Prion Diseases: Diagnosis and Pathogenesis

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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.

Antibody Found for Pathogenic Prions

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 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.

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. 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.

Prion Disease in Dromedary Camels, Algeria-video1

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.

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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. 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.

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. The prion hypothesis states that the main component of the TSE agent is composed of a misfolded protein. The prion hypothesis can be divided into two sub-hypotheses: the protein-only hypothesis, and the multi-component hypothesis. Prior to the discovery of prions, it was thought that all pathogens used nucleic acids to direct their replication. The "protein-only hypothesis" states that a protein structure can replicate without the use of nucleic acids.

This was initially controversial as it contradicts the central dogma of molecular biology , which describes nucleic acid as the central form of replicative information. Evidence in favor of a protein-only hypothesis includes: [41]. A gene for the normal protein has been identified: the PRNP gene. Many different PRNP mutations have been identified and these proteins are more likely to fold into abnormal prion. These mutations can occur throughout the gene.

Some mutations involve expansion of the octapeptide repeat region at the N-terminal of PrP. The cause of prion disease can be sporadic , genetic , or infectious , or a combination of these factors. Despite much effort, significant titers of prion infectivity have never been produced by refolding pure PrP molecules, raising doubt about the validity of the protein-only hypothesis. In addition, the protein-only hypothesis fails to provide a molecular explanation for the ability of prion strains to target specific areas of the brain in distinct patterns. These shortcomings, along with additional experimental data, have given rise to the "multi-component" or "cofactor variation" hypothesis.

In , biochemist Surachai Supattapone and his colleagues at Dartmouth College produced purified infectious prions de novo from defined components PrP C , co-purified lipids, and a synthetic polyanionic molecule.

Prion diseases of humans and farm animals: epidemiology, genetics, and pathogenesis

In , Supattapone and colleagues purified the membrane lipid phosphatidylethanolamine as a solitary endogenous cofactor capable of facilitating the formation of high-titer recombinant prions derived from multiple prion strains. The following are some of the current difficulties and challenges: [].

Whether prions cause disease or are merely a symptom resulting from a different agent is still a matter of debate and research. 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. Reports suggest that imbalance of brain metal homeostasis may be a cause of PrP Sc -associated neurotoxicity, though the underlying mechanisms are difficult to explain based on existing information.

Proposed hypotheses include a functional role for PrP C in metal metabolism, and loss of this function due to aggregation to the disease-associated PrP Sc form as the cause of brain metal imbalance. Other views suggest gain of toxic function by PrP Sc due to sequestration of PrP C -associated metals within the aggregates, resulting in the generation of redox-active PrP Sc complexes.

The physiological implications of some PrP C -metal interactions are known, while others are still unclear. The protein-only hypothesis has been criticised by those maintaining that the simplest explanation of the evidence to date is viral.


Evidence in favor of a viral hypothesis includes: [41]. Studies propagating TSE infectivity in cell-free reactions [] and in purified component chemical reactions [65] is thought to strongly suggest against TSE viral nature. However, some viruses, such as poliovirus , have the ability to replicate in cell-free reactions.

The ' virino hypothesis' postulates that the TSE agent is a foreign, self replicating nucleic acid or nucleic acid fragment bound to PrP. Spiroplasma is a cell wall —deficient bacterium related to Mycoplasma , which some think may be the cause of the TSEs. The lack of a cell wall means it is not susceptible to conventional antibiotics such as penicillin , which target cell wall synthesis. Frank O. Bastian of Louisiana State University first discovered Spiroplasma -like inclusions in the brain of a CJD patient during an autopsy in [] and has hypothesized that this bacterium could possibly be the cause of the TSEs.

However, as of [update] , with the exception of Spiroplasma mirum strain SMCA causing spongiform microcystic encephalitis in suckling rats, other researchers have been unable to duplicate these findings, [] [] [] casting doubt on the Spiroplasma hypothesis. In defense of the Spiroplasma hypothesis, Bastian pointed out that Spiroplasma is hard to culture and that strain variation makes it hard to detect certain strains using PCR and other techniques, thus giving a false negative.

Acinetobacter is a bacterium which some think is the cause of the TSEs. Mainly because some CJD patients produce antibodies against Acinetobacter calcoaceticus. Prion-like domains have been found in a variety of other mammalian proteins. Some of these proteins have been implicated in the ontogeny of age-related neurodegenerative disorders such as amyotrophic lateral sclerosis ALS a motor neuron disease , frontotemporal lobar degeneration with ubiquitin-positive inclusions FTLD-U , Alzheimer's disease , Parkinson's disease , and Huntington's disease.

Prion Diseases - Diagnosis and Pathogenesis | Martin H. Groschup | Springer

AA amyloidosis, like prion disease, may be transmissible. The definition of a prion-like domain arises from the study of fungal prions. In yeast, prionogenic proteins have a portable prion domain that is both necessary and sufficient for self-templating and protein aggregation.

This has been shown by attaching the prion domain to a reporter protein, which then aggregates like a known prion.

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Similarly, removing the prion domain from a fungal prion protein inhibits prionogenesis. This modular view of prion behaviour has led to the hypothesis that similar prion domains are present in animal proteins, in addition to PrP. They are typically enriched in asparagine, glutamine, tyrosine and glycine residues, with an asparagine bias being particularly conducive to the aggregative property of prions.

Historically, prionogenesis has been seen as independent of sequence and only dependent on relative residue content. However, this has been shown to be false, with the spacing of prolines and charged residues having been shown to be critical in amyloid formation. Bioinformatic screens have predicted that over human proteins contain prion-like domains PrLD.