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

Baron, Thierry; Crozet, Carole; Biacabe, Anne-Gaëlle; Philippe, Sandrine; Verchere, Jérémie; Bencsik, Anna; Madec, Jean‐Yves; Calavas, Didier; Samarut, Jacques

doi:10.1128/jvi.78.12.6243-6251.2004

Cited by 55 publications

(68 citation statements)

References 60 publications

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“…In accordance with our predictions, prions are readily transmitted within 170S mammals: sheep scrapie prions infect cattle (72)(73)(74) and mice (75,76), and cattle BSE prions readily infect sheep (77-79) and mice (14,80). BSE (170S) has also been transmitted to other 170S species, including greater kudu, nyala, eland, scimitar-horned oryx, bison, rhesus macaque, domestic cat, and mink (13,16,81,82).…”

Section: Figuresupporting

confidence: 86%

A molecular switch controls interspecies prion disease transmission in mice

Sigurdson¹,

Nilsson²,

Hornemann³

et al. 2010

J. Clin. Invest.

130

139

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Transmissible spongiform encephalopathies are lethal neurodegenerative disorders that present with aggregated forms of the cellular prion protein (PrP C ), which are known as PrP Sc . Prions from different species vary considerably in their transmissibility to xenogeneic hosts. The variable transmission barriers depend on sequence differences between incoming PrP Sc and host PrP C and additionally, on strain-dependent conformational properties of PrP Sc . The β 2 -α 2 loop region within PrP C varies substantially between species, with its structure being influenced by the residue types in the 2 amino acid sequence positions 170 (most commonly S or N) and 174 (N or T). In this study, we inoculated prions from 5 different species into transgenic mice expressing either disordered-loop or rigid-loop PrP C variants. Similar β 2 -α 2 loop structures correlated with efficient transmission, whereas dissimilar loops correlated with strong transmission barriers. We then classified literature data on cross-species transmission according to the 170S/N polymorphism. Transmission barriers were generally low between species with the same amino acid residue in position 170 and high between those with different residues. These findings point to a triggering role of the local β 2 -α 2 loop structure for prion transmissibility between different species.

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Section: Figuresupporting

confidence: 86%

A molecular switch controls interspecies prion disease transmission in mice

Sigurdson¹,

Nilsson²,

Hornemann³

et al. 2010

J. Clin. Invest.

130

139

View full text Add to dashboard Cite

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“…TSE sheep isolates included the CH1641 experimental scrapie isolate (kindly provided by N. Hunter, Institute for Animal Health, Edinburgh, United Kingdom) and three unusual French natural TSE isolates. Molecular analyses of CH1641 transmitted to TgOvPrP4 ovine transgenic mice have been previously described (2). The three natural isolates were two V 136 R 154 Q 171 homozygous sheep diagnosed with TSE in 1996 and 1997 within a scrapie-infected flock (32) in Pyrénées-Atlantiques and a case identified in 2003 in an A 136 R 154 Q 171 homozygous sheep in another region of France (Allier).…”

Section: Methodsmentioning

confidence: 99%

“…The usefulness of transgenic mice expressing the ovine prion protein for the detection and characterization of the infectious agent involved in sheep prion diseases has been emphasized by several studies in recent years (2,16,17,43). The transmission in TgOvPrP4 ovine transgenic mice of the CH1641 isolate, which had previously consistently failed to transmit to wild-type mice, was previously reported (24).…”

mentioning

confidence: 99%

Molecular Behaviors of “CH1641-Like” Sheep Scrapie Isolates in Ovine Transgenic Mice (TgOvPrP4)

Baron

Biacabe

2007

J Virol

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Molecular analyses of the protease-resistant prion protein (PrPres) from a few natural scrapie isolates showed by Western blotting some partial similarities with those observed in experimental ovine bovine spongiform encephalopathy (BSE). They showed a low apparent molecular mass of unglycosylated PrPres, although diglycosylated PrPres was less abundant than in ovine BSE. The prototype of such cases is the CH1641 experimental scrapie isolate. We analyzed PrPres molecular features from three French natural “CH1641-like” isolates, in comparison with CH1641 and BSE, after transmission of the disease in ovine transgenic mice (TgOvPrP4). One of these isolates (TR316211) behaved like the CH1641 isolate, with PrPres features in mice similar to those in the sheep brain. From two other isolates (O100 and O104), two distinct PrPres phenotypes were identified in mouse brains, with either high (h-type) or low (l-type) apparent molecular masses of unglycosylated PrPres, the latter being similar to that observed with CH1641, TR316211, or BSE. Both phenotypes could be found in variable proportions in the brains of the individual mice. In contrast with BSE, l-type PrPres from “CH1641-like” isolates showed lower levels of diglycosylated PrPres. From one of these cases (O104), a second passage in mice was performed for two mice with distinct PrPres profiles. This showed a partial selection of the l-type phenotype in mice infected with a mouse brain with predominant l-type PrPres, and it was accompanied by a significant increase in the proportions of the diglycosylated band. These results are discussed in relation to the diversity of scrapie and BSE strains.

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“…Some exhibited features similar to CH1641 (∼19 kDa PrP res signature). In other, ∼21 kDa forms predominated and there was a mixture of both [6,9]. It is noteworthy that similar strain typing studies are currently being pursued with the newly developed bank vole model ([140] What is the state of knowledge about the cross-species potential of sheep scrapie, besides rodents?…”

Section: Assessment Of Scrapie Strain Diversity With Transgenic Mousementioning

confidence: 99%

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

Cited by 55 publications

References 60 publications

A molecular switch controls interspecies prion disease transmission in mice

A molecular switch controls interspecies prion disease transmission in mice

Molecular Behaviors of “CH1641-Like” Sheep Scrapie Isolates in Ovine Transgenic Mice (TgOvPrP4)

Prion agent diversity and species barrier

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