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Volume 23, Number 9—September 2017

Protective Effect of Val129-PrP against Bovine Spongiform Encephalopathy but not Variant Creutzfeldt-Jakob Disease

Natalia Fernández-Borges1, Juan Carlos Espinosa1, Alba Marín-Moreno, Patricia Aguilar-Calvo, Emmanuel A. Asante, Tetsuyuki Kitamoto, Shirou Mohri, Olivier Andréoletti, and Juan María TorresComments to Author 
Author affiliations: Centro de Investigación en Sanidad Animal, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (CISA-INIA); Valdeolmos, Madrid, Spain (N. Fernández-Borges, J.C. Espinosa, A. Marín-Moreno, P. Aguilar-Calvo, J.M. Torres); MRC Prion Unit, Department of Neurodegenerative Disease, University College London, Institute of Neurology, London, UK (E.A. Asante); Tohoku University Graduate School of Medicine, Sendai, Japan (T. Kitamoto, S. Mohri); UMR INRA ENVT 1225, Interactions Hôtes Agents Pathogènes, Ecole Nationale Vétérinaire de Toulouse, Toulouse, France (O. Andréoletti)

Main Article

Figure 3

Biochemical comparison of brain protease-resistant prion protein (PrPres) detected in transgenic mice expressing prion protein Met129, and Val129 mice and inoculated with vCJD brain homogenate. Similar quantities of PrPres were loaded for adequate comparison, and immunoblots were detected by using Sha31 monoclonal antibody. Lanes 4 and 6 show passages from this study; lane 5 shows sample codification I-10629, and lane 7, sample codification I-11724 from the MRC Prion Unit in the United Kingdom (

Figure 3. Biochemical comparison of brain protease-resistant prion protein (PrPres) detected in transgenic mice expressing prion protein Met129, and Val129 mice and inoculated with vCJD brain homogenate. Similar quantities of PrPres were loaded for adequate comparison, and immunoblots were detected by using Sha31 monoclonal antibody. Lanes 4 and 6 show passages from this study; lane 5 shows sample codification I-10629 and lane 7 sample codification I-11724 from the MRC Prion Unit in the United Kingdom (27); lane 8 shows sample codification #139-A5603 from Tohoku University Graduate School of Medicine, Sendai, Japan (30). The original vCJD isolate (Hu-vCJD2) used for mouse inoculations in this study was also included on the blot (lanes 3 and 9); sCJD MM1 (lane 1) and VV2 (lane 2) isolates were included for biochemical comparative purposes. Molecular weight (MW) in kDa is shown. CJD, Creutzfeldt-Jakob disease; sCJD, sporadic CJD; vCJD, variant CJD.

Main Article

  1. Collinge  J, Sidle  KC, Meads  J, Ironside  J, Hill  AF. Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature. 1996;383:68590. DOIPubMed
  2. Hill  AF, Desbruslais  M, Joiner  S, Sidle  KC, Gowland  I, Collinge  J, et al. The same prion strain causes vCJD and BSE. Nature. 1997;389:44850, 526. DOIPubMed
  3. Bruce  ME, Will  RG, Ironside  JW, McConnell  I, Drummond  D, Suttie  A, et al. Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature. 1997;389:498501. DOIPubMed
  4. Llewelyn  CA, Hewitt  PE, Knight  RS, Amar  K, Cousens  S, Mackenzie  J, et al. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet. 2004;363:41721. DOIPubMed
  5. Peden  AH, Head  MW, Ritchie  DL, Bell  JE, Ironside  JW. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet. 2004;364:5279. DOIPubMed
  6. Wroe  SJ, Pal  S, Siddique  D, Hyare  H, Macfarlane  R, Joiner  S, et al. Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt-Jakob disease associated with blood transfusion: a case report. Lancet. 2006;368:20617. DOIPubMed
  7. Peden  A, McCardle  L, Head  MW, Love  S, Ward  HJ, Cousens  SN, et al. Variant CJD infection in the spleen of a neurologically asymptomatic UK adult patient with haemophilia. Haemophilia. 2010;16:296304 . DOIPubMed
  8. Prusiner  SB, Scott  MR, DeArmond  SJ, Cohen  FE. Prion protein biology. Cell. 1998;93:33748. DOIPubMed
  9. Prusiner  SB. Prions. Proc Natl Acad Sci U S A. 1998;95:1336383. DOIPubMed
  10. Collinge  J. Prion diseases of humans and animals: their causes and molecular basis. Annu Rev Neurosci. 2001;24:51950. DOIPubMed
  11. Will  RG, Ironside  JW, Zeidler  M, Cousens  SN, Estibeiro  K, Alperovitch  A, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet. 1996;347:9215. DOIPubMed
  12. Parchi  P, Castellani  R, Capellari  S, Ghetti  B, Young  K, Chen  SG, et al. Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann Neurol. 1996;39:76778. DOIPubMed
  13. Hill  AF, Joiner  S, Wadsworth  JD, Sidle  KC, Bell  JE, Budka  H, et al. Molecular classification of sporadic Creutzfeldt-Jakob disease. Brain. 2003;126:133346. DOIPubMed
  14. Torres  JM, Espinosa  JC, Aguilar-Calvo  P, Herva  ME, Relaño-Ginés  A, Villa-Diaz  A, et al. Elements modulating the prion species barrier and its passage consequences. PLoS One. 2014;9:e89722. DOIPubMed
  15. Wadsworth  JD, Collinge  J. Update on human prion disease. Biochim Biophys Acta. 2007;1772:598–609.
  16. Palmer  MS, Dryden  AJ, Hughes  JT, Collinge  J. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature. 1991;352:3402. DOIPubMed
  17. Collinge  J, Palmer  MS, Dryden  AJ. Genetic predisposition to iatrogenic Creutzfeldt-Jakob disease. Lancet. 1991;337:14412. DOIPubMed
  18. Mead  S, Stumpf  MP, Whitfield  J, Beck  JA, Poulter  M, Campbell  T, et al. Balancing selection at the prion protein gene consistent with prehistoric kurulike epidemics. Science. 2003;300:6403. DOIPubMed
  19. Baker  HE, Poulter  M, Crow  TJ, Frith  CD, Lofthouse  R, Ridley  RM, et al. Aminoacid polymorphism in human prion protein and age at death in inherited prion disease. Lancet. 1991;337:1286. DOIPubMed
  20. Poulter  M, Baker  HF, Frith  CD, Leach  M, Lofthouse  R, Ridley  RM, et al. Inherited prion disease with 144 base pair gene insertion. 1. Genealogical and molecular studies. Brain. 1992;115:67585. DOIPubMed
  21. Will  RG, Zeidler  M, Stewart  GE, Macleod  MA, Ironside  JW, Cousens  SN, et al. Diagnosis of new variant Creutzfeldt-Jakob disease. Ann Neurol. 2000;47:57582. DOIPubMed
  22. Bishop  MT, Diack  AB, Ritchie  DL, Ironside  JW, Will  RG, Manson  JC. Prion infectivity in the spleen of a PRNP heterozygous individual with subclinical variant Creutzfeldt-Jakob disease. Brain. 2013;136:113945. DOIPubMed
  23. Hilton  DA, Ghani  AC, Conyers  L, Edwards  P, McCardle  L, Ritchie  D, et al. Prevalence of lymphoreticular prion protein accumulation in UK tissue samples. J Pathol. 2004;203:7339. DOIPubMed
  24. Ironside  JW, Bishop  MT, Connolly  K, Hegazy  D, Lowrie  S, Le Grice  M, et al. Variant Creutzfeldt-Jakob disease: prion protein genotype analysis of positive appendix tissue samples from a retrospective prevalence study. BMJ. 2006;332:11868. DOIPubMed
  25. Gill  ON, Spencer  Y, Richard-Loendt  A, Kelly  C, Dabaghian  R, Boyes  L, et al. Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey. BMJ. 2013;347(oct15 5):f5675. DOIPubMed
  26. Asante  EA, Linehan  JM, Desbruslais  M, Joiner  S, Gowland  I, Wood  AL, et al. BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein. EMBO J. 2002;21:635866. DOIPubMed
  27. Wadsworth  JD, Asante  EA, Desbruslais  M, Linehan  JM, Joiner  S, Gowland  I, et al. Human prion protein with valine 129 prevents expression of variant CJD phenotype. Science. 2004;306:17936. DOIPubMed
  28. Asante  EA, Linehan  JM, Gowland  I, Joiner  S, Fox  K, Cooper  S, et al. Dissociation of pathological and molecular phenotype of variant Creutzfeldt-Jakob disease in transgenic human prion protein 129 heterozygous mice. Proc Natl Acad Sci U S A. 2006;103:1075964. DOIPubMed
  29. Bishop  MT, Hart  P, Aitchison  L, Baybutt  HN, Plinston  C, Thomson  V, et al. Predicting susceptibility and incubation time of human-to-human transmission of vCJD. Lancet Neurol. 2006;5:3938. DOIPubMed
  30. Takeuchi  A, Kobayashi  A, Ironside  JW, Mohri  S, Kitamoto  T. Characterization of variant Creutzfeldt-Jakob disease prions in prion protein-humanized mice carrying distinct codon 129 genotypes. J Biol Chem. 2013;288:2165966. DOIPubMed
  31. Padilla  D, Béringue  V, Espinosa  JC, Andreoletti  O, Jaumain  E, Reine  F, et al. Sheep and goat BSE propagate more efficiently than cattle BSE in human PrP transgenic mice. PLoS Pathog. 2011;7:e1001319 . DOIPubMed
  32. Espinosa  JC, Herva  ME, Andréoletti  O, Padilla  D, Lacroux  C, Cassard  H, et al. Transgenic mice expressing porcine prion protein resistant to classical scrapie but susceptible to sheep bovine spongiform encephalopathy and atypical scrapie. Emerg Infect Dis. 2009;15:121421. DOIPubMed
  33. Castilla  J, Gutiérrez Adán  A, Brun  A, Pintado  B, Ramírez  MA, Parra  B, et al. Early detection of PrPres in BSE-infected bovine PrP transgenic mice. Arch Virol. 2003;148:67791. DOIPubMed
  34. Castilla  J, Gutiérrez-Adán  A, Brun  A, Doyle  D, Pintado  B, Ramírez  MA, et al. Subclinical bovine spongiform encephalopathy infection in transgenic mice expressing porcine prion protein. J Neurosci. 2004;24:50639. DOIPubMed
  35. Aguilar-Calvo  P, Fast  C, Tauscher  K, Espinosa  JC, Groschup  MH, Nadeem  M, et al. Effect of Q211 and K222 PRNP polymorphic variants in the susceptibility of goats to oral infection with goat bovine spongiform encephalopathy. J Infect Dis. 2015;212:66472. DOIPubMed
  36. Foster  JD, Hope  J, Fraser  H. Transmission of bovine spongiform encephalopathy to sheep and goats. Vet Rec. 1993;133:33941. DOIPubMed
  37. Goldmann  W, Martin  T, Foster  J, Hughes  S, Smith  G, Hughes  K, et al. Novel polymorphisms in the caprine PrP gene: a codon 142 mutation associated with scrapie incubation period. J Gen Virol. 1996;77:288591. DOIPubMed
  38. Eloit  M, Adjou  K, Coulpier  M, Fontaine  JJ, Hamel  R, Lilin  T, et al. BSE agent signatures in a goat. Vet Rec. 2005;156:5234. DOIPubMed
  39. Cooper  JK, Ladhani  K, Minor  PD. Reference materials for the evaluation of pre-mortem variant Creutzfeldt-Jakob disease diagnostic assays. Vox Sang. 2007;92:30210.PubMed
  40. Cassard  H, Torres  JM, Lacroux  C, Douet  JY, Benestad  SL, Lantier  F, et al. Evidence for zoonotic potential of ovine scrapie prions. Nat Commun. 2014;5:5821. DOIPubMed
  41. Notari  S, Xiao  X, Espinosa  JC, Cohen  Y, Qing  L, Aguilar-Calvo  P, et al. Transmission characteristics of variably protease-sensitive prionopathy. Emerg Infect Dis. 2014;20:200614. DOIPubMed
  42. Féraudet  C, Morel  N, Simon  S, Volland  H, Frobert  Y, Créminon  C, et al. Screening of 145 anti-PrP monoclonal antibodies for their capacity to inhibit PrPSc replication in infected cells. J Biol Chem. 2005;280:1124758. DOIPubMed
  43. Andréoletti  O, Berthon  P, Levavasseur  E, Marc  D, Lantier  F, Monks  E, et al. Phenotyping of protein-prion (PrPsc)-accumulating cells in lymphoid and neural tissues of naturally scrapie-affected sheep by double-labeling immunohistochemistry. J Histochem Cytochem. 2002;50:135770. DOIPubMed
  44. Fraser  H, Dickinson  AG. The sequential development of the brain lesion of scrapie in three strains of mice. J Comp Pathol. 1968;78:30111. DOIPubMed
  45. Andréoletti  O, Simon  S, Lacroux  C, Morel  N, Tabouret  G, Chabert  A, et al. PrPSc accumulation in myocytes from sheep incubating natural scrapie. Nat Med. 2004;10:5913. DOIPubMed
  46. Wadsworth  JD, Powell  C, Beck  JA, Joiner  S, Linehan  JM, Brandner  S, et al. Molecular diagnosis of human prion disease. Methods Mol Biol. 2008;459:197227. DOIPubMed
  47. Vidal  E, Fernández-Borges  N, Pintado  B, Ordóñez  M, Márquez  M, Fondevila  D, et al. Bovine spongiform encephalopathy induces misfolding of alleged prion-resistant species cellular prion protein without altering its pathobiological features. J Neurosci. 2013;33:777886. DOIPubMed
  48. de Marco  MF, Linehan  J, Gill  ON, Clewley  JP, Brandner  S. Large-scale immunohistochemical examination for lymphoreticular prion protein in tonsil specimens collected in Britain. J Pathol. 2010;222:3807. DOIPubMed
  49. Collinge  J. Medicine. Prion strain mutation and selection. Science. 2010;328:11112. DOIPubMed
  50. Douet  JY, Zafar  S, Perret-Liaudet  A, Lacroux  C, Lugan  S, Aron  N, et al. Detection of infectivity in blood of persons with variant and sporadic Creutzfeldt-Jakob disease. Emerg Infect Dis. 2014;20:1147. DOIPubMed

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1These authors contributed equally to this article.

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