Evidence of a molecular barrier limiting susceptibility of humans, cattle and sheep to chronic wasting disease

Raymond, Gregory J.; Bossers, Alex; Raymond, Lynne D.; O’Rourke, Katherine I.; McHolland, Linda E.; Bryant, Patricia; Miller, Michael W.; Williams, Elizabeth; Smits, M.A.; Caughey, Byron

doi:10.1093/emboj/19.17.4425

Cited by 258 publications

(239 citation statements)

References 21 publications

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“…In vitro cell free conversion of human and bovine PrP C by CWD PrP Sc was poor, suggesting a substantial molecular barrier that would limit susceptibility of these species to disease [162,163]. These results were further confirmed in transgenic mice expressing bovine and human PrP (Met allele) and extended to ovine PrP VRQ mice.…”

Section: Potential Of Interspecies Transmission Of Cwdmentioning

confidence: 78%

“…Thus conversion of mouse PrP C by hamster PrP Sc (263K) was inefficient [112]. At a time where in vivo data were limited, the cellfree conversion approach has suggested that the potential susceptibility of humans to TSE agents such as BSE, scrapie or CWD might be relatively low [162,161]. The pronounced influence of sheep PrP genotypes on susceptibility to the scrapie agent was also modeled with some accuracy in vitro [29].…”

Section: Cell-free Systemsmentioning

confidence: 99%

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Prion agent diversity and species barrier

2008

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-Mammalian prions are the infectious agents responsible for transmissible spongiform encephalopathies (TSE), a group of fatal, neurodegenerative diseases, affecting both domestic animals and humans. The most widely accepted view to date is that these agents lack a nucleic acid genome and consist primarily of PrP Sc , a misfolded, aggregated form of the host-encoded cellular prion protein (PrP C ) that propagates by autocatalytic conversion and accumulates mainly in the brain. The BSE epizooty, allied with the emergence of its human counterpart, variant CJD, has focused much attention on two characteristics that prions share with conventional infectious agents. First, the existence of multiple prion strains that impose, after inoculation in the same host, specific and stable phenotypic traits such as incubation period, molecular pattern of PrP Sc and neuropathology. Prion strains are thought to be enciphered within distinct PrP Sc conformers. Second, a transmission barrier exists that restricts the propagation of prions between different species. Here we discuss the possible situations resulting from the confrontation between species barrier and prion strain diversity, the molecular mechanisms involved and the potential of interspecies transmission of animal prions, including recently discovered forms of TSE in ruminants.prion / strain / misfolding / species barrier / PrP Table of Mammalian prion diseases or transmissible spongiform encephalopathies (TSE) form a group of related, invariably fatal neurodegenerative disorders of both animals and humans. The brain pathology consists of spongiosis, astrocytosis, neuronal loss and neural tissue from affected individuals contains an infectious agent, the prion, setting these diseases apart from other neurodegenerative diseases. Prion replication is thought to involve in essence the self-perpetuating conversion of the host-encoded cellular prion protein (PrP C ) into a misfolded form (PrP Sc ) that tends to aggregate and may be neurotoxic (for reviews [1,157]). Prion replication may also occur in lymphoid tissues but is there poorly if not pathogenic (for review [126], [133]). PrP C is a protein with two variably occupied glycosylation sites. It is attached at the outer of the plasma membrane by a glycosylphosphatidylinositol anchor. Its secondary structure is rich in alpha-helix and the protein is likely to be in a monomeric state in mild detergents. While its precise physiological function has not been assigned, PrP C is essential for prion replication and neurotoxicity to occur [57,129]. Upon infection, PrP C is refolded -without apparent post-translational modification -into beta-sheet -rich PrP Sc , initially in the presence of exogenous PrP Sc and then by an autocatalytic process. It leads to the formation of aggregates, sometimes of amyloid type, that can be differentiated from PrP C because of their partial resistance to protease digestion and of their insolubility into non-denaturing detergents [153]. Proteinase K, the most commonly used protease, di...

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Section: Potential Of Interspecies Transmission Of Cwdmentioning

confidence: 78%

Section: Cell-free Systemsmentioning

confidence: 99%

Prion agent diversity and species barrier

2008

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“…Analysis of SNPs at prion loci of caribou from Alaska might offer opportunities to determine whether allelic and genotypic frequencies carry an unambiguous signature of balancing selection. The fieldcollected data could complement experiments with purified proteins (Raymond et al, 2000) and with ''cervidized'' mice (Browning et al, 2004) as well as with controlled infections in captive cervids.…”

Section: Discussionmentioning

confidence: 99%

“…Chronic wasting disease is known in three species of cervids with similar or identical PrP genes (Heaton et al, 2003;Johnson et al, 2003). Efficient transmission requires a close conformational fit between the invasive PrP sc and the PrP c of the host (Raymond et al, 2000;Caughey, 2003). The sequence of the most common caribou allele (GenBank accession no.…”

Section: Discussionmentioning

confidence: 99%

Prion Protein Genes in Caribou From Alaska

Happ

Huson

Beckmen

et al. 2007

Journal of Wildlife Diseases

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ABSTRACT:Prion protein genes were sequenced in free-ranging Alaska caribou (Rangifer tarandus grantii). Caribou prion alleles are identical or nearly so to those of wapiti, white-tailed deer, and mule deer. Five single-nucleotide polymorphisms were detected with substitutions at residues 2 (VRM), 129 (GRS), 138 (SRN), 146 (NRN), and 169 (VRM). The 138N codon had been previously reported only in prion pseudogenes of other cervids. In caribou, the 138S and 138N alleles are present at frequencies of approximately 0.7 and 0.3, respectively, and they are seen in both homozygotes and heterozygotes of three geographically separated herds, each a component of the continental metapopulation. Genetics seems to permit the spread of chronic wasting disease from middle-latitude deer to high-latitude caribou in North America.

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“…In biochemical conversion studies, Raymond et al [68] showed that the efficiency of CWD to convert recombinant human PrP into amyloid fibrils was low, but similar to that of both BSE and scrapie fibrils to do the same. These results suggest that there is a molecular incompatibility in the conversion of human PrP C by CWD, sheep scrapie, or BSE, and that cross species infections in humans may be rare events.…”

Section: Human Susceptibility To Cwdmentioning

confidence: 99%

A prion disease of cervids: Chronic wasting disease

2008

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-Chronic wasting disease (CWD) is a prion disease of deer, elk, and moose, initially recognized in Colorado mule deer. The discovery of CWD beyond the borders of Colorado and Wyoming, in Canada and as far east as New York, has led to its emergence as a prion disease of international importance. Epidemiological studies indicate that CWD is horizontally transmitted among free-ranging animals, potentially indirectly by prion-containing secreta or excreta contaminating the environment. Experimental CWD transmission attempts to other wild and domestic mammals and to transgenic mice expressing the prion protein of cattle, sheep, and humans have shed light on CWD species barriers. Transgenic mice expressing the cervid prion protein have proven useful for assessing the genetic influences of Prnp polymorphisms on CWD susceptibility. Accumulating evidence of CWD pathogenesis indicates that the misfolded prion protein or prion infectivity seems to be widely disseminated in many nonneural organs and in blood. This review highlights contemporary research findings in this prion disease of free-ranging wildlife.

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Evidence of a molecular barrier limiting susceptibility of humans, cattle and sheep to chronic wasting disease

Cited by 258 publications

References 21 publications

Prion agent diversity and species barrier

Prion agent diversity and species barrier

Prion Protein Genes in Caribou From Alaska

A prion disease of cervids: Chronic wasting disease

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