Molecular Pathology of the Prions

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Francis Crick recognized the potential significance 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. In , Stanley B.

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Prusiner of the University of California, San Francisco announced that his team had purified the hypothetical infectious protein, which did not appear to be present in healthy hosts, though they did not manage to isolate the protein until two years after Prusiner's announcement. When the prion was discovered, Griffith's first hypothesis, that the protein was the product of a normally silent gene was favored by many.

It was subsequently discovered, however, that the same protein exists in normal hosts but in different form. Following the discovery of the same protein in different form in uninfected individuals, the specific protein that the prion was composed of was named the Prion Protein PrP , and Griffith's second hypothesis that an abnormal form of a host protein can convert other proteins of the same type into its abnormal form, became the dominant theory. 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 proteases , the enzymes in the body that can normally break down proteins. PrP can be induced to fold into other more-or-less well-defined isoforms in vitro, and their relationship to the form s that are pathogenic in vivo is not yet clear. PrP C is a normal protein found on the membranes of cells.

It has amino acids in humans , one disulfide bond , a molecular mass 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. PrP C binds copper II ions with high affinity. Protease-resistant PrP Sc -like protein PrP res is the name given to any isoform of PrP c which is structurally altered and converted into a misfolded proteinase K -resistant form in vitro. The infectious isoform of PrP, known as PrP Sc , or simply the prion, is able to convert normal PrP C proteins into the infectious isoform by changing their conformation , or shape; this, in turn, alters the way the proteins interconnect.

PrP Sc always causes prion disease. It is unclear as to whether these aggregates are the cause of cell damage or are simply a side-effect of the underlying disease process. Under most circumstances, only PrP molecules with an identical amino acid sequence to the infectious PrP Sc are incorporated into the growing fiber. The physiological function of the prion protein remains poorly understood.

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 research done in mice, it was found that the cleavage of PrP proteins in peripheral nerves causes the activation of myelin repair in Schwann cells and that the lack of PrP proteins caused demyelination in those cells.

They also polymerise into filamentous amyloid fibers which initiate regulated cell death in the case of a viral infection to prevent the spread of virions to other, surrounding cells. A review of evidence in suggested that PrP may have a normal function in maintenance of long-term memory. The prion-like formation of CPEB is essential for maintaining long-term synaptic changes associated with long term memory formation.

A 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 express PrP on their cell membrane and that hematopoietic tissues with PrP-null stem cells exhibit increased sensitivity to cell depletion. The first hypothesis that tried to explain how prions replicate in a protein-only manner was the heterodimer model. However, a model of prion replication must explain both how prions propagate, and why their spontaneous appearance is so rare.

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Manfred Eigen showed that the heterodimer model requires PrP Sc to be an extraordinarily effective catalyst, increasing the rate of the conversion reaction by a factor of around 10 What is more, despite considerable effort, infectious monomeric PrP Sc has never been isolated. If this were all, then the quantity of prions would increase linearly , forming ever longer fibrils. But exponential growth of both PrP Sc and of the quantity of infectious particles is observed during prion disease. 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. Until all known mammalian prion diseases were considered to be caused by the prion protein, PrP ; in multiple system atrophy was found to be transmissible and was hypothesized to be caused by a new prion, the misfolded form of a protein called alpha-synuclein.

Fungal prions do not appear to cause disease in their hosts. 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. All known prion diseases are untreatable and fatal. Many different mammalian species can be affected by prion diseases, as the prion protein PrP is very similar in all mammals.

The human prion disease variant Creutzfeldt—Jakob disease, however, is thought to be caused by a prion that typically infects cattle, causing bovine spongiform encephalopathy and is transmitted through infected meat. It has been recognized that prion diseases can arise in three different ways: acquired, familial, or sporadic. One idea, the "Protein X" hypothesis, is that an as-yet unidentified cellular protein Protein X enables the conversion of PrP C to PrP Sc 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.

Prion Diseases and their Prpsc-Based Molecular Diagnostics

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 provided evidence for the theory that infection can occur from prions in manure.

It was reported in January that researchers had discovered prions spreading through airborne transmission on aerosol particles, in an animal testing experiment focusing on scrapie infection in laboratory mice. When researchers fed hamsters grass that grew on ground where a deer that died with chronic wasting disease CWD was buried, the hamsters became ill with CWD, suggesting that prions can bind to plants, which then take them up into the leaf and stem structure, where they can be eaten by herbivores, thus completing the cycle.

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It is thus possible that there is a progressively accumulating number of prions in the environment. 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, requires the denaturation of the protein to a state in which the molecule is no longer able to induce the abnormal folding of normal proteins. In general, prions are quite resistant to proteases , heat, ionizing radiation , and formaldehyde treatments, [85] 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 sodium hypochlorite , sodium hydroxide , and strongly acidic detergents such as LpH. 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:.

In yeast, protein refolding to the prion configuration is assisted by chaperone proteins such as Hsp Amyloid aggregates are fibrils, growing at their ends, and replicate 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. Fungal proteins exhibiting templated conformational change [ further explanation needed ] were discovered in the yeast Saccharomyces cerevisiae by Reed Wickner in the early s.

For their mechanistic similarity to mammalian prions, they were termed yeast prions. Subsequent to this, a prion has also been found in the fungus Podospora anserina. These prions behave similarly to PrP, but, in general, are 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 that fungal prions could be considered a diseased state.

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.

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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.

Advancements in computer modeling have allowed scientists to identify compounds that can treat prion-caused diseases, such as one compound found to bind a cavity in the PrP C and stabilize the conformation, reducing the amount of harmful PrP Sc. Antiprion antibodies capable of crossing the blood-brain-barrier and targeting cytosolic prion protein an otherwise major obstacle in prion therapeutics have been described. In the last decade, some progress dealing with ultra-high-pressure inactivation of prion infectivity in processed meat has been reported.

In , it was reported that prions could be degraded by lichens.

Molecular pathology of human prion disease

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 PrP Sc reliably except by examining the brain using neuropathological and immunohistochemical methods after death. Accumulation of the abnormally folded PrP Sc 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 PrP Sc , but there are still no fully accepted methods for use in materials such as blood. After amplifying and then concentrating any PrP Sc , the samples are labelled with a fluorescent dye using an antibody for specificity and then finally loaded into a micro-capillary tube.

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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 RT-QuIC assay, a microplate reader -based prion detection method which uses as reagents normally folded prions, fluorescently labelled so that they "light up" when they are misfolded; samples suspected of containing misfolded prions are added and misfolded reagents can be detected by standard fluorescence detection methods.

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A study found that a naturally occurring variant of the human prion protein in transgenic mice protected them against kuru and CJD. SGI and related compounds were identified as a novel class of potential anti-prion agents that preferentially function through direct interaction with PrP C. The cause of the transmissible spongiform encephalopathies TSE is currently unknown, but the diseases are known to be associated with prions. Whether prions cause TSEs or are the result of infection with another agent such as a virus is a matter of debate by a minority of scientists.

The following are some hypotheses.

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Molecular Pathology of the Prions Molecular Pathology of the Prions
Molecular Pathology of the Prions Molecular Pathology of the Prions
Molecular Pathology of the Prions Molecular Pathology of the Prions
Molecular Pathology of the Prions Molecular Pathology of the Prions
Molecular Pathology of the Prions Molecular Pathology of the Prions
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