Acta Neuropathologica

, Volume 121, Issue 1, pp 79–90 | Cite as

Molecular biology and pathology of prion strains in sporadic human prion diseases

  • Pierluigi GambettiEmail author
  • Ignazio Cali
  • Silvio Notari
  • Qingzhong Kong
  • Wen-Quan Zou
  • Witold K. Surewicz


Prion diseases are believed to propagate by the mechanism involving self-perpetuating conformational conversion of the normal form of the prion protein, PrPC, to the misfolded, pathogenic state, PrPSc. One of the most intriguing aspects of these disorders is the phenomenon of prion strains. It is believed that strain properties are fully encoded in distinct conformations of PrPSc. Strains are of practical relevance to human prion diseases as their diversity may explain the unusual heterogeneity of these disorders. The first insight into the molecular mechanisms underlying heterogeneity of human prion diseases was provided by the observation that two distinct disease phenotypes and their associated PrPSc conformers co-distribute with distinct PrP genotypes as determined by the methionine/valine polymorphism at codon 129 of the PrP gene. Subsequent studies identified six possible combinations of the three genotypes (determined by the polymorphic codon 129) and two common PrPSc conformers (named types 1 and 2) as the major determinants of the phenotype in sporadic human prion diseases. This scenario implies that each 129 genotype–PrPSc type combination would be associated with a distinct disease phenotype and prion strain. However, notable exceptions have been found. For example, two genotype–PrPSc type combinations are linked to the same phenotype, and conversely, the same combination was found to be associated with two distinct phenotypes. Furthermore, in some cases, PrPSc conformers naturally associated with distinct phenotypes appear, upon transmission, to lose their phenotype-determining strain characteristics. Currently it seems safe to assume that typical sporadic prion diseases are associated with at least six distinct prion strains. However, the intrinsic characteristics that distinguish at least four of these strains remain to be identified.


Creutzfeldt–Jakob disease Sporadic fatal insomnia Variably protease-sensitive prionopathy 129 polymorphism PrPSc type PrP sequencing 



We are grateful to Dr. Jiri Safar for the critical reading of the manuscript. This research was supported by the National Institutes of Health (NIH) grants AG14359 (to P.G., Q.K. and W.K.S.), AG08702 (to P.G.), NS062787 (to W.Q.Z.), NS44158 (to W.K.S.), NS38604 (to W.K.S.); the Centers for Disease Control and Prevention grant CCU 515004 (to P.G.); the Britton Fund; CJD Foundation, Alliance BioSecure and the University Center on Aging and Health with the support of the McGregor Foundation and the President’s Discretionary Fund (Case Western Reserve University to W.Q.Z.).


  1. 1.
    Angers RC, Kang HE, Napier D et al (2010) Prion strain mutation determined by prion protein conformational compatibility and primary structure. Science 328:1154–1158CrossRefPubMedGoogle Scholar
  2. 2.
    Apetri AC, Vanik DL, Surewicz WK (2005) Polymorphism at residue 129 modulates the conformational conversion of the D178N variant of human prion protein 90-231. Biochemistry 44:15880–15888CrossRefPubMedGoogle Scholar
  3. 3.
    Apostol MI, Sawaya MR, Cascio D, Eisenberg D (2010) Crystallographic studies of PrP segments suggest how structural changes encoded by polymorphism at residue 129 modulate susceptibility to human prion disease. J Biol Chem 285(39):29671–29675Google Scholar
  4. 4.
    Bessen RA, Marsh RF (1992) Identification of two biologically distinct strains of transmissible mink encephalopathy in hamsters. J Gen Virol 73:329–334CrossRefPubMedGoogle Scholar
  5. 5.
    Bishop MT, Will RG, Manson JC (2010) Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties. Proc Natl Acad Sci USA 107:12005–12010CrossRefPubMedGoogle Scholar
  6. 6.
    Breusing N, Grune T (2008) Regulation of proteasome-medicated protein degradation during oxidative stress and aging. Biol Chem 386:203–209CrossRefGoogle Scholar
  7. 7.
    Cali I, Castellani R, Alshekhlee A et al (2009) Co-existence of scrapie prion protein types 1 and 2 in sporadic Creutzfeldt-Jakob disease: its effect on the phenotype and prion-type characteristics. Brain 132:2643–2658CrossRefPubMedGoogle Scholar
  8. 8.
    Cancellotti E, Wiseman F, Tuzi NL et al (2005) Altered glycosylated PrP proteins can have different neuronal trafficking in brain but do not acquire scrapie-like properties. J Biol Chem 280:42909–42918CrossRefPubMedGoogle Scholar
  9. 9.
    Castilla J, Morales R, Saá P et al (2008) Cell-free propagation of prion strains. EMBO J 27:2557–2566CrossRefPubMedGoogle Scholar
  10. 10.
    Chen SG, Zou W, Parchi P, Gambetti P (2000) PrP(Sc) typing by N-terminal sequencing and mass spectrometry. Arch Virol Suppl 16:209–216PubMedGoogle Scholar
  11. 11.
    Collinge J, Sidle KC, Meads J, Ironside J, Hill AF (1996) Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature 383:685–690CrossRefPubMedGoogle Scholar
  12. 12.
    Collinge J, Clarke AR (2007) A general model of prion strains and their pathogenicity. Science 318:930–936CrossRefPubMedGoogle Scholar
  13. 13.
    Collinge J (2010) Prion strain mutation and selection. Science 328:1111–1112CrossRefPubMedGoogle Scholar
  14. 14.
    Deleault NR, Harris BT, Rees JR, Supattapone S (2007) Formation of native prions from minimal components in vitro. Proc Natl Acad Sci USA 104:9741–9746CrossRefPubMedGoogle Scholar
  15. 15.
    Edgeworth JA, Gros N, Alden J et al (2010) Spontaneous generation of mammalian prions. Proc Natl Acad Sci USA 107:14402–14406CrossRefPubMedGoogle Scholar
  16. 16.
    Faucheux BA, Privat N, Brandel JP et al (2009) Loss of cerebellar granule neurons is associated with punctate but not with large focal deposits of prion protein in Creutzfeldt-Jakob disease. J Neuropathol Exp Neurol 68:892–901CrossRefPubMedGoogle Scholar
  17. 17.
    Gambetti P, Kong Q, Zou W, Parchi P, Chen SG (2003) Sporadic and familial CJD: classification and characterisation. Br Med Bull 66:213–239CrossRefPubMedGoogle Scholar
  18. 18.
    Gambetti P, Dong Z, Yuan J et al (2008) A novel human disease with abnormal prion protein sensitive to protease. Ann Neurol 63:697–708CrossRefPubMedGoogle Scholar
  19. 19.
    Gambetti P, Puoti G, Cali I et al (2010) Sporadic Creutzfeldt-Jakob disease. In: Kompoliti K, Verhagen L (eds) Encyclopaedia of movement disorders, 1st edn. Elsevier Oxford, London, UK, pp 263–269Google Scholar
  20. 20.
    Goldfarb LG, Petersen RB, Tabaton M et al (1992) Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. Science 258:806–808CrossRefPubMedGoogle Scholar
  21. 21.
    Gorbunova V, Seluanov A (2005) Making ends meet in old age: DSB repair and aging. Mech Ageing Dev 126:621–628CrossRefPubMedGoogle Scholar
  22. 22.
    Head MW, Bunn TJ, Bishop MT et al (2004) Prion protein heterogeneity in sporadic but not variant Creutzfeldt-Jakob disease: UK cases 1991–2002. Ann Neurol 55:851–859CrossRefPubMedGoogle Scholar
  23. 23.
    Head MW, Knight R, Zeidler M et al (2009) A case of protease sensitive prionopathy in a patient in the UK. Neuropathol Appl Neurobiol 35:628–632CrossRefPubMedGoogle Scholar
  24. 24.
    Heinemann U, Krasnianski A, Meissner B et al (2007) Creutzfeldt-Jakob disease in Germany: a prospective 12-year surveillance. Brain 130:1350–1359CrossRefPubMedGoogle Scholar
  25. 25.
    Hill AF, Desbruslais M, Joiner S et al (1997) The same prion strain causes vCJD and BSE. Nature 389:448–450, 526Google Scholar
  26. 26.
    Hill AF, Joiner S, Wadsworth JD et al (2003) Molecular classification of sporadic Creutzfeldt-Jakob disease. Brain 126:1333–1346CrossRefPubMedGoogle Scholar
  27. 27.
    Hosszu LL, Jackson GS, Trevitt CR et al (2004) The residue 129 polymorphism in human prion protein does not confer susceptibility to Creutzfeldt-Jakob disease by altering the structure or global stability of PrPC. J Biol Chem 279:28515–28521CrossRefPubMedGoogle Scholar
  28. 28.
    Jansen C, Head MW, van Gool WA et al (2010) The first case of protease-sensitive prionopathy (PSPr) in the Netherlands: a patient with an unusual GSS-like clinical phenotype. J Neurol Neurosurg Psychiatry 81(9):1052–1055Google Scholar
  29. 29.
    Jones EM, Surewicz WK (2005) Fibril conformation as the basis of species- and strain-dependent seeding specificity of mammalian prion amyloids. Cell 121:63–72CrossRefPubMedGoogle Scholar
  30. 30.
    Jones EM, Surewicz K, Surewicz WK (2006) Role of N-terminal familial mutations in prion protein fibrillization and prion amyloid propagation in vitro. J Biol Chem 281:8190–8196CrossRefPubMedGoogle Scholar
  31. 31.
    Jones M, Peden AH, Wight D et al (2008) Effects of human PrPSc type and PRNP genotype in an in vitro conversion assay. Neuroreport 19:1783–1786CrossRefPubMedGoogle Scholar
  32. 32.
    Kim JI, Cali I, Surewicz K et al (2010) Mammalian prions generated from bacterially expressed prion protein in the absence of any mammalian cofactors. J Biol Chem 285:14083–14087CrossRefPubMedGoogle Scholar
  33. 33.
    Kirkwood TB, Austad SN (2000) Why do we age? Nature 408:233–238CrossRefPubMedGoogle Scholar
  34. 34.
    Kirschbaum WR (1968) Closing remarks. In: Kirschbaum WR (ed) Jakob-Creutzfeldt disease. 1st edn. Elsevier, New York, p 229Google Scholar
  35. 35.
    Kitamoto T, Mohri S, Ironside JW et al (2002) Follicular dendritic cell of the knock-in mouse provides a new bioassay for human prions. Biochem Biophys Res Commun 294:280–286CrossRefPubMedGoogle Scholar
  36. 36.
    Kobayashi A, Satoh S, Ironside JW, Mohri S, Kitamoto T (2005) Type 1 and type 2 human PrPSc have different aggregation sizes in methionine homozygotes with sporadic, iatrogenic and variant Creutzfeldt-Jakob disease. J Gen Virol 86:237–240CrossRefPubMedGoogle Scholar
  37. 37.
    Kong Q, Surewicz WK, Petersen RB et al (2004) Inherited prion diseases. In: Prusiner SB (ed) Prion biology and diseases, 2nd edn. Cold Spring Harbor Laboratory Press, New York, pp 673–776Google Scholar
  38. 38.
    Korth C, Kaneko K, Groth D et al (2003) Abbreviated incubation times for human prions in mice expressing a chimeric mouse-human prion protein transgene. Proc Natl Acad Sci USA 100:4784–4789CrossRefPubMedGoogle Scholar
  39. 39.
    Krebs B, Bader B, Klehmet J et al (2007) A novel subtype of Creutzfeldt-Jakob disease characterized by a small 6 kDa PrP fragment. Acta Neuropathol 114:195–199CrossRefPubMedGoogle Scholar
  40. 40.
    Lee S, Antony L, Hartmann R et al (2010) Conformational diversity in prion protein variants influences intermolecular beta-sheet formation. EMBO J 29:251–262CrossRefPubMedGoogle Scholar
  41. 41.
    Legname G, Baskakov IV, Nguyen HO et al (2004) Synthetic mammalian prions. Science 305:673–676CrossRefPubMedGoogle Scholar
  42. 42.
    Lewis V, Hill AF, Klug GM et al (2005) Australian sporadic CJD analysis supports endogenous determinants of molecular-clinical profiles. Neurology 65:113–118CrossRefPubMedGoogle Scholar
  43. 43.
    Li J, Browning S, Mahal SP, Oelschlegel AM, Weissmann C (2010) Darwinian evolution of prions in cell culture. Science 327:869–872CrossRefPubMedGoogle Scholar
  44. 44.
    Lugaresi E, Medori R, Montagna P et al (1986) Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med 315:997–1003CrossRefPubMedGoogle Scholar
  45. 45.
    Makarava N, Kovacs GG, Bocharova O et al (2010) Recombinant prion protein induces a new transmissible prion disease in wild-type animals. Acta Neuropathol 119:177–187CrossRefPubMedGoogle Scholar
  46. 46.
    Medori R, Montagna P, Tritschler HJ et al (1992) Fatal familial insomnia: a second kindred with mutation of prion protein gene at codon 178. Neurology 42:669–670PubMedGoogle Scholar
  47. 47.
    Medori R, Tritschler HJ, LeBlanc A et al (1992) Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. N Engl J Med 326:444–449CrossRefPubMedGoogle Scholar
  48. 48.
    Monari L, Chen SG, Brown P et al (1994) Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism. Proc Natl Acad Sci USA 91:2839–2842CrossRefPubMedGoogle Scholar
  49. 49.
    Nonno R, Di Bari MA, Cardone F et al (2006) Efficient transmission and characterization of Creutzfeldt-Jakob disease strains in bank voles. PLoS Pathog 2:e12CrossRefPubMedGoogle Scholar
  50. 50.
    Notari S, Capellari S, Giese A et al (2004) Effects of different experimental conditions on the PrPSc core generated by protease digestion: implications for strain typing and molecular classification of CJD. J Biol Chem 279(16):16797–16804CrossRefPubMedGoogle Scholar
  51. 51.
    Notari S, Capellari S, Langeveld J et al (2007) A refined method for molecular typing reveals that co-occurrence of PrP(Sc) types in Creutzfeldt-Jakob disease is not the rule. Lab Invest 87:1103–1112CrossRefPubMedGoogle Scholar
  52. 52.
    Notari S, Strammiello R, Capellari S et al (2008) Characterization of truncated forms of abnormal prion protein in Creutzfeldt-Jakob disease. J Biol Chem 283:30557–30565CrossRefPubMedGoogle Scholar
  53. 53.
    Palmer MS, Dryden AJ, Hughes JT, Collinge J (1991) Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature 352:340–342CrossRefPubMedGoogle Scholar
  54. 54.
    Pan T, Colucci M, Wong BS et al (2001) Novel differences between two human prion strains revealed by two-dimensional gel electrophoresis. J Biol Chem 276:37284–37288CrossRefPubMedGoogle Scholar
  55. 55.
    Parchi P, Castellani R, Capellari S et al (1996) Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann Neurol 39:767–778CrossRefPubMedGoogle Scholar
  56. 56.
    Parchi P, Giese A, Capellari S et al (1999) Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 46:224–233CrossRefPubMedGoogle Scholar
  57. 57.
    Parchi P, Capellari S, Chin S et al (1999) A subtype of sporadic prion disease mimicking fatal familial insomnia. Neurology 52:1757–1763PubMedGoogle Scholar
  58. 58.
    Parchi P, Zou W, Wang W et al (2000) Genetic influence on the structural variations of the abnormal prion protein. Proc Natl Acad Sci USA 97:10168–10172CrossRefPubMedGoogle Scholar
  59. 59.
    Parchi P, Strammiello R, Notari S et al (2009) Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification. Acta Neuropathol 118:659–671CrossRefPubMedGoogle Scholar
  60. 60.
    Partridge L, Gems D (2002) Mechanisms of ageing: public or private? Nat Rev Genet 3:165–175CrossRefPubMedGoogle Scholar
  61. 61.
    Peretz D, Scott MR, Groth D et al (2001) Strain-specified relative conformational stability of the scrapie prion protein. Protein Sci 10:854–863CrossRefPubMedGoogle Scholar
  62. 62.
    Petkova AT, Leapman RD, Guo Z et al (2005) Self-propagating, molecular-level polymorphism in Alzheimer’s beta-amyloid fibrils. Science 307:262–265CrossRefPubMedGoogle Scholar
  63. 63.
    Piro JR, Harris BT, Nishina K et al (2009) Prion protein glycosylation is not required for strain-specific neurotropism. J Virol 83:5321–5328CrossRefPubMedGoogle Scholar
  64. 64.
    Puoti G, Giaccone G, Rossi G et al (1999) Sporadic Creutzfeldt-Jakob disease: co-occurrence of different types of PrP(Sc) in the same brain. Neurology 53:2173–2176PubMedGoogle Scholar
  65. 65.
    Riek R, Wider G, Billeter M et al (1998) Prion protein NMR structure and familial human spongiform encephalopathies. Proc Natl Acad Sci USA 95:11667–11672CrossRefPubMedGoogle Scholar
  66. 66.
    Russo C, Schettini G, Saido TC et al (2000) Presenilin-1 mutations in Alzheimer’s disease. Nature 405:531–532CrossRefPubMedGoogle Scholar
  67. 67.
    Saborio GP, Permanne B, Soto C (2001) Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 411:810–813CrossRefPubMedGoogle Scholar
  68. 68.
    Safar J, Wille H, Itri V et al (1998) Eight prion strains have PrP(Sc) molecules with different conformations. Nat Med 4:1157–1165CrossRefPubMedGoogle Scholar
  69. 69.
    Schoch G, Seeger H, Bogousslavsky J et al (2006) Analysis of prion strains by PrPSc profiling in sporadic Creutzfeldt-Jakob disease. PLoS Med 3:e14CrossRefPubMedGoogle Scholar
  70. 70.
    Taguchi Y, Mohri S, Ironside JW, Muramoto T, Kitamoto T (2003) Humanized knock-in mice expressing chimeric prion protein showed varied susceptibility to different human prions. Am J Pathol 163:2585–2593PubMedGoogle Scholar
  71. 71.
    Telling GC, Parchi P, DeArmond SJ et al (1996) Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274:2079–2082CrossRefPubMedGoogle Scholar
  72. 72.
    Uro-Coste E, Cassard H, Simon S et al (2008) Beyond PrPres type 1/type 2 dichotomy in Creutzfeldt-Jakob disease. PLoS Pathog 4:e1000029CrossRefGoogle Scholar
  73. 73.
    Wang F, Wang X, Yuan CG, Ma J (2010) Generating a prion with bacterially expressed recombinant prion protein. Science 327:1132–1135CrossRefPubMedGoogle Scholar
  74. 74.
    Weissmann C (2009) Thoughts on mammalian prion strains. Folia Neuropathol 47:104–113PubMedGoogle Scholar
  75. 75.
    Yuan J, Xiao X, McGeehan J et al (2006) Insoluble aggregates and protease-resistant conformers of prion protein in uninfected human brains. J Biol Chem 281:34848–34858CrossRefPubMedGoogle Scholar
  76. 76.
    Yuan J, Dong Z, Guo JP et al (2008) Accessibility of a critical prion protein region involved in strain recognition and its implications for the early detection of prions. Cell Mol Life Sci 65:631–643CrossRefPubMedGoogle Scholar
  77. 77.
    Zou W, Puoti G, Xiao X et al (2010) Protease-sensitive prionopathy: a new sporadic disease of the prion protein. Ann Neurol 68:162–172CrossRefPubMedGoogle Scholar
  78. 78.
    Zou WQ, Langeveld J, Xiao X et al (2010) PrP conformational transitions alter species preference of a PrP-specific antibody. J Biol Chem 285:13874–13884CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Pierluigi Gambetti
    • 1
    Email author
  • Ignazio Cali
    • 1
  • Silvio Notari
    • 1
  • Qingzhong Kong
    • 1
  • Wen-Quan Zou
    • 1
  • Witold K. Surewicz
    • 2
  1. 1.Department of PathologyCase Western Reserve UniversityClevelandUSA
  2. 2.Department of Physiology and Biophysics, School of MedicineCase Western Reserve UniversityClevelandUSA

Personalised recommendations