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Volume 15, Number 12—December 2009

Molecular Model of Prion Transmission to Humans

Michael JonesComments to Author , Darren Wight, Rona Barron, Martin Jeffrey, Jean C. Manson, Christopher Prowse, James W. Ironside, and Mark W. Head
Author affiliations: University of Edinburgh, Edinburgh, Scotland, UK (M. Jones, D. Wight, R. Barron, J. Manson, J.W. Ironside, M.W. Head), Veterinary Laboratory Agency, Edinburgh (M. Jeffrey); Scottish National Blood Transfusion Service, Edinburgh (C. Prowse)

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Summary of the properties of the sources used in PMCA of vCJD, bovine BSE, ovine scrapie, and experimental ovine BSE PrPres*

Seed homogenate Species Bovine† Human‡ Ovine§ Ovine§
Disease BSE vCJD BSE Scrapie
Tissue Brain Brain Brain Brain
PRNP amino acid sequence Bovine Human Ovine Ovine
PRNP polymorphism 140MM 129MM ARQ/ARQ (132MM) ARQ/ARQ (132MM)
PrPd “conformer” BSE BSE BSE Scrapie
Substrate homogenate¶ Species Mouse Mouse Mouse Mouse
Tissue Brain Brain Brain Brain
PrP amino acid sequence Human Human Human Human
PRNP-129 polymorphism MM, MV, and VV MM, MV, and VV MM, MV, and VV MM, MV, and VV
Background genotype 129 Ola prnp−/− 129 Ola prnp−/− 129 Ola prnp−/− 129 Ola prnp−/−

*PMCA, protein misfolding cyclic amplification; vCJD, variant Creutzfeldt-Jakob disease; BSE, bovine spongiform encephalopathy; PrPres, protease-resistant prion protein; PrPd, disease-associated prion protein; MM, methionine homozygous; MV, methionine/valine heterozygous; VV, valine homozygous.
†Bovine brain tissue was sampled from brain tissue taken from a Friesian cow with terminal BSE (11).
‡Human brain tissue (frontal cortex) was sampled from a frozen half brain that had been collected at autopsy with the appropriate consent for tissue retention and research use from a patient methionine homozygous at PRNP codon 129, who received a final diagnosis of definite vCJD by established criteria. Ethical approval for its use in this study was covered by LREC 2000/4/157 (J.W.I.).
§Both the ovine scrapie (12) and ovine BSE (13) brain tissue (hind brain) were sampled from clinically sick sheep. The distinctive disease phenotypes were confirmed by histopathologic, immunohistochemical, and Western blot characteristics.
¶Frozen half brains from inbred transgenic mouse lines expressing human PrP of the 3 major PRNP codon-129 genotypes (MM, MV, VV) were used to prepare substrate homogenates. These mice had identical genetic backgrounds, were produced to express human PrP by direct replacement of the murine PrP gene, and all expressed equivalent amounts of human PrP regardless of the PRNP-129 genotype (14). The transgenic mice were bred under license to the UK Home Office in accordance with the UK Animals (Scientific Procedures) Act of 1986, and the use of brain tissue from these mice was reviewed and approved by the local Ethics Review Committee.

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