Summary: Scrapie-responsive protein 1
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Scrapie Edit Wikipedia article
Scrapie is a fatal, degenerative disease that affects the nervous systems of sheep and goats. It is one of several transmissible spongiform encephalopathies (TSEs), which are related to bovine spongiform encephalopathy (BSE or "mad cow disease") and chronic wasting disease of deer. Like other spongiform encephalopathies, scrapie is caused by a prion. Scrapie has been known since 1732, and does not appear to be transmissible to humans.
The name scrapie is derived from one of the clinical signs of the condition, wherein affected animals will compulsively scrape off their fleeces against rocks, trees, or fences. The disease apparently causes an itching sensation in the animals. Other clinical signs include excessive lip smacking, altered gaits, and convulsive collapse.
Scrapie is infectious and transmissible among conspecifics, so one of the most common ways to contain it (since it is incurable) is to quarantine and destroy those affected. However, scrapie tends to persist in flocks and can also arise apparently spontaneously in flocks that have not previously had cases of the disease. The mechanism of transmission between animals and other aspects of the biology of the disease are only poorly understood, and these are active areas of research. Recent studies suggest prions may be spread through urine and persist in the environment for decades.
Scrapie usually affects sheep around three to five years of age. The potential for transmission at birth and from contact with placental tissues is apparent. No evidence indicates scrapie is infectious to humans.
Uptake of prions
The protein enters through the intestines or through cuts in the skin. The prions cause normal proteins of the sheep to fold into the wrong shape. These proteins are gradually accumulated in the body, especially in nerve cells, which subsequently die. When the prions are absorbed through the intestines, they first appear in the lymph nodes, especially in Peyer's patches at the small intestine.
An experiment has shown lambs risk being infected through milk from infected ewes, but the lambs in the experiment also infected each other, making the risk of infection difficult to assess. The experiment did not continue long enough to show the lambs developed symptoms, but merely the prion was present in their bodies.
Clinical signs and diagnosis
Changes are mild at first; slight behavioural changes and an increase in chewing movements may occur. Ataxia and neurological signs then develop, and affected sheep struggle to keep up with the flock.
Some sheep scratch excessively and show patches of wool loss and lesions on the skin. Scratching sheep over the rump area may lead to a nibbling reflex, which is characteristic for the condition.
Signs of a chronic systemic disease appear later, with weight loss, anorexia, lethargy, and possibly death.
Post mortem examination is important for the diagnosis of scrapie. Histology of tissues shows accumulation of prions in the central nervous system, and immunohistochemical staining and ELISA can also be used to demonstrate the protein.
Treatment and preventive action
No treatment is available for affected sheep.
In the United Kingdom, the government has put in place a National Scrapie Plan, which encourages breeding from sheep that are genetically more resistant to scrapie. This is intended to eventually reduce the incidence of the disease in the UK sheep population. Scrapie occurs in Europe and North America, but to date, Australia and New Zealand (both major sheep-producing countries) are scrapie-free.
Breeds such as Cheviot and Suffolk are more susceptible to scrapie than other breeds. Specifically, this is determined by the genes coding for the naturally occurring prion proteins. The most resistant sheep have a double set of ARR alleles, while sheep with the VRQ allele are the most susceptible. A simple blood test reveals the allele of the sheep, and many countries are actively breeding away the VRQ allele.
In 2010, A team from New York described detection of PrPSc even when initially present at only one part in a hundred billion (10−11) in brain tissue. The method combines amplification with a novel technology called surround optical fiber immunoassay and some specific antibodies against PrPSc. 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. They 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. After further development and testing, this method could be of great value in surveillance as a blood- or urine-based screening test for scrapie.
Various studies have indicated prions (PrPSC) that infect sheep and goats with the fatal transmissible encephalopathy known as scrapie, are able to persist in soil for years without losing their pathogenic activity. Dissemination of prions into the environment can occur from several sources: mainly, infectious placenta or amniotic fluid of sheep and possibly environmental contamination by saliva or excrement.
Confirmatory testing for scrapie can only be achieved by applying immunohistochemistry of disease-associated prion protein (PrPSC) to tissues collected post mortem, including obex, retropharyngeal lymph node and palatine tonsil. A live animal diagnostic, not confirmatory, test was approved in 2008 for immunochemistry testing on rectal biopsy-derived lymphoid tissue by USDA.
Natural transmission of scrapie in the field seems to occur via the alimentary tract in the majority of cases, and scrapie-free sheep flocks can become infected on pastures where outbreaks of scrapie had been observed before. These findings point to a sustained contagion in the environment, and notably the soil.
Prion concentration in birth fluids does not alter the infectivity of the prions. Naturally or experimentally infected does and ewes transmit the infection to the kids, even when placentas have little PrPSC. PrPSC is shed at a higher percentage in sheep placentas (52%-72%) than in goat placenta (5-10%) in study trials at the USDA Agricultural Research Service.
Fecal concentration of PrPSC has been reported in the feces of sheep both in the terminal and the early preclinical stages of the disease, suggesting the prions are likely to be shed into the environment throughout the pathogenesis. Several sources of prions in feces could be postulated, including environmental ingestion and swallowing infected saliva; however, the most likely source is shedding from the gut-associated lymphoid tissue. Ruminants have specialized Peyer's patches that throughout the length of the ileum amount to about 100,000 follicles, and all of these could be infected and shedding prions into the lumen. Scrapie prions have been found in the Peyer's patches of naturally infected nonclinical lambs as young as four months of age.
Exposure through contaminated soil
Ingestion of soil by grazing sheep has been measured in two soil types, at two stocking rates, and over two grazing seasons. Animals ingested up to 44 g soil per kg of body weight between May and November. Rainfall and stocking rate emerged as factors influencing ingestion. The effect of soil type and herbage on offer was less evident.
The average weight of an adult sheep is around 250 pounds. If an adult sheep ate 400g/kg of soil as predicted by D. McGrath et al., then the average sheep would ingest about 45,000 g over six months, or 251 g per day. Assuming the soil was contaminated with prions (PrPSC) from feces or birth fluids, then potentially the sheep would be infected. The concentration of the prions is uncertain, and concentration is not directly proportional to infectivity. Factors affecting prion infectivity in the soil have been shown to include the length of time in the soil and the binding abilities of the soil.
For a detailed risk assessment of scrapie-contaminated soil, it was of major importance to analyze whether the detectable PrPSc in the soil extracts still exhibited oral infectivity after incubation times up to 29 months. A bioassay with Syrian hamsters was performed by feeding the animals with contaminated soil or aqueous soil extracts that had been collected after soil incubation for 26 and 29 months, respectively. Hamsters fed with contaminated soil exhibited first scrapie-associated symptoms at two weeks to six months (95% CI) after the first application. The hamsters reached the terminal stage of scrapie at five to 21 months (95% CI) after the first feeding. This indicated substantial amounts of persistent infectivity in soil that had been incubated for 26 and 29 months. In Iceland in 1978, a program was implemented to eradicate scrapie, and affected flocks were culled, premises were disinfected, and sheep houses were burnt; after two to three years, the premises were restocked with lambs from scrapie-free areas. Between 1978 and 2004, scrapie recurred on 33 farms. Nine recurrences occurred 14–21 years after culling as a result of environmental contamination.
The binding abilities of different soil types have been shown to enhance disease penetrance. Soil containing the common clay mineral montmorillonite (Mte) and kaolinite (Kte) binds more effectively with the prions than soil containing quartz. Enhanced transmissibility of soil-bound prions may explain the environmental spread of scrapie despite low levels shed into the environment. The mechanism by which Mte or other soil components enhances the transmissibility of particle bound prions remains to be clarified. Prion binding to Mte or other soil components may partially protect PrPSC from denaturation or proteolysis in the digestive tract, allowing more disease agent to be taken up from the gut. Adsorption of PrPSc soil may alter aggregation state of the protein, shifting the size distribution toward more infectious prion protein particles, thereby increasing the infectious units. For prion disease to be transmitted via ingestion of prion contaminated soil, prions must also remain infectious by the oral route of exposure. Researchers at the University of Wisconsin investigated the oral infectivity of Mte and soil-bound prions. The effects of prion source (via infected brain homogenate and purified PrPSc) and dose on penetrance (proportion of animals eventually exhibiting clinical signs of scrapie) and incubation period (time to onset of clinical symptoms) was evaluated. About 38% of animals receiving 200 ng of unbound, clarified PrPSc orally exhibited clinical symptoms, with an incubation period for infected animals of 203 to 633 days. In contrast, all animals orally dosed with an equivalent amount of Mte-bound PrPSc manifested disease symptoms in 195 to 637 days. Animals orally receiving Mte soil alone or one-tenth as much unbound clarified PrPSc (20 ng) remained asymptomatic throughout the course of the experiment. These data established that Mte-bound prions remain infectious via the oral route of exposure, but that the agent binding Mte increases disease penetrance, enhancing the efficiency of oral transmission.
Prions (PrPSc) are shed from sheep and goats in birth fluids, feces and other excrement. The concentration of the prions is uncertain, but is not directly proportional to infectivity. Sheep ingest soil, so soil represents a plausible environmental reservoir of scrapie, which can persist in the environment for years. Longevity of the prions and the attachment of soil particles likely influences the persistence and infectivity of prions in the environment.
Effective methods to inactivate prions in the soil are currently lacking, and the effects of natural degradation mechanisms on prion infectivity are largely unknown. An improved understanding of the processes affecting the mobility, persistence and bioavailability of prions in soil is needed for the management of prion-contaminated environments. A system for estimating the prion-binding capacity of soil on farms using simple soil analysis may allow an estimate of the prion risk in the environment, and whether prion binding by the use of soil amendments or top dressings may help to mitigate the infectious prions. Lichens, Lobaria pulmonaria, may have potential for reducing the number of prions because some species contain proteases that show promise in breaking down the prion. Further work to clone and characterize the proteases, assess their effects on prion infectivity, and determine which organism or organisms present in lichens produce or influence the protease activity is warranted and is currently under investigation.
- Detwiler LA (1992). "Scrapie". Rev. - Off. Int. Epizoot. 11 (2): 491–537. PMID 1617202.
- Hunter N (2007). "Scrapie: uncertainties, biology and molecular approaches". Biochim. Biophys. Acta 1772 (6): 619–28. doi:10.1016/j.bbadis.2007.04.007. PMID 17560089.
- National Scrapie Education Initiative. "Scrapie Fact Sheet". National Institute for Animal Agriculture. Retrieved 4 December 2011.
- Rolf, George. "From Sheep to Humans: Scrapie and Creutzfeldt-Jakob Disease". Ecclectica. Retrieved 4 December 2011.
- Foster JD, Parnham D, Chong A, Goldmann W, Hunter N (2001). "Clinical signs, histopathology and genetics of experimental transmission of BSE and natural scrapie to sheep and goats". Vet. Rec. 148 (6): 165–71. doi:10.1136/vr.148.6.165. PMID 11258721.
- Detwiler LA, Baylis M (2003). "The epidemiology of scrapie". Rev. - Off. Int. Epizoot. 22 (1): 121–43. PMID 12793776.
- Scrapie reviewed and published by WikiVet, accessed 12 October 2011.
- Tarmen viktig for skrapesyke - forskning.no
- Konold Moore, Bellworthy Simmons (2008). "Evidence of scrapie transmission via milk". BMC Veterinary Research 4: 16. doi:10.1186/1746-6148-4-16.
- O'Rourke KI, Duncan JV, Logan JR; et al. (2002). "Active surveillance for scrapie by third eyelid biopsy and genetic susceptibility testing of flocks of sheep in Wyoming". Clin. Diagn. Lab. Immunol. 9 (5): 966–71. doi:10.1128/CDLI.9.5.966-971.2002. PMC 120069. PMID 12204945.
- Eddie Straiton, "Sheep Ailments - recognition and treatment", 7th edition (2001) ISBN 1-86126-397-X
- Synnøve Vatn, Lisbeth Hektoen, Ola Nafstad "Helse og Velferd hos sau" 1. utgave, Tun Forlag (2008) ISBN 978-82-529-3180-8
- Heim D, Kihm U (2003). "Risk management of transmissible spongiform encephalopathies in Europe". Rev. - Off. Int. Epizoot. 22 (1): 179–99. PMID 12793779.
- "Detecting Prions in Blood" (PDF). Microbiology Today.: 195. August 2010. Retrieved 2011-08-21.
- "SOFIA: An Assay Platform for Ultrasensitive Detection of PrPSc in Brain and Blood" (PDF). SUNY Downstate Medical Center. Retrieved 2011-08-19.
- Saunders, Samuel E.; Shannon L. Bartelt-Hunt; Jason C. Bartz (Oct–Nov 2008/Dec). "Prions in the environment". Prion 2 (4): 162–169. doi:10.4161/pri.2.4.7951. Check date values in:
- Seidel, Bjoern; Thomzig A; Buschmann A; Groschup M; Peters R; Beekes M; Terytze K (9 May 2007). "Scrapie Agent (Strain 263K) Can Transmit Disease via the Oral Route after Persistence in Soil Over Years". PLOS ONE (5). doi:10.1371/journal.pone.0000435.
- O'Rourke, Catherine. "PP - USDA ARS".
- Terry, Linda; et al. (18 May 2011). "Detection of Prions in the faeces of sheep naturally infected with classical scrapie". Veterinary Research 42 (65).
- McGrath, D; et al. (1982). "Soil Ingestion by Grazing Sheep". Irish Journal of Agriculture.
- USDA, National Statistical Service. "Livestock Slaughter 2010".
- Georgsson, Gudmundu; et al. (2006). "Infectious agent of sheep scrapie may persist in the environment for at least 16 years". Journal of General Virology.
- O'Rourke, Katherine. "USDA-ARS 2011".
- Pederson, Joel; et al. (July 2007). "Oral transmissibility of prion disease is enhanced by binding to soil particles". Plos Pathog.
- Johnson, CJ; et al. (2011). "Degradation of the disease-associated prion protein by a serine protease from lichens". PLOS ONE.
- Article about scrapie and the aforementioned diagnostic test
- UK government scrapie information
- UK government National Scrapie Plan
- Scrapie research at the Institute for Animal Health (UK)
- Sheep genetics research at the Institute for Animal Health (includes photo of a sheep with scrapie)
- Scrapie in the United States
- US Department of Agriculture video of infected sheep demonstrating Hopping Gait
- Striking a Nerve: Prions Not the Last Word in TSEs – opinion article by Frank Bastian that proposes a different causation for scrapie and other prion diseases
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Scrapie-responsive protein 1 Provide feedback
This protein family has an important function in acting against the prion protein, Scrapie [1,2].This family of proteins is found in eukaryotes. Proteins in this family are approximately 98 amino acids in length.
Dron M, Dandoy-Dron F, Guillo F, Benboudjema L, Hauw JJ, Lebon P, Dormont D, Tovey MG;, J Biol Chem. 1998;273:18015-18018.: Characterization of the human analogue of a Scrapie-responsive gene. PUBMED:9660755 EPMC:9660755
Dandoy-Dron F, Guillo F, Benboudjema L, Deslys JP, Lasmezas C, Dormont D, Tovey MG, Dron M;, J Biol Chem. 1998;273:7691-7697.: Gene expression in scrapie. Cloning of a new scrapie-responsive gene and the identification of increased levels of seven other mRNA transcripts. PUBMED:9516475 EPMC:9516475
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR028063
This protein family has an important function in acting against the prion protein, scrapie [PUBMED:9660755, PUBMED:9516475]. This family of proteins is found in eukaryotes. Proteins in this family are approximately 98 amino acids in length.
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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|Author:||Eberhardt RY, Coggill P, Hetherington K|
|Number in seed:||6|
|Number in full:||48|
|Average length of the domain:||73.90 aa|
|Average identity of full alignment:||81 %|
|Average coverage of the sequence by the domain:||72.93 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 80369284 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||2|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
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Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
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There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
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Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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