Amino acid polymorphisms of PrP with reference to onset of scrapie in Suffolk and Corriedale sheep in Japan

Ikeda, Tetsuya; Horiuchi, Motohiro; Ishiguro, Naotaka; Muramatsu, Yasukazu; Kai-Uwe, Grathwohl D.; Shinagawa, Morikazu

doi:10.1099/0022-1317-76-10-2577

Cited by 145 publications

(120 citation statements)

References 17 publications

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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: 77%

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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Section: Discussionmentioning

confidence: 77%

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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“…The PrP gene is identical to the scrapie incubation period (Sip) gene (Dickinson & Outram, 1988 ;Moore et al, 1998). In all breeds studied, an amino acid change from glutamine (Q) to arginine (R) at codon 171 in the PrP gene renders the animal more resistant towards natural and experimental scrapie as well as experimental bovine spongiform encephalopathy , and only a single case of scrapie has been reported in sheep with a homozygous RR "(" PrP genotype (Ikeda et al, 1995). In several breeds, scrapie susceptibility is greatly enhanced by a valine (V) substitution for alanine (A) at codon 136.…”

Section: Introductionmentioning

confidence: 99%

Prion protein gene polymorphisms in sheep with natural scrapie and healthy controls in Norway.

Tranulis¹,

Osland²,

Bratberg

et al. 1999

Journal of General Virology

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Two-hundred and forty healthy sheep and 32 cases of natural scrapie in Norway were analysed for disease-linked polymorphisms in the prion protein (PrP) gene. Scrapie was strongly associated with the presence of a valine polymorphism at codon 136 (V 136 ), as 68n8 % of the cases were homozygous (VV 136 ) and 15n6 % were valine/alanine heterozygous (VA 136 ). All cases were homozygous arginine/arginine at codon 154 (RR 154 ), except two which were homozygous histidine/histidine (HH 154 ). All cases except two were homozygous glutamine/glutamine at codon 171 (QQ 171 ), the two exceptions being heterozygous glutamine/arginine (QR 171 ). More than 80 % of all scrapie cases in Norway have occurred in a Cheviot-related crossbred type of sheep called Rygja. This type of sheep, which is largely restricted to the south-western coast, carries the V 136 allele at a higher frequency than do other breeds of Norwegian sheep. Polymorphisms at codons 138 and 151 are also described.

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“…Sheep encoding the R͞R polymorphism at position 171 seem to be resistant to scrapie (199,232,(338)(339)(340)(341)(342)(343)(344); presumably, this was the genetic basis of Parry's scrapie eradication program in Great Britain 30 years ago (44,46). A more effective approach using dominant negatives for producing prion-resistant domestic animals, including sheep and cattle, is probably the expression of PrP transgenes encoding R171 as well as additional basic residues at the putative protein X binding site (Fig.…”

mentioning

confidence: 99%

Molecular characterization of proteolytic cleavage sites of the Pseudomonas syringae effector AvrRpt2

Chisholm

Dahlbeck

Krishnamurthy

et al. 2005

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

136

138

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Prions are unprecedented infectious pathogens that cause a group of invariably fatal neurodegenerative diseases by an entirely novel mechanism. Prion diseases may present as genetic, infectious, or sporadic disorders, all of which involve modification of the prion protein (PrP). Bovine spongiform encephalopathy (BSE), scrapie of sheep, and Creutzfeldt-Jakob disease (CJD) of humans are among the most notable prion diseases. Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrP Sc ). The normal, cellular PrP (PrP C ) is converted into PrP Sc through a posttranslational process during which it acquires a high ␤-sheet content. The species of a particular prion is encoded by the sequence of the chromosomal PrP gene of the mammals in which it last replicated. In contrast to pathogens carrying a nucleic acid genome, prions appear to encipher strain-specific properties in the tertiary structure of PrP Sc . Transgenetic studies argue that PrP Sc acts as a template upon which PrP C is refolded into a nascent PrP Sc molecule through a process facilitated by another protein. Miniprions generated in transgenic mice expressing PrP, in which nearly half of the residues were deleted, exhibit unique biological properties and should facilitate structural studies of PrP Sc . While knowledge about prions has profound implications for studies of the structural plasticity of proteins, investigations of prion diseases suggest that new strategies for the prevention and treatment of these disorders may also find application in the more common degenerative diseases.

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Amino acid polymorphisms of PrP with reference to onset of scrapie in Suffolk and Corriedale sheep in Japan

Cited by 145 publications

References 17 publications

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

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

Prion protein gene polymorphisms in sheep with natural scrapie and healthy controls in Norway.

Molecular characterization of proteolytic cleavage sites of the Pseudomonas syringae effector AvrRpt2

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