Human prion protein with valine 129 prevents expression of variant CJD phenotype.
Variant Creutzfeldt-Jakob disease (vCJD) is a unique and highly distinctive clinicopathological and molecular phenotype of human prion disease associated with infection with bovine spongiform encephalopathy (BSE)-like prions. Here, we found that generation of this phenotype in transgenic mice required expression of human prion protein (PrP) with methionine 129. Expression of human PrP with valine 129 resulted in a distinct phenotype and, remarkably, persistence of a barrier to transmission of BSE-derived prions on subpassage. Polymorphic residue 129 of human PrP dictated propagation of distinct prion strains after BSE prion infection. Thus, primary and secondary human infection with BSE-derived prions may result in sporadic CJD-like or novel phenotypes in addition to vCJD, depending on the genotype of the prion source and the recipient.
Wadsworth
Jonathan D F
JD
Medical Research Council (MRC) Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
Asante
Emmanuel A
EA
Desbruslais
Melanie
M
Linehan
Jacqueline M
JM
Joiner
Susan
S
Gowland
Ian
I
Welch
Julie
J
Stone
Lisa
L
Lloyd
Sarah E
SE
Hill
Andrew F
AF
Brandner
Sebastian
S
Collinge
John
J
D000682:Amyloid / Q000235:genetics; D000818:Animals; D001921:Brain / Q000473:pathology; D002417:Cattle; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000635:transmission; D016643:Encephalopathy, Bovine Spongiform / Q000473:pathology / Q000635:transmission; D006801:Humans; D008715:Methionine; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011110:Polymorphism, Genetic; D018621:PrPC Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018620:PrPSc Proteins / Q000378:metabolism / Q000472:pathogenicity*; D000072002:Prion Proteins; D011328:Prions; D011487:Protein Conformation; D011498:Protein Precursors / Q000235:genetics; D014633:Valine
D000682:Amyloid; C512656:PRNP protein, human; D018621:PrPC Proteins; D018620:PrPSc Proteins; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; D011498:Protein Precursors; D008715:Methionine; D014633:Valine