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An Amino Acid Substitution Found in Animals with Low Susceptibility to Prion Diseases Confers a Protective Dominant-Negative Effect in Prion-Infected Transgenic Mice

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Abstract

While prion diseases have been described in numerous species, some, including those of the Canidae family, appear to show resistance or reduced susceptibility. A better understanding of the factors underlying prion susceptibility is crucial for the development of effective treatment and control measures. We recently demonstrated resistance to prion infection in mice overexpressing a mutated prion protein (PrP) carrying a specific amino acid substitution characteristic of canids. Here, we show that coexpression of this mutated PrP and wild-type mouse PrP in transgenic mice inoculated with different mouse-adapted prion strains (22 L, ME7, RML, and 301C) significantly increases survival times (by 45 to 113%). These data indicate that this amino acid substitution confers a dominant-negative effect on PrP, attenuating the conversion of PrPC to PrPSc and delaying disease onset without altering the neuropathological properties of the prion strains. Taken together, these findings have important implications for the development of new treatment approaches for prion diseases based on dominant-negative proteins.

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References

  1. Prusiner SB (1998) The prion diseases. Brain Pathol 8(3):499–513

    Article  PubMed  CAS  Google Scholar 

  2. Prusiner SB (1998) Prions. Proc Natl Acad Sci U S A 95(23):13363–13383. https://doi.org/10.1073/pnas.95.23.13363

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Prusiner SB (1982) Novel proteinaceous infectious particles cause scrapie. Science 216(4542):136–144. https://doi.org/10.1126/science.6801762

    Article  PubMed  CAS  Google Scholar 

  4. Smirnovas V, Baron GS, Offerdahl DK, Raymond GJ, Caughey B, Surewicz WK (2011) Structural organization of brain-derived mammalian prions examined by hydrogen-deuterium exchange. Nat Struct Mol Biol 18(4):504–506. https://doi.org/10.1038/nsmb.2035

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Vazquez-Fernandez E, Vos MR, Afanasyev P, Cebey L, Sevillano AM, Vidal E, Rosa I, Renault L et al (2016) The structural architecture of an infectious mammalian prion using electron cryomicroscopy. PLoS Pathog 12(9):e1005835. https://doi.org/10.1371/journal.ppat.1005835

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Fraser H (1976) The pathology of a natural and experimental scrapie. Front Biol 44:267–305

    PubMed  CAS  Google Scholar 

  7. Budka H, Aguzzi A, Brown P, Brucher JM, Bugiani O, Gullotta F, Haltia M, Hauw JJ et al (1995) Neuropathological diagnostic criteria for Creutzfeldt-Jakob disease (CJD) and other human spongiform encephalopathies (prion diseases). Brain Pathol 5(4):459–466. https://doi.org/10.1111/j.1750-3639.1995.tb00625.x

    Article  PubMed  CAS  Google Scholar 

  8. Vidal E, Acin C, Foradada L, Monzon M, Marquez M, Monleon E, Pumarola M, Badiola JJ et al (2009) Immunohistochemical characterisation of classical scrapie neuropathology in sheep. J Comp Pathol 141(2–3):135–146. https://doi.org/10.1016/j.jcpa.2009.04.002

    Article  PubMed  CAS  Google Scholar 

  9. Collins SJ, Lawson VA, Masters CL (2004) Transmissible spongiform encephalopathies. Lancet 363(9402):51–61. https://doi.org/10.1016/S0140-6736(03)15171-9

    Article  PubMed  CAS  Google Scholar 

  10. Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, Poser S, Pocchiari M et al (1996) A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 347(9006):921–925. https://doi.org/10.1016/S0140-6736(96)91412-9

    Article  PubMed  CAS  Google Scholar 

  11. Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, McCardle L, Chree A et al (1997) Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature 389(6650):498–501. https://doi.org/10.1038/39057

    Article  PubMed  CAS  Google Scholar 

  12. Kirkwood JK, Cunningham AA (1994) Epidemiological observations on spongiform encephalopathies in captive wild animals in the British Isles. Vet Rec 135(13):296–303. https://doi.org/10.1136/vr.135.13.296

    Article  PubMed  CAS  Google Scholar 

  13. Kirkwood JK, Cunningham AA, Wells GA, Wilesmith JW, Barnett JE (1993) Spongiform encephalopathy in a herd of greater kudu (Tragelaphus strepsiceros): epidemiological observations. Vet Rec 133(15):360–364. https://doi.org/10.1136/vr.133.15.360

    Article  PubMed  CAS  Google Scholar 

  14. Sigurdson CJ, Miller MW (2003) Other animal prion diseases. Br Med Bull 66(1):199–212. https://doi.org/10.1093/bmb/66.1.199

    Article  PubMed  CAS  Google Scholar 

  15. Fernandez-Borges N, Chianini F, Eraña H, Vidal E, Eaton SL, Pintado B, Finlayson J, Dagleish MP et al (2012) Naturally prion resistant mammals: a utopia? Prion 6(5):425–429. https://doi.org/10.4161/pri.22057

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Fernandez-Borges N, de Castro J, Castilla J (2009) In vitro studies of the transmission barrier. Prion 3(4):220–223. https://doi.org/10.4161/pri.3.4.10500

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Chianini F, Fernandez-Borges N, Vidal E, Gibbard L, Pintado B, de Castro J, Priola SA, Hamilton S et al (2012) Rabbits are not resistant to prion infection. Proc Natl Acad Sci U S A 109(13):5080–5085. https://doi.org/10.1073/pnas.1120076109

    Article  PubMed  PubMed Central  Google Scholar 

  18. Bian J, Khaychuk V, Angers RC, Fernandez-Borges N, Vidal E, Meyerett-Reid C, Kim S, Calvi CL et al (2017) Prion replication without host adaptation during interspecies transmissions. Proc Natl Acad Sci U S A 114(5):1141–1146. https://doi.org/10.1073/pnas.1611891114

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Khan MQ, Sweeting B, Mulligan VK, Arslan PE, Cashman NR, Pai EF, Chakrabartty A (2010) Prion disease susceptibility is affected by beta-structure folding propensity and local side-chain interactions in PrP. Proc Natl Acad Sci U S A 107(46):19808–19813. https://doi.org/10.1073/pnas.1005267107

    Article  PubMed  PubMed Central  Google Scholar 

  20. Vidal E, Fernandez-Borges N, Pintado B, Ordoñez M, Marquez M, Fondevila D, Torres JM, Pumarola M et al (2013) Bovine spongiform encephalopathy induces misfolding of alleged prion-resistant species cellular prion protein without altering its pathobiological features. J Neurosci 33(18):7778–7786. https://doi.org/10.1523/JNEUROSCI.0244-13.2013

    Article  PubMed  CAS  Google Scholar 

  21. Fernández-Borges N, Parra B, Vidal E, Eraña H, Sánchez-Martín MA, de Castro J, Elezgarai SR, Pumarola M, Mayoral T, Castilla J (2017) Unraveling the key to the resistance of canids to prion diseases. PLoS Pathog 13 (11):e1006716. https://doi.org/10.1371/journal.ppat.1006716

  22. Fischer M, Rulicke T, Raeber A, Sailer A, Moser M, Oesch B, Brandner S, Aguzzi A et al (1996) Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO J 15(6):1255–1264

  23. Manson JC, Clarke AR, Hooper ML, Aitchison L, McConnell I, Hope J (1994) 129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal. Mol Neurobiol 8(2–3):121–127. https://doi.org/10.1007/BF02780662

    Article  PubMed  CAS  Google Scholar 

  24. Kang HE, Weng CC, Saijo E, Saylor V, Bian J, Kim S, Ramos L, Angers R et al (2012) Characterization of conformation-dependent prion protein epitopes. J Biol Chem 287(44):37219–37232. https://doi.org/10.1074/jbc.M112.395921

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Fraser H, Dickinson AG (1968) The sequential development of the brain lesion of scrapie in three strains of mice. J Comp Pathol 78(3):301–311. https://doi.org/10.1016/0021-9975(68)90006-6

    Article  PubMed  CAS  Google Scholar 

  26. Schulz-Schaeffer WJ, Tschoke S, Kranefuss N, Drose W, Hause-Reitner D, Giese A, Groschup MH, Kretzschmar HA (2000) The paraffin-embedded tissue blot detects PrP(Sc) early in the incubation time in prion diseases. Am J Pathol 156(1):51–56. https://doi.org/10.1016/S0002-9440(10)64705-0

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Sarasa R, Martinez A, Monleon E, Bolea R, Vargas A, Badiola JJ, Monzon M (2012) Involvement of astrocytes in transmissible spongiform encephalopathies: a confocal microscopy study. Cell Tissue Res 350(1):127–134. https://doi.org/10.1007/s00441-012-1461-1

    Article  PubMed  Google Scholar 

  28. Karapetyan YE, Saa P, Mahal SP, Sferrazza GF, Sherman A, Sales N, Weissmann C, Lasmezas CI (2009) Prion strain discrimination based on rapid in vivo amplification and analysis by the cell panel assay. PLoS One 4(5):e5730. https://doi.org/10.1371/journal.pone.0005730

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Tuzi NL, Cancellotti E, Baybutt H, Blackford L, Bradford B, Plinston C, Coghill A, Hart P et al (2008) Host PrP glycosylation: a major factor determining the outcome of prion infection. PLoS Biol 6(4):e100. https://doi.org/10.1371/journal.pbio.0060100

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Belt PB, Muileman IH, Schreuder BE, Bos-de Ruijter J, Gielkens AL, Smits MA (1995) Identification of five allelic variants of the sheep PrP gene and their association with natural scrapie. J Gen Virol 76(Pt 3):509–517. https://doi.org/10.1099/0022-1317-76-3-509

    Article  PubMed  CAS  Google Scholar 

  31. Westaway D, Zuliani V, Cooper CM, Da Costa M, Neuman S, Jenny AL, Detwiler L, Prusiner SB (1994) Homozygosity for prion protein alleles encoding glutamine-171 renders sheep susceptible to natural scrapie. Genes Dev 8(8):959–969. https://doi.org/10.1101/gad.8.8.959

    Article  PubMed  CAS  Google Scholar 

  32. Clouscard C, Beaudry P, Elsen JM, Milan D, Dussaucy M, Bounneau C, Schelcher F, Chatelain J et al (1995) Different allelic effects of the codons 136 and 171 of the prion protein gene in sheep with natural scrapie. J Gen Virol 76(Pt 8):2097–2101. https://doi.org/10.1099/0022-1317-76-8-2097

    Article  PubMed  CAS  Google Scholar 

  33. Hunter N, Cairns D, Foster JD, Smith G, Goldmann W, Donnelly K (1997) Is scrapie solely a genetic disease? Nature 386(6621):137. https://doi.org/10.1038/386137a0

    Article  PubMed  CAS  Google Scholar 

  34. Shibuya S, Higuchi J, Shin RW, Tateishi J, Kitamoto T (1998) Codon 219 Lys allele of PRNP is not found in sporadic Creutzfeldt-Jakob disease. Ann Neurol 43(6):826–828. https://doi.org/10.1002/ana.410430618

    Article  PubMed  CAS  Google Scholar 

  35. Kaneko K, Zulianello L, Scott M, Cooper CM, Wallace AC, James TL, Cohen FE, Prusiner SB (1997) Evidence for protein X binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation. Proc Natl Acad Sci U S A 94(19):10069–10074. https://doi.org/10.1073/pnas.94.19.10069

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Zulianello L, Kaneko K, Scott M, Erpel S, Han D, Cohen FE, Prusiner SB (2000) Dominant-negative inhibition of prion formation diminished by deletion mutagenesis of the prion protein. J Virol 74(9):4351–4360. https://doi.org/10.1128/JVI.74.9.4351-4360.2000

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Perrier V, Kaneko K, Safar J, Vergara J, Tremblay P, DeArmond SJ, Cohen FE, Prusiner SB et al (2002) Dominant-negative inhibition of prion replication in transgenic mice. Proc Natl Acad Sci U S A 99(20):13079–13084. https://doi.org/10.1073/pnas.182425299

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Lee CI, Yang Q, Perrier V, Baskakov IV (2007) The dominant-negative effect of the Q218K variant of the prion protein does not require protein X. Protein Sci 16(10):2166–2173. https://doi.org/10.1110/ps.072954607

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Stewart P, Campbell L, Skogtvedt S, Griffin KA, Arnemo JM, Tryland M, Girling S, Miller MW et al (2012) Genetic predictions of prion disease susceptibility in carnivore species based on variability of the prion gene coding region. PLoS One 7(12):e50623. https://doi.org/10.1371/journal.pone.0050623

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Prusiner SB, Scott M, Foster D, Pan KM, Groth D, Mirenda C, Torchia M, Yang SL et al (1990) Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell 63(4):673–686. https://doi.org/10.1016/0092-8674(90)90134-Z

    Article  PubMed  CAS  Google Scholar 

  41. Bueler H, Raeber A, Sailer A, Fischer M, Aguzzi A, Weissmann C (1994) High prion and PrPSc levels but delayed onset of disease in scrapie-inoculated mice heterozygous for a disrupted PrP gene. Mol Med 1(1):19–30

    PubMed  CAS  Google Scholar 

  42. Priola SA, Caughey B, Race RE, Chesebro B (1994) Heterologous PrP molecules interfere with accumulation of protease-resistant PrP in scrapie-infected murine neuroblastoma cells. J Virol 68(8):4873–4878

    PubMed  PubMed Central  CAS  Google Scholar 

  43. Bolton DC, Bendheim PE (1988) A modified host protein model of scrapie. CIBA Found Symp 135:164–181

    PubMed  CAS  Google Scholar 

  44. Hope J, Morton LJ, Farquhar CF, Multhaup G, Beyreuther K, Kimberlin RH (1986) The major polypeptide of scrapie-associated fibrils (SAF) has the same size, charge distribution and N-terminal protein sequence as predicted for the normal brain protein (PrP). EMBO J 5(10):2591–2597

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Jahandideh S, Jamalan M, Faridounnia M (2015) Molecular dynamics study of the dominant-negative E219K polymorphism in human prion protein. J Biomol Struct Dyn 33(6):1315–1325. https://doi.org/10.1080/07391102.2014.945486

    Article  PubMed  CAS  Google Scholar 

  46. Geoghegan JC, Miller MB, Kwak AH, Harris BT, Supattapone S (2009) Trans-dominant inhibition of prion propagation in vitro is not mediated by an accessory cofactor. PLoS Pathog 5(7):e1000535. https://doi.org/10.1371/journal.ppat.1000535

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Yuan J, Zhan YA, Abskharon R, Xiao X, Martinez MC, Zhou X, Kneale G, Mikol J et al (2013) Recombinant human prion protein inhibits prion propagation in vitro. Sci Rep 3(1):2911. https://doi.org/10.1038/srep02911

    Article  PubMed  PubMed Central  Google Scholar 

  48. Fraser H, Dickinson AG (1973) Scrapie in mice. Agent-strain differences in the distribution and intensity of grey matter vacuolation. J Comp Pathol 83(1):29–40. https://doi.org/10.1016/0021-9975(73)90024-8

    Article  PubMed  CAS  Google Scholar 

  49. Bruce ME, McConnell I, Fraser H, Dickinson AG (1991) The disease characteristics of different strains of scrapie in Sinc congenic mouse lines: implications for the nature of the agent and host control of pathogenesis. J Gen Virol 72(Pt 3):595–603. https://doi.org/10.1099/0022-1317-72-3-595

    Article  PubMed  CAS  Google Scholar 

  50. Bruce ME (1993) Scrapie strain variation and mutation. Br Med Bull 49(4):822–838. https://doi.org/10.1093/oxfordjournals.bmb.a072649

    Article  PubMed  CAS  Google Scholar 

  51. Baron T, Crozet C, Biacabe AG, Philippe S, Verchere J, Bencsik A, Madec JY, Calavas D et al (2004) Molecular analysis of the protease-resistant prion protein in scrapie and bovine spongiform encephalopathy transmitted to ovine transgenic and wild-type mice. J Virol 78(12):6243–6251. https://doi.org/10.1128/JVI.78.12.6243-6251.2004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Kascsak RJ, Rubenstein R, Merz PA, Carp RI, Wisniewski HM, Diringer H (1985) Biochemical differences among scrapie-associated fibrils support the biological diversity of scrapie agents. J Gen Virol 66(Pt 8):1715–1722. https://doi.org/10.1099/0022-1317-66-8-1715

    Article  PubMed  CAS  Google Scholar 

  53. Sim VL, Caughey B (2009) Ultrastructures and strain comparison of under-glycosylated scrapie prion fibrils. Neurobiol Aging 30(12):2031–2042. https://doi.org/10.1016/j.neurobiolaging.2008.02.016

    Article  PubMed  CAS  Google Scholar 

  54. Atarashi R, Sim VL, Nishida N, Caughey B, Katamine S (2006) Prion strain-dependent differences in conversion of mutant prion proteins in cell culture. J Virol 80(16):7854–7862. https://doi.org/10.1128/JVI.00424-06

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Telling GC, Scott M, Mastrianni J, Gabizon R, Torchia M, Cohen FE, DeArmond SJ, Prusiner SB (1995) Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell 83(1):79–90. https://doi.org/10.1016/0092-8674(95)90236-8

    Article  PubMed  CAS  Google Scholar 

  56. Buschmann A, Biacabe AG, Ziegler U, Bencsik A, Madec JY, Erhardt G, Luhken G, Baron T et al (2004) Atypical scrapie cases in Germany and France are identified by discrepant reaction patterns in BSE rapid tests. J Virol Methods 117(1):27–36. https://doi.org/10.1016/j.jviromet.2003.11.017

    Article  PubMed  CAS  Google Scholar 

  57. Houston F, Goldmann W, Chong A, Jeffrey M, Gonzalez L, Foster J, Parnham D, Hunter N (2003) Prion diseases: BSE in sheep bred for resistance to infection. Nature 423(6939):498. https://doi.org/10.1038/423498a

    Article  PubMed  CAS  Google Scholar 

  58. Fraser H (1979) Neuropathology of scrapie: the precision of the lesions and their diversity. In: Prusiner SB, Hadlow WJ (eds) Slow transmissible diseases of the nervous system, vol 1. Academic Press, New York, pp. 387–406

    Google Scholar 

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Acknowledgments

We thank MINECO for the Severo Ochoa Excellence Accreditation (SEV-2016-0644). The authors would like to thank the following for their support: the IKERBasque Foundation, the staff at the CIC bioGUNE animal facility, Dr. Belén Pintado for the Tga20 mouse embryo rederivation, Dr. Glenn Telling for kindly providing the 5C6 antibody, and Patricia Piñeiro, Silvia Ruiz, and Sonia Gómez for their technical assistance. The authors would also like to acknowledge Sara Gutiérrez for the image editing. Alicia Otero was supported by a research grant from the Government of Aragón (C020/2014) cofinanced by the European Social Fund.

Funding

This work was supported financially by grants from the Spanish (AGL2015-65046-C2-1-R, AGL2015-65560-R, and PCIN-2013-065) and Basque (2014111157) governments.

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Authors and Affiliations

  1. Centro de Encefalopatías y Enfermedades Transmisibles Emergentes, Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain

    Alicia Otero, Rosa Bolea, Carlos Hedman, Belén Marín, Óscar López-Pérez, Tomás Barrio, Marta Monzón & Juan José Badiola

  2. CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160, Derio, Bizkaia, Spain

    Natalia Fernández-Borges, Hasier Eraña & Joaquín Castilla

  3. Laboratorio de Genética Bioquímica (LAGENBIO), Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain

    Óscar López-Pérez

  4. Servicio de Transgénesis, Nucleus, Universidad de Salamanca, Salamanca, Spain

    Manuel A. Sánchez-Martín

  5. IBSAL, Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain

    Manuel A. Sánchez-Martín

  6. IKERBASQUE, Basque Foundation for Science, Bilbao, Bizkaia, Spain

    Joaquín Castilla

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  1. Alicia Otero
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Correspondence to Joaquín Castilla.

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This study was approved by the Ethics Committee for Animal Experiments of the University of Zaragoza (permit number PI32/13) and was performed in accordance with the recommendations for the care and use of experimental animals and with Spanish national law (R.D. 1201/05).

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Otero, A., Bolea, R., Hedman, C. et al. An Amino Acid Substitution Found in Animals with Low Susceptibility to Prion Diseases Confers a Protective Dominant-Negative Effect in Prion-Infected Transgenic Mice. Mol Neurobiol 55, 6182–6192 (2018). https://doi.org/10.1007/s12035-017-0832-8

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