Measuring prions causing bovine spongiform encephalopathy or chronic wasting disease by immunoassays and transgenic mice

Safar, Jiri; Scott, Michael; Monaghan, Jeff; Deering, Camille; Didorenko, Svetlana; Vergara, Julie; Ball, Haydn L.; Legname, Giuseppe; Leclerc, Estelle; Solforosi, Laura; Serban, Hana; Groth, Darlene; Burton, Dennis R.; Prusiner, Stanley B.; Williamson, R. Anthony

doi:10.1038/nbt748

Cited by 222 publications

(208 citation statements)

References 18 publications

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“…Although most transmission data are consistent with the existence of one single strain [188], there has been variations in either incubation periods, which were conserved on subpassage, or neuropathological features among the transmitted isolates [30,82,117], suggesting straindependent variations. LaFauci et al proposed in particular that strains might differ among the mule deer and elk [117], as previously evidenced with PrP Sc conformation studies [170]. The emergence of two strains has been observed on serial adaptation of CWD inocula to hamsters [163].…”

Section: Strain Diversity In Cwd?mentioning

confidence: 79%

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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: Strain Diversity In Cwd?mentioning

confidence: 79%

“…However a deeper comparison of the isolates through conformation-dependant immunoassay (CDI, Tab. II) identified two distinct populations, one in the elk, and the other in deer [170]. Recently, an alternative 19 kDa pattern has also been observed in diseased elk with leucine at codon 132 [142].…”

Section: Strain Diversity In Cwd?mentioning

confidence: 98%

Prion agent diversity and species barrier

2008

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“…Also, it was recently described that, by using immunohistochemical methods, different scrapie sources could differ in their labeling with different antibodies, including P4 monoclonal antibody (26). Immunological characterization of strains suggesting the existence of PrP conformational differences has already been reported for scrapie-infected hamsters and more recently for bovine transgenic mice infected with BSE or variant CJD by using a conformation-dependent immunological assay of abnormal PrP prior to proteinase K digestion (46,47). Together these data show the usefulness of PrP res immunological characterization, which could allow the demonstration of a greater molecular diversity of scrapie strains than previously thought.…”

Section: Discussionmentioning

confidence: 99%

Molecular Analysis of the Protease-Resistant Prion Protein in Scrapie and Bovine Spongiform Encephalopathy Transmitted to Ovine Transgenic and Wild-Type Mice

Baron¹,

Crozet²,

Biacabe³

et al. 2004

J Virol

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The existence of different strains of infectious agents involved in scrapie, a transmissible spongiform encephalopathy (TSE) of sheep and goats, remains poorly explained. These strains can, however, be differentiated by characteristics of the disease in mice and also by the molecular features of the protease-resistant prion protein (PrP res ) that accumulates into the infected tissues. For further analysis, we first transmitted the disease from brain samples of TSE-infected sheep to ovine transgenic [Tg(OvPrP4)] and to wild-type (C57BL/6) mice. We show that, as in sheep, molecular differences of PrP res detected by Western blotting can differentiate, in both ovine transgenic and wild-type mice, infection by the bovine spongiform encephalopathy (BSE) agent from most scrapie sources. Similarities of an experimental scrapie isolate (CH1641) with BSE were also likewise found following transmission in ovine transgenic mice. Secondly, we transmitted the disease to ovine transgenic mice by inoculation of brain samples of wild-type mice infected with different experimental scrapie strains (C506M3, 87V, 79A, and Chandler) or with BSE. Features of these strains in ovine transgenic mice were reminiscent of those previously described for wild-type mice, by both ratios and by molecular masses of the different PrP res glycoforms. Moreover, these studies revealed the diversity of scrapie strains and their differences with BSE according to labeling by a monoclonal antibody (P4). These data, in an experimental model expressing the prion protein of the host of natural scrapie, further suggest a genuine diversity of TSE infectious agents and emphasize its linkage to the molecular features of the abnormal prion protein.

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“…In some of these studies, it is not clear whether mule deer and elk possess heterogeneous PrP aggregates (strain mixture), or whether the strains may have developed in the new host. However, Safar et al have reported differing conformational characteristics for PrP Sc from CWD-infected white-tailed deer and elk directly, using a conformation dependent immunoassay (CDI) [71], which supports the existence of CWD strains. The possible existence of CWD strains is perhaps not entirely surprising, considering that there are genetic Prnp differences among deer and elk that could influence PrP Sc conformation [34,36,58].…”

Section: Cwd Strains Among Deer and Elkmentioning

confidence: 98%

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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Measuring prions causing bovine spongiform encephalopathy or chronic wasting disease by immunoassays and transgenic mice

Cited by 222 publications

References 18 publications

Prion agent diversity and species barrier

Prion agent diversity and species barrier

Molecular Analysis of the Protease-Resistant Prion Protein in Scrapie and Bovine Spongiform Encephalopathy Transmitted to Ovine Transgenic and Wild-Type Mice

A prion disease of cervids: Chronic wasting disease

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