A prion combination of the first two syllables of the words proteinaceous and infectious It is a poorly-understood hypothetical infectious agent that, according to the "protein only" hypothesis, is composed entirely of proteins. Prions are thought to cause a number of diseases in a variety of mammals, including bovine spongiform encephalopathy (BSE, also known as "mad cow disease") in cattle and Creutzfeldt-Jakob disease (CJD) in humans. All thus-far hypothesized prion diseases affect the structure of the brain or other neural tissue, and all are currently untreatable and thought to be fatal. In general usage, prion can refer to both the theoretical unit of infection or the specific protein (e.g. PrP) that is thought to be the infective agent, whether or not it is in an infective state.
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Prions are hypothesized to infect and propagate by refolding abnormally into a structure which is able to convert normal molecules of the protein into the abnormally structured form. All known prions induce the formation of an amyloid fold, in which the protein polymerises into an aggregate consisting of tightly packed beta sheets. This altered structure is extremely stable and accumulates in infected tissue, causing cell death and tissue damage. This stability means that prions are resistant to denaturation by chemical and physical agents, making disposal and containment of these particles difficult.
Structure
Isoforms
The protein that prions are made of is found throughout the body, even in healthy people and animals. However, the prion protein found in infectious material has a different folding pattern and is resistant to proteases, the enzymes in the body that can normally break down proteins. The normal form of the protein is called PrPC, while the infectious form is called PrPSc — the C refers to 'cellular' or 'common' PrP, while the Sc refers to 'scrapie', a prion disease occurring in sheep. 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.
PrPC
PrPC is a normal protein found on the membranes of cells. It has 209 amino acids (in humans), one disulfide bond, a molecular weight of 35-36kDa and a mainly alpha-helical structure. Several topological forms exist; one cell surface form anchored via glycolipid and two transmembrane forms. Its function has not been fully resolved. PrPC binds copper (II) ions with high affinity. The significance of this 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.
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Isoforms
The protein that prions are made of is found throughout the body, even in healthy people and animals. However, the prion protein found in infectious material has a different folding pattern and is resistant to proteases, the enzymes in the body that can normally break down proteins. The normal form of the protein is called PrPC, while the infectious form is called PrPSc — the C refers to 'cellular' or 'common' PrP, while the Sc refers to 'scrapie', a prion disease occurring in sheep. 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.
PrPC
PrPC is a normal protein found on the membranes of cells. It has 209 amino acids (in humans), one disulfide bond, a molecular weight of 35-36kDa and a mainly alpha-helical structure. Several topological forms exist; one cell surface form anchored via glycolipid and two transmembrane forms. Its function has not been fully resolved. PrPC binds copper (II) ions with high affinity. The significance of this 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.
PrPSc The infectious isoform of PrPC, known as PrPSc, is able to convert normal PrPC proteins into the infectious isoform by changing their conformation. Although the exact 3D structure of PrPSc is not known, there is increased β-sheet content in the diseased form of the molecule, replacing normal areas of α-helix. Aggregations of these abnormal isoforms may form highly structured amyloid fibers. The end of a fiber acts as a template for the free protein molecules, causing the fiber to grow. Small differences in the amino acid sequence of prion-forming regions lead to distinct structural features on the surface of prion fibers. As a result, only free protein molecules that are identical in amino acid sequence to the prion protein can be recruited into the growing fiber.
Function
It has now been conclusively proven that the prion protein's normal cellular role is as a copper dependent antioxidant. While a small number of researchers in the field pursue other possibilities, the majority of evidence from many researcher supports this finding.
PrP and long-term memory
There is evidence that PrP may have a normal function in maintenance of long term memory.Maglio and colleagues have shown that mice without the genes for normal cellular PrP protein have altered hippocampal LTP.
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 marrow. The study showed that all long-term hematopoietic stem cells expressed PrP on their cell membrane and that hematopoietic tissues with such PrP-null stem cells exhibited increased sensitivity to cell depletion.
Prion disease
Prions cause neurodegenerative disease by aggregating extracellularly within the central nervous system to form plaques known as amyloids, which disrupt the normal tissue structure. This disruption is characterized by "holes" in the tissue with resultant spongy architecture due to the vacuole formation in the neurons.Other histological changes include astrogliosis and the absence of an inflammatory reaction. While the incubation period for prion diseases is generally quite long, once symptoms appear the disease progresses rapidly, leading to brain damage and death. Neurodegenerative symptoms can include convulsions, dementia, ataxia (balance and coordination dysfunction), and behavioural or personality changes. All known prion diseases, collectively called transmissible spongiform encephalopathies (TSEs), are untreatable and fatal. However, a vaccine has been developed in mice that may provide insight into providing a vaccine in humans to resist prion infections. Additionally, in 2006 scientists announced that they had genetically engineered cattle lacking a necessary gene for prion production - thus theoretically making them immune to BSE, building on research indicating that mice lacking normally-occurring prion protein are resistant to infection by scrapie prion protein. Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all mammals. Due to small differences in PrP between different species, it is unusual for a prion disease to be transmitted from one species to another. However, the human prion disease variant Creutzfeldt-Jakob disease is believed to be caused by a prion which typically infects cattle and is transmitted through infected meat.
Function
It has now been conclusively proven that the prion protein's normal cellular role is as a copper dependent antioxidant. While a small number of researchers in the field pursue other possibilities, the majority of evidence from many researcher supports this finding.
PrP and long-term memory
There is evidence that PrP may have a normal function in maintenance of long term memory.Maglio and colleagues have shown that mice without the genes for normal cellular PrP protein have altered hippocampal LTP.
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 marrow. The study showed that all long-term hematopoietic stem cells expressed PrP on their cell membrane and that hematopoietic tissues with such PrP-null stem cells exhibited increased sensitivity to cell depletion.
Prion disease
Prions cause neurodegenerative disease by aggregating extracellularly within the central nervous system to form plaques known as amyloids, which disrupt the normal tissue structure. This disruption is characterized by "holes" in the tissue with resultant spongy architecture due to the vacuole formation in the neurons.Other histological changes include astrogliosis and the absence of an inflammatory reaction. While the incubation period for prion diseases is generally quite long, once symptoms appear the disease progresses rapidly, leading to brain damage and death. Neurodegenerative symptoms can include convulsions, dementia, ataxia (balance and coordination dysfunction), and behavioural or personality changes. All known prion diseases, collectively called transmissible spongiform encephalopathies (TSEs), are untreatable and fatal. However, a vaccine has been developed in mice that may provide insight into providing a vaccine in humans to resist prion infections. Additionally, in 2006 scientists announced that they had genetically engineered cattle lacking a necessary gene for prion production - thus theoretically making them immune to BSE, building on research indicating that mice lacking normally-occurring prion protein are resistant to infection by scrapie prion protein. Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all mammals. Due to small differences in PrP between different species, it is unusual for a prion disease to be transmitted from one species to another. However, the human prion disease variant Creutzfeldt-Jakob disease is believed to be caused by a prion which typically infects cattle and is transmitted through infected meat.
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