate proteins of identical amino acid make up. These mutations can occur throughout the gene. Some mutations involve expansion of the octapeptide repeat region at the N-terminal of PrP. Other mutations that have been identified as a cause of inherited prion disease occur at positions 102, 117 & 198 (GSS), 178, 200, 210 & 232 (CJD) and 178 (Fatal Familial Insomnia
, FFI). The cause of prion disease can be sporadic, genetic
, and infectious
, or a combination of these factors. For example, in order to have scrapie, both an infectious agent and a susceptible genotype need to be present.
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.
In 2010, Jiyan Ma and colleagues at The Ohio State University produced infectious prions from a recipe of bacterially expressed recombinant PrP, POPG phospholipid, and RNA, further supporting the multi-component hypothesis. This finding is in contrast to studies that found minimal infectious prions produced from recombinant PrP alone.
neuropathologist Laura Manuelidis
has been proposing that prion diseases are caused instead by an unidentified slow virus
. In January 2007, she and her colleagues published an article reporting to have found a virus
in 10%, or less, of their scrapie-infected cells in culture.
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.
Evidence in favor of a viral hypothesis includes:
Recent studies propagating TSE infectivity in cell-free reactions and in purified component chemical reactions strongly suggest against TSE viral nature. More recently, using a similar defined recipe of multiple components (PrP, POPG lipid, RNA), Jiyan Ma and colleagues generated infectious prions from recombinant PrP expressed from E. coli, casting further doubt on the viral hypothesis.
by Reed Wickner
in the early 1990s. For their mechanistic similarity to the prion hypothesis, they were termed yeast prions. Subsequently, a prion has also been found in the fungus Podospora anserina. These prions behave similarly to PrP, but are generally nontoxic to their hosts. Susan Lindquist
's group at the Whitehead Institute
has argued some of the fungal prions are not associated with any disease state, but may have a useful role; however, researchers at the NIH have also provided arguments suggesting fungal prions could be considered a diseased state. Thus, the issue of whether fungal proteins are diseases, or have evolved for some specific functions, still remains unresolved.
As of 2010, there are eight known prion proteins in fungi, seven in Saccharomyces cerevisiae
(Sup35, Rnq1, Ure2, Swi1, Mca1, Mot3, Cyc8) and one in Podospora anserina (HET-s).
Research into fungal prions
has given strong support to the protein-only concept, since purified protein extracted from cells with a prion state has been demonstrated to convert the normal form of the protein into a misfolded 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, though fungal prions appear distinct from infectious mammalian prions in the lack of cofactor required for propagation. The characteristic prion domains may vary between species—e.g. characteristic fungal prion domains are not found in mammalian prions.
Recently, antiprion antibodies capable of crossing the blood-brain-barrier and targeting cytosol
ic prion protein (an otherwise major obstacle in prion therapeutics) have been described.
In 2011 it was discovered that prions could be degraded by lichen
s.
There continues to be a very practical problem with diagnosis of prion diseases, including BSE and CJD. They have an incubation period of months to decades during which there are no symptoms, even though the pathway of converting the normal brain PrP protein into the toxic, disease-related PrP
Sc form has started. At present, there is virtually no way to detect PrPSc reliably except by examining the brain using neuropathological and immunohistochemical methods after death. Accumulation of the abnormally folded PrPSc form of the PrP protein is a characteristic of the disease, but it is present at very low levels in easily accessible body fluids like blood or urine. Researchers have tried to develop methods to measure PrPSc, but there are still no fully accepted methods for use in materials such as blood.
In 2010, a team from New York described detection of PrPSc even when initially present at only one part in a hundred thousand million (10−11) in brain tissue. The method combines amplification with a novel technology called Surround Optical Fiber Immunoassay (SOFIA)
and some specific antibodies against PrPSc. After amplifying and then concentrating any PrPSc, the samples are labelled with a fluorescent dye using an antibody for specificity and then finally loaded into a micro-capillary tube. This tube is placed in a specially constructed apparatus so that it is totally surrounded by optical fibres to capture all light emitted once the dye is excited using a laser. The technique allowed detection of PrPSc after many fewer cycles of conversion than others have achieved, substantially reducing the possibility of artefacts, as well as speeding up the assay. The researchers also tested their method on blood samples from apparently healthy sheep that went on to develop scrapie. The animals’ brains were analysed once any symptoms became apparent. The researchers could therefore compare results from brain tissue and blood taken once the animals exhibited symptoms of the diseases, with blood obtained earlier in the animals’ lives, and from uninfected animals. The results showed very clearly that PrPSc could be detected in the blood of animals long before the symptoms appeared.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
in a misfolded
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
form. This is in contrast to all other known infectious agents (virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
/bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
/fungus
Fungus
A fungus is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds , as well as the more familiar mushrooms. These organisms are classified as a kingdom, Fungi, which is separate from plants, animals, and bacteria...
/parasite) which must contain nucleic acid
Nucleic acid
Nucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...
s (either DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
, or both). The word prion, coined in 1982 by Stanley B. Prusiner
Stanley B. Prusiner
Stanley Ben Prusiner is an American neurologist and biochemist. Currently the director of the Institute for Neurodegenerative Diseases at University of California, San Francisco . Prusiner discovered prions, a class of infectious self-reproducing pathogens primarily or solely composed of protein...
, is a portmanteau derived from the words protein and infection. Prions are responsible for the transmissible spongiform encephalopathies
Transmissible spongiform encephalopathy
Transmissible spongiform encephalopathies , also known as prion diseases, are a group of progressive conditions that affect the brain and nervous system of many animals, including humans. According to the most widespread hypothesis they are transmitted by prions, though some other data suggest an...
in a variety of mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s, including bovine spongiform encephalopathy
Bovine spongiform encephalopathy
Bovine spongiform encephalopathy , commonly known as mad-cow disease, is a fatal neurodegenerative disease in cattle that causes a spongy degeneration in the brain and spinal cord. BSE has a long incubation period, about 30 months to 8 years, usually affecting adult cattle at a peak age onset of...
(BSE, also known as "mad cow disease") in cattle
Cattle
Cattle are the most common type of large domesticated ungulates. They are a prominent modern member of the subfamily Bovinae, are the most widespread species of the genus Bos, and are most commonly classified collectively as Bos primigenius...
and Creutzfeldt–Jakob disease (CJD) in humans. All known prion diseases affect the structure of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
or other neural
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
tissue and all are currently untreatable and universally fatal.
Prions propagate by transmitting a misfolded protein
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
state. When a prion enters a healthy organism, it induces existing, properly folded proteins to convert into the disease-associated, prion form; the prion acts as a template to guide the misfolding of more protein into prion form. These newly formed prions can then go on to convert more proteins themselves; this triggers a chain reaction that produces large amounts of the prion form. All known prions induce the formation of an amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
fold, in which the protein polymerises into an aggregate consisting of tightly packed beta sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
s. Amyloid aggregates are fibrils, growing at their ends, and replicating when breakage causes two growing ends to become four growing ends. The incubation period
Incubation period
Incubation period is the time elapsed between exposure to a pathogenic organism, a chemical or radiation, and when symptoms and signs are first apparent...
of prion diseases is determined by the exponential growth
Exponential growth
Exponential growth occurs when the growth rate of a mathematical function is proportional to the function's current value...
rate associated with prion replication, which is a balance between the linear growth and the breakage of aggregates. (Note that the propagation of the prion depends on the presence of normally folded protein in which the prion can induce misfolding; animals which do not express the normal form of the prion protein cannot develop or transmit the disease.)
This altered structure is extremely stable and accumulates in infected tissue, causing tissue damage and cell death. This structural stability means that prions are resistant to denaturation
Denaturation (biochemistry)
Denaturation is a process in which proteins or nucleic acids lose their tertiary structure and secondary structure by application of some external stress or compound, such as a strong acid or base, a concentrated inorganic salt, an organic solvent , or heat...
by chemical and physical agents, making disposal and containment of these particles difficult. Prions come in different strains, each with a slightly different structure, and most of the time, strains breed true. Prion replication is nevertheless subject to occasional epimutation and then natural selection
Natural selection
Natural selection is the nonrandom process by which biologic traits become either more or less common in a population as a function of differential reproduction of their bearers. It is a key mechanism of evolution....
just like other forms of replication. However, the number of possible distinct prion strains is likely far smaller than the number of possible DNA sequences, so evolution takes place within a limited space.
All known mammalian prion diseases are caused by the so-called prion protein, PrP
PRP
PRP may stand for:* Park Royal Partnership in London* Patriotic Renewal Party or Partido Renovación Patriótica, a political party in Honduras* Peel Regional Police* People's Reconciliation Party* People's Republic of Poland* Personnel Reliability Program...
. The endogenous, properly folded, form is denoted PrPC (for common or cellular) while the disease-linked, misfolded form is denoted PrPSc (for Scrapie
Scrapie
Scrapie is a fatal, degenerative disease that affects the nervous systems of sheep and goats. It is one of several transmissible spongiform encephalopathies , which are related to bovine spongiform encephalopathy and chronic wasting disease of deer. Like other spongiform encephalopathies, scrapie...
, after one of the diseases first linked to prions and neurodegeneration.) The precise structure of the prion is not known, though they can be formed by combining PrPC, polyadenylic acid, and lipids in a Protein Misfolding Cyclic Amplification
Protein Misfolding Cyclic Amplification
Protein Misfolding Cyclic Amplification is an amplification technique to multiply misfolded prions originally developed by Soto and colleagues...
(PMCA) reaction.
Proteins showing prion-type behavior are also found in some fungi
Fungus
A fungus is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds , as well as the more familiar mushrooms. These organisms are classified as a kingdom, Fungi, which is separate from plants, animals, and bacteria...
, which has been useful in helping to understand mammalian prions. Interestingly, fungal prions
Fungal prions
Fungal prions provide an excellent model for the understanding of disease-forming mammalian prions. Fungal prions are naturally occurring proteins that can undergo a structural conversion that becomes self-propagating and infectious. They represent an epigenetic phenomenon in which information is...
do not appear to cause disease in their hosts.
Discovery
Radiation biologist Tikvah Alper and mathematician John Stanley Griffith developed the hypothesis during the 1960s that some transmissible spongiform encephalopathiesTransmissible spongiform encephalopathy
Transmissible spongiform encephalopathies , also known as prion diseases, are a group of progressive conditions that affect the brain and nervous system of many animals, including humans. According to the most widespread hypothesis they are transmitted by prions, though some other data suggest an...
are caused by an infectious agent consisting solely of proteins. Their theory was developed to explain the discovery that the mysterious infectious agent causing the diseases scrapie
Scrapie
Scrapie is a fatal, degenerative disease that affects the nervous systems of sheep and goats. It is one of several transmissible spongiform encephalopathies , which are related to bovine spongiform encephalopathy and chronic wasting disease of deer. Like other spongiform encephalopathies, scrapie...
and Creutzfeldt–Jakob disease resisted ionizing radiation
Ionizing radiation
Ionizing radiation is radiation composed of particles that individually have sufficient energy to remove an electron from an atom or molecule. This ionization produces free radicals, which are atoms or molecules containing unpaired electrons...
. A single ionizing "hit" normally destroys an entire infectious particle, and the dose needed to hit half the particles depends on the size of the particles. The data suggested that the infectious agent was too small to be a virus.
Francis Crick
Francis Crick
Francis Harry Compton Crick OM FRS was an English molecular biologist, biophysicist, and neuroscientist, and most noted for being one of two co-discoverers of the structure of the DNA molecule in 1953, together with James D. Watson...
recognized the potential importance of the Griffith protein-only hypothesis for scrapie propagation in the second edition of his "Central dogma of molecular biology
Central dogma of molecular biology
The central dogma of molecular biology was first articulated by Francis Crick in 1958 and re-stated in a Nature paper published in 1970:In other words, the process of producing proteins is irreversible: a protein cannot be used to create DNA....
": while asserting that the flow of sequence information from protein to protein, or from protein to RNA and DNA was "precluded", he noted that Griffith's hypothesis was a potential contradiction (although it was not so promoted by Griffith). The revised hypothesis was later formulated, in part, to accommodate discovery of reverse transcription by Howard Temin
Howard Martin Temin
Howard Martin Temin was a U.S. geneticist. Along with Renato Dulbecco and David Baltimore he discovered reverse transcriptase in the 1970s at the University of Wisconsin–Madison, for which he shared the 1975 Nobel Prize in Physiology or Medicine.-Scientific career:Temin's description of how tumor...
and David Baltimore
David Baltimore
David Baltimore is an American biologist, university administrator, and Nobel laureate in Physiology or Medicine. He served as president of the California Institute of Technology from 1997 to 2006, and is currently the Robert A. Millikan Professor of Biology at Caltech...
.
Stanley B. Prusiner
Stanley B. Prusiner
Stanley Ben Prusiner is an American neurologist and biochemist. Currently the director of the Institute for Neurodegenerative Diseases at University of California, San Francisco . Prusiner discovered prions, a class of infectious self-reproducing pathogens primarily or solely composed of protein...
of the University of California, San Francisco
University of California, San Francisco
The University of California, San Francisco is one of the world's leading centers of health sciences research, patient care, and education. UCSF's medical, pharmacy, dentistry, nursing, and graduate schools are among the top health science professional schools in the world...
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 isolate the protein until two years after Prusiner's announcement. Prusiner coined the word "prion" as a name for the infectious agent. While the infectious agent was named a prion, the specific protein that the prion was composed of is also known as the Prion Protein (PrP), though this protein may occur both in infectious and non-infectious forms. Prusiner was awarded the Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
in 1997 for his research into prions, albeit not without controversy.
Isoforms
The protein that prions are made of (PrP) is found throughout the body, even in healthy people and animals. However, PrP found in infectious material has a different structure and is resistant to proteaseProtease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s, 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
Scrapie
Scrapie is a fatal, degenerative disease that affects the nervous systems of sheep and goats. It is one of several transmissible spongiform encephalopathies , which are related to bovine spongiform encephalopathy and chronic wasting disease of deer. Like other spongiform encephalopathies, scrapie...
', a prion disease occurring in sheep. While PrPC is structurally well-defined, PrPSc is certainly polydisperse
Polydisperse
A collection of objects is called polydisperse or polysized if they have a broad range of size, shape and mass characteristics. A sample of objects that have a uniform size, shape and mass distribution are called monodisperse. In practice, polydisperse collections are common because it is...
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.
PrPC
PrPC is a normal protein found on the membranesCell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
of cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. It has 209 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s (in humans), one disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
, a molecular weight of 35-36 kDa
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
and a mainly alpha-helical
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
structure. Several topological
Membrane topology
In biochemistry, the membrane topology of an transmembrane protein describes which portions of the amino-acid sequence of the protein lie within the plane of the surrounding lipid bilayer and which portions protrude into the watery environment on either side...
forms exist; one cell surface form anchored via glycolipid
Glycolipid
Glycolipids are lipids with a carbohydrate attached. Their role is to provide energy and also serve as markers for cellular recognition.-Metabolism:...
and two transmembrane forms. The normal protein is not sedimentable; meaning it cannot be separated by centrifuging techniques. Its function is a complex issue that continues to be investigated. PrPC binds copper
Copper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...
(II) ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s with high affinity. The significance of this finding is not clear, but it presumably relates to PrP structure or function. PrPC is readily digested by proteinase K
Proteinase K
Proteinase K is a broad-spectrum serine protease. The enzyme was discovered in 1974 in extracts of the fungus Engyodontium album . Proteinase K is able to digest native keratin , hence, the name "Proteinase K"...
and can be liberated from the cell surface in vitro by the enzyme phosphoinositide phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
(PI-PLC), which cleaves the glycophosphatidylinositol
Glycophosphatidylinositol
Glycosylphosphatidylinositol is a glycolipid that can be attached to the C-terminus of a protein during posttranslational modification...
(GPI) glycolipid anchor. PrP has been reported to play important roles in cell-cell adhesion and intracellular signaling in vivo, and may therefore be involved in cell-cell communication in the brain.
PrPSc
The infectious isoform of PrP, known as PrPSc, is able to convert normal PrPC proteins into the infectious isoform by changing their conformationProtein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
, or shape; this, in turn, alters the way the proteins interconnect. Although the exact 3D structure of PrPSc is not known, it has a higher proportion of β-sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
structure in place of the normal α-helix
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
structure. Aggregations of these abnormal isoforms form highly structured amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
fibers, which accumulate to form plaques. It is unclear if these aggregates are the cause of cell damage or are simply a side effect of the underlying disease process. The end of each fiber acts as a template onto which free protein molecules may attach, allowing the fiber to grow. Only PrP molecules with an identical amino acid sequence to the infectious PrPSc are incorporated into the growing fiber. However, this property is not strictly shared by other proteins considered prions. The sup35p
Sup35p
Sup35p is the Saccharomyces cerevisiae eukaryotic translation release factor. More specifically, it is the yeast eukaryotic release factor 3 , which forms the translation termination complex with eRF1 . This complex recognizes and catalyzes the release of the nascent polypeptide chain when the...
was shown to be able to be incorporated into existing aggregations even when three of the five oligopeptide repeats normally present were deleted.
Prion replication mechanism
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
its conversion into PrPSc. The two PrPSc molecules then come apart and can go on to convert more PrPC. However, Manfred Eigen
Manfred Eigen
Manfred Eigen is a German biophysical chemist who won the 1967 Nobel Prize in Chemistry for work on measuring fast chemical reactions.-Career:...
showed that since PrPC has a very low rate of spontaneous conversion into PrPSc, the heterodimer model requires PrPSc to be an extraordinarily effective catalyst
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
, increasing the rate of the conversion reaction by a factor of around 1015. What is more, despite considerable effort, infectious monomeric PrPSc has never been isolated. Theory and experiments both suggest that PrPSc exists only in aggregated forms such as amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
, and that prion replication involves cooperativity
Cooperativity
Cooperativity is a phenomenon displayed by enzymes or receptors that have multiple binding sites where the affinity of the binding sites for a ligand is increased, positive cooperativity, or decreased, negative cooperativity, upon the binding of a ligand to a binding site...
.
An alternative model assumes that PrPSc exists only as fibrils, and that fibril ends bind PrPC and convert it into PrPSc. If this were all, then the quantity of prions would increase linearly
Linear function
In mathematics, the term linear function can refer to either of two different but related concepts:* a first-degree polynomial function of one variable;* a map between two vector spaces that preserves vector addition and scalar multiplication....
, forming ever longer fibrils. But exponential growth
Exponential growth
Exponential growth occurs when the growth rate of a mathematical function is proportional to the function's current value...
of both PrPSc and of the quantity of infectious particles is observed during prion disease. This can be explained by taking into account fibril breakage. A mathematical solution for the exponential growth rate resulting from the combination of fibril growth and fibril breakage has been found. The exponential growth rate depends largely on the square root
Square root
In mathematics, a square root of a number x is a number r such that r2 = x, or, in other words, a number r whose square is x...
of the PrPC concentration. The incubation period
Incubation period
Incubation period is the time elapsed between exposure to a pathogenic organism, a chemical or radiation, and when symptoms and signs are first apparent...
is determined by the exponential growth rate, and in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
data on prion diseases in transgenic mice match this prediction. The same square root dependence is also seen in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
in experiments with a variety of different amyloid proteins
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
.
The mechanism of prion replication has implications for designing drugs. Since the incubation period of prion diseases is so long, an effective drug does not need to eliminate all prions, but simply needs to slow down the rate of exponential growth. Models predict that the most effective way to achieve this, using a drug with the lowest possible dose, is to find a drug that binds to fibril ends and blocks them from growing any further.
PrP function
It has been proposed that neurodegeneration caused by prions may be related to abnormal function of PrP. However, the physiological function of the prion protein remains a controversial matter. While data from in vitro experiments suggest many dissimilar roles, studies on PrP knockout mice have provided only limited information because these animals exhibit only minor abnormalities. In recent research done in mice, it was found that the cleavage of prions in peripheral nerves causes the activation of myelinMyelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
repair in Schwann Cells and that the lack of prions caused demyelination in those cells.
PrP and long-term memory
A review of evidence in 2005 suggested that PrP may have a normal function in maintenance of long-term memoryLong-term memory
Long-term memory is memory in which associations among items are stored, as part of the theory of a dual-store memory model. According to the theory, long term memory differs structurally and functionally from working memory or short-term memory, which ostensibly stores items for only around 20–30...
. As well, a 2004 study found that mice lacking genes for normal cellular PrP protein show altered hippocampal
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
.
PrP and stem cell renewal
A 2006 article from the Whitehead Institute for Biomedical Research indicates that PrP expression on stem cells is necessary for an organism's self-renewal of bone marrowBone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
. The study showed that all long-term hematopoietic stem cells expressed PrP on their cell membrane and that hematopoietic tissues with PrP-null stem cells exhibited increased sensitivity to cell depletion.
Prion disease
| Affected animal(s) | Disease |
|---|---|
| sheep Domestic sheep Sheep are quadrupedal, ruminant mammals typically kept as livestock. Like all ruminants, sheep are members of the order Artiodactyla, the even-toed ungulates. Although the name "sheep" applies to many species in the genus Ovis, in everyday usage it almost always refers to Ovis aries... , goat Goat The domestic goat is a subspecies of goat domesticated from the wild goat of southwest Asia and Eastern Europe. The goat is a member of the Bovidae family and is closely related to the sheep as both are in the goat-antelope subfamily Caprinae. There are over three hundred distinct breeds of... |
Scrapie Scrapie Scrapie is a fatal, degenerative disease that affects the nervous systems of sheep and goats. It is one of several transmissible spongiform encephalopathies , which are related to bovine spongiform encephalopathy and chronic wasting disease of deer. Like other spongiform encephalopathies, scrapie... |
| cattle Cattle Cattle are the most common type of large domesticated ungulates. They are a prominent modern member of the subfamily Bovinae, are the most widespread species of the genus Bos, and are most commonly classified collectively as Bos primigenius... |
Bovine spongiform encephalopathy Bovine spongiform encephalopathy Bovine spongiform encephalopathy , commonly known as mad-cow disease, is a fatal neurodegenerative disease in cattle that causes a spongy degeneration in the brain and spinal cord. BSE has a long incubation period, about 30 months to 8 years, usually affecting adult cattle at a peak age onset of... (BSE), mad cow disease |
| mink Mink There are two living species referred to as "mink": the European Mink and the American Mink. The extinct Sea Mink is related to the American Mink, but was much larger. All three species are dark-colored, semi-aquatic, carnivorous mammals of the family Mustelidae, which also includes the weasels and... |
Transmissible mink encephalopathy Transmissible mink encephalopathy Transmissible mink encephalopathy is rare sporadic disease that affects the central nervous system of ranch-raised mink. It is classified as a transmissible spongiform encephalopathy, believed to be caused by proteins called prions... (TME) |
| white-tailed deer, elk, mule deer, moose | Chronic wasting disease Chronic wasting disease Chronic wasting disease is a transmissible spongiform encephalopathy of mule deer, whitetailed deer, elk , and moose. TSEs are caused by unusual infectious agents known as prions. To date, CWD has been found mainly in cervids... (CWD) |
| cat Cat The cat , also known as the domestic cat or housecat to distinguish it from other felids and felines, is a small, usually furry, domesticated, carnivorous mammal that is valued by humans for its companionship and for its ability to hunt vermin and household pests... |
Feline spongiform encephalopathy Feline spongiform encephalopathy Feline spongiform encephalopathy is a disease that affects the brains and livers of felines. It is caused by proteins called prions.-Disease:Feline spongiform encephalopathy is a prion disease thought to be related to Bovine spongiform encephalopathy . This disease is known to affect domestic and... (FSE) |
| nyala Nyala The Nyala is a Southern African antelope. It is a spiral-horned dense-forest antelope that is uncomfortable in open spaces and is most often seen at water holes. Nyalas live alone or in small family groups of up to 10 individuals.The male stands up to 110 cm , the female is up to 90 cm ... , oryx Oryx Oryx is one of four large antelope species of the genus Oryx. Three of the species are native to arid parts of Africa, with a fourth native to the Arabian Peninsula. Their pelage is pale with contrasing dark markings in the face and on the legs, and their long horns are almost straight... , greater kudu Greater Kudu The Greater Kudu is a woodland antelope found throughout eastern and southern Africa. Despite occupying such widespread territory, they are sparsely populated in most areas, due to a declining habitat, deforestation and hunting.... |
Exotic ungulate encephalopathy Exotic ungulate encephalopathy Exotic ungulate encephalopathy is a transmissible spongiform encephalopathy , or prion disease, identified in infected organs of zoo animals. This subgroup of the TSEs in captive animals was identified in zoo animals in Great Britain including species of greater kudu, nyala, gemsbok, the common... (EUE) |
| ostrich Ostrich The Ostrich is one or two species of large flightless birds native to Africa, the only living member of the genus Struthio. Some analyses indicate that the Somali Ostrich may be better considered a full species apart from the Common Ostrich, but most taxonomists consider it to be a... |
Spongiform encephalopathy (Not been shown to be transmissible.) |
| human | Creutzfeldt–Jakob disease (CJD) |
| iatrogenic Iatrogenesis Iatrogenesis, or an iatrogenic artifact is an inadvertent adverse effect or complication resulting from medical treatment or advice, including that of psychologists, therapists, pharmacists, nurses, physicians and dentists... Creutzfeldt–Jakob disease (iCJD) |
|
| variant Creutzfeldt–Jakob disease (vCJD) | |
| familial Creutzfeldt–Jakob disease (fCJD) | |
| sporadic Creutzfeldt–Jakob disease (sCJD) | |
| Gerstmann–Sträussler–Scheinker syndrome (GSS) | |
| Fatal familial insomnia Fatal familial insomnia Fatal familial insomnia is a very rare autosomal dominant inherited prion disease of the brain. It is almost always caused by a mutation to the protein PrPC, but can also develop spontaneously in patients with a non-inherited mutation variant called sporadic fatal insomnia... (FFI) |
|
| Kuru Kuru (disease) Kuru is an incurable degenerative neurological disorder that is a type of transmissible spongiform encephalopathy, caused by a prion found in humans... |
Prions cause neurodegenerative disease by aggregating extracellularly within the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
to form plaques known as amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
, which disrupt the normal tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
structure. This disruption is characterized by "holes" in the tissue with resultant spongy architecture due to the vacuole
Vacuole
A vacuole is a membrane-bound organelle which is present in all plant and fungal cells and some protist, animal and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water containing inorganic and organic molecules including enzymes in solution, though in certain...
formation in the neurons. Other histological changes include astrogliosis
Astrogliosis
Astrocytosis is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons, typically because of hypoglycemia or oxygen deprivation .It usually takes place in prion infections...
and the absence of an inflammatory reaction
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. While the incubation period
Incubation period
Incubation period is the time elapsed between exposure to a pathogenic organism, a chemical or radiation, and when symptoms and signs are first apparent...
for prion diseases is generally quite long, once symptoms appear the disease progresses rapidly, leading to brain damage and death. Neurodegenerative symptoms can include convulsion
Convulsion
A convulsion is a medical condition where body muscles contract and relax rapidly and repeatedly, resulting in an uncontrolled shaking of the body. Because a convulsion is often a symptom of an epileptic seizure, the term convulsion is sometimes used as a synonym for seizure...
s, dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
(balance and coordination dysfunction), and behavioural or personality changes.
All known prion diseases, collectively called transmissible spongiform encephalopathies (TSEs), are untreatable and fatal. A vaccine has been developed in mice, however, 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. The human prion disease variant Creutzfeldt-Jakob disease, however, is believed to be caused by a prion which typically infects cattle, causing Bovine spongiform encephalopathy
Bovine spongiform encephalopathy
Bovine spongiform encephalopathy , commonly known as mad-cow disease, is a fatal neurodegenerative disease in cattle that causes a spongy degeneration in the brain and spinal cord. BSE has a long incubation period, about 30 months to 8 years, usually affecting adult cattle at a peak age onset of...
and is transmitted through infected meat.
Transmission
It has been recognized that prion diseases can arise in three different ways: acquired, familial, or sporadic. 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.
A University of California research team, led by Nobel prize winner Stanley Prusiner, has proven that infection can occur from prions in manure. And since manure is present in many areas surrounding water reservoirs, as well as used on many crop fields, it raises the possibility of widespread transmission. It was reported in January 2011 that researchers had discovered prions spreading through airborne transmission on aerosol
Aerosol
Technically, an aerosol is a suspension of fine solid particles or liquid droplets in a gas. Examples are clouds, and air pollution such as smog and smoke. In general conversation, aerosol usually refers to an aerosol spray can or the output of such a can...
particles, in an animal testing
Animal testing
Animal testing, also known as animal experimentation, animal research, and in vivo testing, is the use of non-human animals in experiments. Worldwide it is estimated that the number of vertebrate animals—from zebrafish to non-human primates—ranges from the tens of millions to more than 100 million...
experiment focusing on scrapie
Scrapie
Scrapie is a fatal, degenerative disease that affects the nervous systems of sheep and goats. It is one of several transmissible spongiform encephalopathies , which are related to bovine spongiform encephalopathy and chronic wasting disease of deer. Like other spongiform encephalopathies, scrapie...
infection in laboratory mice. Preliminary evidence supporting the notion that prions can be transmitted through use of urine-derived human menopausal gonadotropin, administered for the treatment of infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
, was published in 2011.
Sterilization
Infectious particles possessing nucleic acid are dependent upon it to direct their continued replication. Prions, however, are infectious by their effect on normal versions of the protein. Sterilizing prions therefore involves the denaturationDenaturation (biochemistry)
Denaturation is a process in which proteins or nucleic acids lose their tertiary structure and secondary structure by application of some external stress or compound, such as a strong acid or base, a concentrated inorganic salt, an organic solvent , or heat...
of the protein to a state where the molecule is no longer able to induce the abnormal folding of normal proteins. Prions are generally quite resistant to protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s, heat
Heat
In physics and thermodynamics, heat is energy transferred from one body, region, or thermodynamic system to another due to thermal contact or thermal radiation when the systems are at different temperatures. It is often described as one of the fundamental processes of energy transfer between...
, radiation
Radiation
In physics, radiation is a process in which energetic particles or energetic waves travel through a medium or space. There are two distinct types of radiation; ionizing and non-ionizing...
, and formalin treatments, although their infectivity can be reduced by such treatments. Effective prion decontamination relies upon protein hydrolysis or reduction or destruction of protein tertiary structure. Examples include bleach
Bleach
Bleach refers to a number of chemicals that remove color, whiten, or disinfect, often via oxidation. Common chemical bleaches include household chlorine bleach , lye, oxygen bleach , and bleaching powder...
, caustic soda, and strongly acidic detergents such as LpH. 134°C (274°F) for 18 minutes in a pressurized steam autoclave
Autoclave
An autoclave is an instrument used to sterilize equipment and supplies by subjecting them to high pressure saturated steam at 121 °C for around 15–20 minutes depending on the size of the load and the contents. It was invented by Charles Chamberland in 1879, although a precursor known as the...
may not be enough to deactivate the agent of disease. Ozone sterilization is currently being studied as a potential method for prion denature and deactivation. Renaturation of a completely denatured prion to infectious status has not yet been achieved; however, partially denatured prions can be renatured to an infective status under certain artificial conditions.
The World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
recommends any of the following three procedures for the sterilization of all heat-resistant surgical instruments to ensure that they are not contaminated with prions:
- Immerse in a pan containing 1N NaOH and heat in a gravity-displacement autoclave at 121°C for 30 minutes; clean; rinse in water; and then perform routine sterilization processes.
- Immerse in 1N NaOH or sodium hypochlorite (20,000 parts per million available chlorine) for 1 hour; transfer instruments to water; heat in a gravity-displacement autoclave at 121°C for 1 hour; clean; and then perform routine sterilization processes.
- Immerse in 1N NaOH or sodium hypochlorite (20,000 parts per million available chlorine) for 1 hour; remove and rinse in water, then transfer to an open pan and heat in a gravity-displacement (121°C) or in a porous-load (134°C) autoclave for 1 hour; clean; and then perform routine sterilization processes.
Debate
Whether prions are the agent which causes disease or merely a symptom caused by a different agent is still debated by a minority of researchers. The following sections describe several hypotheses: some pertain to the composition of the infectious agent (protein-only, protein with other components, virus, or other), while others pertain to its mechanism of reproduction.Protein hypothesis
Prior to the discovery of prions, it was thought that all pathogenPathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
s used nucleic acid
Nucleic acid
Nucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...
s to direct their replication. The "protein hypothesis" states that a protein structure can replicate without the use of nucleic acid. This was initially controversial as it contradicts the so-called "central dogma of molecular biology
Central dogma of molecular biology
The central dogma of molecular biology was first articulated by Francis Crick in 1958 and re-stated in a Nature paper published in 1970:In other words, the process of producing proteins is irreversible: a protein cannot be used to create DNA....
", which describes nucleic acid as the central form of replicative information.
Evidence in favor of a protein hypothesis includes:
- No virus particles, bacteria, or fungi have been conclusively associated with prion diseases, although Saccharomyces cerevisiaeSaccharomyces cerevisiaeSaccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
has been known to be associated with infectious, yet non-lethal prions, such as Sup35pSup35pSup35p is the Saccharomyces cerevisiae eukaryotic translation release factor. More specifically, it is the yeast eukaryotic release factor 3 , which forms the translation termination complex with eRF1 . This complex recognizes and catalyzes the release of the nascent polypeptide chain when the...
. - No nucleic acid has been conclusively associated with infectivity; agent is resistant to ultraviolet radiation.
- No immune response to infection.
- PrPSc experimentally transmitted between one species and another results in PrPSc with the amino-acid sequence of the recipient species, suggesting that replication of the donor agent does not occur.
- Familial prion disease occurs in families with a mutation in the PrP gene, and mice with PrP mutations develop prion disease despite controlled conditions where transmission is prevented.
- Animals lacking PrPC do not contract prion disease.
- Infectious prions can be formed de novo from purified non-infectious components, in the absence of gene-coding nucleic acids.
Genetic factors
A geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
for the normal protein has been identified: the PRNP
PRNP
Major prion protein also known as CD230 is a protein that in humans is encoded by the PRNP gene...
gene. In all inherited cases of prion disease, there is a mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in the PRNP gene. Many different PRNP mutations have been identified and it is thought that the mutations somehow make PrPC more likely to change spontaneously into the abnormal PrPSc form. Although this discovery puts a hole in the general prion hypothesis, that prions can only aggregate proteins of identical amino acid make up. These mutations can occur throughout the gene. Some mutations involve expansion of the octapeptide repeat region at the N-terminal of PrP. Other mutations that have been identified as a cause of inherited prion disease occur at positions 102, 117 & 198 (GSS), 178, 200, 210 & 232 (CJD) and 178 (Fatal Familial Insomnia
Fatal familial insomnia
Fatal familial insomnia is a very rare autosomal dominant inherited prion disease of the brain. It is almost always caused by a mutation to the protein PrPC, but can also develop spontaneously in patients with a non-inherited mutation variant called sporadic fatal insomnia...
, FFI). The cause of prion disease can be sporadic, genetic
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
, and infectious
Infectious disease
Infectious diseases, also known as communicable diseases, contagious diseases or transmissible diseases comprise clinically evident illness resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism...
, or a combination of these factors. For example, in order to have scrapie, both an infectious agent and a susceptible genotype need to be present.
Multi-component hypothesis
In 2007, biochemist Surachai Supattapone and his colleagues at Dartmouth CollegeDartmouth College
Dartmouth College is a private, Ivy League university in Hanover, New Hampshire, United States. The institution comprises a liberal arts college, Dartmouth Medical School, Thayer School of Engineering, and the Tuck School of Business, as well as 19 graduate programs in the arts and sciences...
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.
In 2010, Jiyan Ma and colleagues at The Ohio State University produced infectious prions from a recipe of bacterially expressed recombinant PrP, POPG phospholipid, and RNA, further supporting the multi-component hypothesis. This finding is in contrast to studies that found minimal infectious prions produced from recombinant PrP alone.
Heavy metal poisoning hypothesis
Recent reports suggest that imbalance of brain metal homeostasis is a significant cause of PrPSc-associated neurotoxicity, though the underlying mechanisms are difficult to explain based on existing information. Proposed hypotheses include a functional role for PrPC in metal metabolism, and loss of this function due to aggregation to the disease associated PrPSc form as the cause of brain metal imbalance. Other views suggest gain of toxic function by PrPSc due to sequestration of PrPC-associated metals within the aggregates, resulting in the generation of redox-active PrPSc complexes. The physiological implications of some PrPC-metal interactions are known, while others are still unclear. The pathological implications of PrPC-metal interaction include metal-induced oxidative damage, and in some instances conversion of PrPC to a PrPSc-like form.Viral hypothesis
The protein-only hypothesis has been criticised by those who feel that the simplest explanation of the evidence to date is viral. For more than a decade, Yale UniversityYale University
Yale University is a private, Ivy League university located in New Haven, Connecticut, United States. Founded in 1701 in the Colony of Connecticut, the university is the third-oldest institution of higher education in the United States...
neuropathologist Laura Manuelidis
Laura Manuelidis
Laura Manuelidis is a physician and neuropathologist at Yale University. She earned her B.A. degree from Sarah Lawrence College, where she studied poetry, and her M.D. from Yale Medical School. She is head of the section of Neuropathology in the department of Surgery at Yale. She is also on the...
has been proposing that prion diseases are caused instead by an unidentified slow virus
Slow virus
A slow virus is a virus, or a viruslike agent, etiologically associated with a disease having a long incubation period of months to years with a gradual onset frequently terminating in severe illness and/or death....
. In January 2007, she and her colleagues published an article reporting to have found a virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
in 10%, or less, of their scrapie-infected cells in culture.
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.
Evidence in favor of a viral hypothesis includes:
- Strain variation: differences in prion infectivity, incubation, symptomology and progression among species resembles that seen between viruses, especially RNA virusRNA virusAn RNA virus is a virus that has RNA as its genetic material. This nucleic acid is usually single-stranded RNA but may be double-stranded RNA...
es - The long incubation and rapid onset of symptoms resembles lentivirusLentivirusLentivirus is a genus of slow viruses of the Retroviridae family, characterized by a long incubation period...
es, such as HIVHIVHuman immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
-induced AIDSAIDSAcquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus... - Viral-like particles that do not appear to be composed of PrP have been found in some of the cells of scrapie- or CJD-infected cell lines.
Recent studies propagating TSE infectivity in cell-free reactions and in purified component chemical reactions strongly suggest against TSE viral nature. More recently, using a similar defined recipe of multiple components (PrP, POPG lipid, RNA), Jiyan Ma and colleagues generated infectious prions from recombinant PrP expressed from E. coli, casting further doubt on the viral hypothesis.
Fungi
Fungal proteins exhibiting templated conformational change were discovered in the yeast Saccharomyces cerevisiaeSaccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
by Reed Wickner
Reed Wickner
Reed B. Wickner is an American yeast geneticist. In 1994 he proposed that the [PSI+] and [URE3] phenotypes in Saccharomyces cerevisiae, a form of budding yeast, were caused by prion forms of native proteins. Specifically, the sup35p protein....
in the early 1990s. For their mechanistic similarity to the prion hypothesis, they were termed yeast prions. Subsequently, a prion has also been found in the fungus Podospora anserina. These prions behave similarly to PrP, but are generally nontoxic to their hosts. Susan Lindquist
Susan Lindquist
Susan Lindquist is a professor of biology at MIT specializing in molecular biology, particularly the protein folding problem within a family of molecules known as heat-shock proteins, and prions...
's group at the Whitehead Institute
Whitehead Institute
Founded in 1982, the Whitehead Institute for Biomedical Research is a non-profit research and teaching institution located in Cambridge, Massachusetts, USA....
has argued some of the fungal prions are not associated with any disease state, but may have a useful role; however, researchers at the NIH have also provided arguments suggesting fungal prions could be considered a diseased state. Thus, the issue of whether fungal proteins are diseases, or have evolved for some specific functions, still remains unresolved.
As of 2010, there are eight known prion proteins in fungi, seven in Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
(Sup35, Rnq1, Ure2, Swi1, Mca1, Mot3, Cyc8) and one in Podospora anserina (HET-s).
Research into fungal prions
Fungal prions
Fungal prions provide an excellent model for the understanding of disease-forming mammalian prions. Fungal prions are naturally occurring proteins that can undergo a structural conversion that becomes self-propagating and infectious. They represent an epigenetic phenomenon in which information is...
has given strong support to the protein-only concept, since purified protein extracted from cells with a prion state has been demonstrated to convert the normal form of the protein into a misfolded form in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
, 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, though fungal prions appear distinct from infectious mammalian prions in the lack of cofactor required for propagation. The characteristic prion domains may vary between species—e.g. characteristic fungal prion domains are not found in mammalian prions.
| Fungal Prions | |||||
|---|---|---|---|---|---|
| Protein Protein Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of... |
Natural host | Normal function | Prion state | Prion phenotype | Year identified |
| Ure2p | Saccharomyces cerevisiae Saccharomyces cerevisiae Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes... |
Nitrogen catabolite repressor | [URE3] | Growth on poor nitrogen sources | 1994 |
| Sup35p Sup35p Sup35p is the Saccharomyces cerevisiae eukaryotic translation release factor. More specifically, it is the yeast eukaryotic release factor 3 , which forms the translation termination complex with eRF1 . This complex recognizes and catalyzes the release of the nascent polypeptide chain when the... |
S. cerevisiae | Translation termination factor | [PSI+] | Increased levels of nonsense suppression | 1994 |
| HET-S | Podospora anserina | Regulates heterokaryon Heterokaryon A heterokaryon is a cell that contains multiple, genetically different nuclei. This can occur naturally, such as in the mycelium of fungi during sexual reproduction, or artificially as formed by the experimental fusion of two genetically different cells. A medical example is a heterokaryon composed... incompatibility |
[Het-s] | Heterokaryon formation between incompatible strains | |
| Rnq1p | S. cerevisiae | Protein template factor | [RNQ+],[PIN+] | Promotes aggregation of other prions | |
| Mca1 | S. cerevisiae | Putative yeast caspase | [MCA+] | Unknown | 2008 |
| Swi1 | S. cerevisiae | Chromatin remodeling | [SWI+] | Poor growth on some carbon sources | 2008 |
| Cyc8 | S. cerevisiae | Transcriptional repressor | [OCT+] | Transcriptional derepression of multiple genes | 2009 |
| Mot3 | S. cerevisiae | Nuclear transcription factor | [MOT3+] | Transcriptional derepression of anaerobic genes | 2009 |
- A putative prion protein, forming the [ISP+] element remains to be identified.
Potential treatments and diagnosis
Advancements in computer modeling have allowed for scientists to identify compounds which can serve as a treatment for prion-caused diseases, such as one compound found to bind a cavity in the PrPC and stabilize the conformation, reducing the amount of harmful PrPSc.Recently, antiprion antibodies capable of crossing the blood-brain-barrier and targeting cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
ic prion protein (an otherwise major obstacle in prion therapeutics) have been described.
In 2011 it was discovered that prions could be degraded by lichen
Lichen
Lichens are composite organisms consisting of a symbiotic organism composed of a fungus with a photosynthetic partner , usually either a green alga or cyanobacterium...
s.
There continues to be a very practical problem with diagnosis of prion diseases, including BSE and CJD. They have an incubation period of months to decades during which there are no symptoms, even though the pathway of converting the normal brain PrP protein into the toxic, disease-related PrP
Sc form has started. At present, there is virtually no way to detect PrPSc reliably except by examining the brain using neuropathological and immunohistochemical methods after death. Accumulation of the abnormally folded PrPSc form of the PrP protein is a characteristic of the disease, but it is present at very low levels in easily accessible body fluids like blood or urine. Researchers have tried to develop methods to measure PrPSc, but there are still no fully accepted methods for use in materials such as blood.
In 2010, a team from New York described detection of PrPSc even when initially present at only one part in a hundred thousand million (10−11) in brain tissue. The method combines amplification with a novel technology called Surround Optical Fiber Immunoassay (SOFIA)
Surround Optical Fiber Immunoassay (SOFIA)
Surround Optical Fiber Immunoassay is an ultra-sensitive, in vitro diagnostic platform incorporating a surround optical fiber assembly that captures fluorescence emissions from an entire sample. The technology's defining characteristics are its extremely high limit of detection, sensitivity and...
and some specific antibodies against PrPSc. After amplifying and then concentrating any PrPSc, the samples are labelled with a fluorescent dye using an antibody for specificity and then finally loaded into a micro-capillary tube. This tube is placed in a specially constructed apparatus so that it is totally surrounded by optical fibres to capture all light emitted once the dye is excited using a laser. The technique allowed detection of PrPSc after many fewer cycles of conversion than others have achieved, substantially reducing the possibility of artefacts, as well as speeding up the assay. The researchers also tested their method on blood samples from apparently healthy sheep that went on to develop scrapie. The animals’ brains were analysed once any symptoms became apparent. The researchers could therefore compare results from brain tissue and blood taken once the animals exhibited symptoms of the diseases, with blood obtained earlier in the animals’ lives, and from uninfected animals. The results showed very clearly that PrPSc could be detected in the blood of animals long before the symptoms appeared.
See also
- Prion pseudoknotPrion pseudoknotThe prion pseudoknot is predicted RNA pseudoknot structure found in prion protein mRNA. It has been suggested that this element has a possible effect in prion protein translation. The human prion protein contains 5 copies of a 24 nucleotide repeat that contains this structure....
- Protein foldingProtein foldingProtein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
- Protein Misfolding Cyclic AmplificationProtein Misfolding Cyclic AmplificationProtein Misfolding Cyclic Amplification is an amplification technique to multiply misfolded prions originally developed by Soto and colleagues...
- ProteopathyProteopathyIn medicine, proteopathy refers to a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body...
- Tertiary structureTertiary structureIn biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...
- Creutzfeldt-Jakob diseaseCreutzfeldt-Jakob diseaseCreutzfeldt–Jakob disease or CJD is a degenerative neurological disorder that is incurable and invariably fatal. CJD is at times called a human form of mad cow disease, given that bovine spongiform encephalopathy is believed to be the cause of variant Creutzfeldt–Jakob disease in humans.CJD...
Further reading
- Deadly Feasts: The "Prion" Controversy and the Public's Health, by Richard RhodesRichard RhodesRichard Lee Rhodes is an American journalist, historian, and author of both fiction and non-fiction , including the Pulitzer Prize-winning The Making of the Atomic Bomb , and most recently, The Twilight of the Bombs...
- The Pathological Protein: Mad Cow, Chronic Wasting, and Other Deadly Prion Diseases, Phillip Yam, 2003, Springer, ISBN 0-387-95508-9
- The Family That Couldn't Sleep by D. T. Max provides a history of prion diseases.
- The Prion Protein a special issue of the open-access journal Current Issues in Molecular BiologyCurrent Issues in Molecular BiologyCurrent Issues in Molecular Biology is a peer-reviewed academic journal that publishes high quality critical review papers, in English, in all areas of molecular biology and molecular microbiology. Relevant protocols and technology papers will also be considered for publication...
- The Prion's Elusive Reason for Being Note: Behind a paywall.
External links
General
- CDC – USA Centers for Disease Control and Prevention – information on prion diseases
- World Health Organisation – WHO information on prion diseases
- Prion Animation (Flash required)
Reports and committees
- The UK BSE Inquiry – Report of the UK public inquiry into BSE and variant CJD
- UK Spongiform Encephalopathy Advisory Committee (SEAC)
Genetics
- Mammalian prion classification International Committee on Taxonomy of Viruses – ICTVdb
- Online Mendelian Inheritance in Man: Prion protein – PrP, inherited prion disease and transgenic animal modelsGenetically modified organismA genetically modified organism or genetically engineered organism is an organism whose genetic material has been altered using genetic engineering techniques. These techniques, generally known as recombinant DNA technology, use DNA molecules from different sources, which are combined into one...
. - The Surprising World of Prion Biology--A New Mechanism of Inheritance on-line lecture by Susan LindquistSusan LindquistSusan Lindquist is a professor of biology at MIT specializing in molecular biology, particularly the protein folding problem within a family of molecules known as heat-shock proteins, and prions...
Research
- Institute for Neurodegenerative Diseases – labs studying prion diseases, run by Stanley B. Prusiner, MDStanley B. PrusinerStanley Ben Prusiner is an American neurologist and biochemist. Currently the director of the Institute for Neurodegenerative Diseases at University of California, San Francisco . Prusiner discovered prions, a class of infectious self-reproducing pathogens primarily or solely composed of protein...
- Prion Disease Database (PDDB) - Comprehensive transcriptome resource for systems biology research in prion diseases.
- iBioSeminars - Susan Lindquist's iBioSeminars on I. Protein Folding and Prions and II. Prions and Evolution.
- http://www.prion.ucl.ac.uk/ MRC Prion Unit run by Professor John Collinge. Study of all forms of prion disease and development of therapies.
Other
- UCSF Memory and Aging Center – medical center for diagnosis and care of people with prion disease and research into origin and treatment of prion diseases. (YouTube channel)