Is scrapie solely a genetic disease?

Hunter, Nora; Cairns, D; Foster, Jim; Smith, G; Goldmann, Wilfred; Donnelly, Kirby C.

doi:10.1038/386137a0

Cited by 100 publications

(54 citation statements)

References 10 publications

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“…At codon 171, both heterozygous Q͞R and homozygous R͞R Suffolk sheep were found to be resistant to natural scrapie (17). In studies of experimental scrapie, Cheviot sheep carrying Q͞R or R͞R at residue 171 were found to be resistant to prion infection (16,(35)(36)(37). Similar findings have been reported for flocks of Texel sheep with natural scrapie.…”

Section: Discussionsupporting

confidence: 74%

Dominant-negative inhibition of prion replication in transgenic mice

Perrier

Kaneko

Safar

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

142

102

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Our discovery of dominant-negative inhibition of prion formation in cultured cells provided an explanation for the resistance of some sheep to scrapie and humans to Creutzfeldt-Jakob disease. To determine whether dominant-negative inhibition occurs in vivo, we produced transgenic (Tg) mice expressing prion protein (PrP) with either the Q167R or Q218K mutation alone or in combination with wild-type (wt) PrP. Tg(MoPrP,Q167R)Prnp 0/0 mice expressing mutant PrP at levels equal to non-Tg mice remained healthy for >550 days, indicating that inoculation with prions did not cause disease. Immunoblots of brain homogenates and histologic analysis did not reveal abnormalities. Tg(MoPrP,Q167R)Prnp ؉/؉ mice expressing both mutant and wt PrP did not exhibit neurologic dysfunction, but their brains revealed low levels of the PrP pathogenic isoform (PrP Sc ), and sections showed numerous vacuoles and severe astrocytic gliosis at 300 days after inoculation. Both Tg(MoPrP,Q218K)Prnp 0/0 and Tg(MoPrP,Q218K)Prnp ؉/؉ mice expressing high levels of the transgene product remained healthy for >300 days after inoculation. Neither PrP Sc nor neuropathologic changes were found. Our studies demonstrate that although dominant-negative inhibition of wt PrP Sc formation occurs, expression of the dominant-negative PrP at the same level as wt PrP does not prevent prion formation completely. However, expression of dominant-negative PrP alone had no deleterious effects on the mice and did not support prion propagation.

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Section: Discussionsupporting

confidence: 74%

Dominant-negative inhibition of prion replication in transgenic mice

Perrier

Kaneko

Safar

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

142

102

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“…In sheep, the substitution of a basic residue at position 171 probably prevents scrapie through a dominant-negative mechanism similar to that postulated for a basic residue at 219 protecting humans from CJD. With few exceptions, only sheep that are Q͞Q at 171 develop scrapie; sheep that are Q͞R or R͞R are resistant (31)(32)(33)(34)(35)(36)(37)(38)(39). These findings suggest that R171 creates a PrP C molecule in sheep that acts as a dominant negative in preventing PrP Sc formation (Fig.…”

Section: Discussionmentioning

confidence: 76%

Evidence for protein X binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation

Kaneko

Zulianello

Scott

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

465

420

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Studies on the transmission of human (Hu) prions to transgenic (Tg) mice suggested that another molecule provisionally designated protein X participates in the formation of nascent scrapie isoform of prion protein (PrP Sc ). We report the identification of the site at which protein X binds to the cellular isoform of PrP (PrP C ) using scrapieinfected mouse (Mo) neuroblastoma cells transfected with chimeric Hu͞MoPrP genes even though protein X has not yet been isolated. Substitution of a Hu residue at position 214 or 218 prevented PrP Sc formation. The side chains of these residues protrude from the same surface of the C-terminal ␣-helix and form a discontinuous epitope with residues 167 and 171 in an adjacent loop. Substitution of a basic residue at positions 167, 171, or 218 also prevented PrP Sc formation: at a mechanistic level, these mutant PrPs appear to act as ''dominant negatives'' by binding protein X and rendering it unavailable for prion propagation. Our findings seem to explain the protective effects of basic polymorphic residues in PrP of humans and sheep and suggest therapeutic and prophylactic approaches to prion diseases.

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“…The risk in this group is so high that scrapie was for a long time regarded as a genetic disease. It has however been shown conclusively that VRQ/VRQ sheep can survive into old age when their environment is free of scrapie infection [26,48]. The other three genotypes in R5 are VRQ/ARQ, VRQ/ARH and VRQ/AHQ.…”

Section: Classical Scrapie In Sheepmentioning

confidence: 99%

PrPgenetics in ruminant transmissible spongiform encephalopathies

2008

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-Scrapie, bovine spongiform encephalopathy (BSE), and chronic wasting disease (CWD) are prion diseases in ruminants with considerable impact on animal health and welfare. They can also pose a risk to human health and control is therefore an important issue. Prion protein (PrP) genetics may be used to control and eventually eradicate animal prion diseases. The PrP gene in sheep and other representatives of the order Artiodactyles has many polymorphisms of which several are crucial determinants of susceptibility to prion diseases, also known as transmissible spongiform encephalopathies (TSE). This review will present the current understanding of PrP genetics in ruminants highlighting similarity and difference between the species in the context of TSE.

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Is scrapie solely a genetic disease?

Cited by 100 publications

References 10 publications

Dominant-negative inhibition of prion replication in transgenic mice

Dominant-negative inhibition of prion replication in transgenic mice

Evidence for protein X binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation

PrPgenetics in ruminant transmissible spongiform encephalopathies

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