Skip to main content

Advertisement

Log in

Phenotypic variability of sporadic human prion disease and its molecular basis: past, present, and future

  • Review
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Human prion diseases are rare neurodegenerative disorders related to prion protein misfolding that can occur as sporadic, familial or acquired forms. In comparison to other more common neurodegenerative disorders, prion diseases show a wider range of phenotypic variation and largely transmit to experimental animals, a feature that led to the isolation and characterization of different strains of the transmissible agent or prion with distinct biological properties. Biochemically distinct PrPSc types have been demonstrated which differ in their size after proteinase cleavage, glycosylation pattern, and possibly other features related to their conformation. These PrPSc types, possibly enciphering the prion strains, together with the naturally occurring polymorphism at codon 129 in the prion protein gene have a major influence on the disease phenotype. In the sporadic form, the most common but perhaps least understood form of human prion disease, there are at least six major combinations of codon 129 genotype and prion protein isotype, which are significantly related to distinctive clinical–pathological subgroups of the disease. In this review, we provide an update on the current knowledge and classification of the disease subtypes of the sporadic human prion diseases as defined by molecular features and pathological changes. Furthermore, we discuss the molecular basis of phenotypic variability taking into account the results of recent transmission studies that shed light on the extent of prion strain variation in humans.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Adams H, Beck E, Shenkin AM (1974) Creutzfeldt–Jakob disease: further similarities with kuru. J Neurol Neurosurg Psychiatry 37:195–200

    Article  CAS  PubMed  Google Scholar 

  2. Alema G, Bignami A (1959) Subacute degenerative presenile polioencephalopathy with akinetic stupor and decorticate rigidity with myoclonus (“myoclonic” variety of the Jakob–Creutzfeldt disease). Riv Sper Freniatr Med Leg Alien Ment 83(4 Suppl):1485–1623

    Google Scholar 

  3. Aucouturier P, Kascsak RJ, Frangione B, Wisniewski T (1999) Biochemical and conformational variability of human prion strains in sporadic Creutzfeldt–Jakob disease. Neurosci Lett 274:33–36

    Article  CAS  PubMed  Google Scholar 

  4. Baker CA, Lu ZY, Zaitsev I, Manuelidis L (1999) Microglial activation varies in different models of Creutzfeldt–Jakob disease. J Virol 73:5089–5097

    CAS  PubMed  Google Scholar 

  5. Baron TG, Madec JY, Calavas D, Richard Y, Barillet F (2000) Comparison of French natural scrapie isolates with bovine spongiform encephalopathy and experimental scrapie infected sheep. Neurosci Lett 284:175–178

    Article  CAS  PubMed  Google Scholar 

  6. Beck JA, Mead S, Campbell TA, Dickinson A, Wientjens DP, Croes EA, Van Duijn CM, Collinge J (2001) Two-octapeptide repeat deletion of prion protein associated with rapidly progressive dementia. Neurology 57:354–356

    CAS  PubMed  Google Scholar 

  7. Berciano J, Berciano MT, Polo JM, Figols J, Ciudad J, Lafarga M (1990) Creutzfeldt–Jakob disease with severe involvement of cerebral white matter and cerebellum. Virchows Arch A Pathol Anat Histopathol 417:533–538

    Article  CAS  PubMed  Google Scholar 

  8. Bishop MT, Will RG, Manson JC (2010) Defining sporadic Creutzfeldt–Jakob disease strains and their transmission properties. Proc Natl Acad Sci USA 107:12005–12010

    Article  CAS  PubMed  Google Scholar 

  9. Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, Fraser PE, Kruck T, von Bohlen A, Schulz-Schaeffer W, Giese A, Westaway D, Kretzschmar H (1997) The cellular prion protein binds copper in vivo. Nature 390:684–687

    Article  CAS  PubMed  Google Scholar 

  10. Brown P, Cathala F, Castaigne P, Gajdusek DC (1986) Creutzfeldt–Jakob disease: clinical analysis of a consecutive series of 230 neuropathologically verified cases. Ann Neurol 20:597–602

    Article  CAS  PubMed  Google Scholar 

  11. Brown P, Wolff A, Gajdusek DC (1990) A simple and effective method for inactivating virus infectivity in formalin-fixed tissue samples from patients with Creutzfeldt–Jakob disease. Neurology 40:887–890

    CAS  PubMed  Google Scholar 

  12. Brownell B, Oppenheimer DR (1965) An ataxic form of subacute presenile polioencephalopathy (Creutzfeldt–Jakob Disease). J Neurol Neurosurg Psychiatry 28:350–361

    Article  CAS  PubMed  Google Scholar 

  13. Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, McCardle L, Chree A, Hope J, Birkett C, Cousens S, Fraser H, Bostock CJ (1997) Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature 389:498–501

    Article  CAS  PubMed  Google Scholar 

  14. Cali I, Castellani R, Alshekhlee A, Cohen Y, Blevins J, Yuan J, Langeveld JP, Parchi P, Safar JG, Zou WQ, Gambetti P (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 132:2643–2658

    Article  PubMed  Google Scholar 

  15. Cali I, Castellani R, Yuan J, Al-Shekhlee A, Cohen ML, Xiao X, Moleres FJ, Parchi P, Zou WQ, Gambetti P (2006) Classification of sporadic Creutzfeldt–Jakob disease revisited. Brain 129:2266–2277

    Article  PubMed  Google Scholar 

  16. Cancellotti E, Bradford BM, Tuzi NL, Hickey RD, Brown D, Brown KL, Barron RM, Kisielewski D, Piccardo P, Manson JC (2010) Glycosylation of PrPC determines timing of neuroinvasion and targeting in the brain following transmissible spongiform encephalopathy infection by a peripheral route. J Virol 84:3464–3475

    Article  CAS  PubMed  Google Scholar 

  17. Capellari S, Parchi P, Russo CM, Sanford J, Sy MS, Gambetti P, Petersen RB (2000) Effect of the E200K mutation on prion protein metabolism. Comparative study of a cell model and human brain. Am J Pathol 157:613–622

    CAS  PubMed  Google Scholar 

  18. Capellari S, Parchi P, Wolff BD, Campbell J, Atkinson R, Posey DM, Petersen RB, Gambetti P (2002) Creutzfeldt–Jakob disease associated with a deletion of two repeats in the prion protein gene. Neurology 59:1628–1630

    CAS  PubMed  Google Scholar 

  19. Castellani RJ, Colucci M, Xie Z, Zou W, Li C, Parchi P, Capellari S, Pastore M, Rahbar MH, Chen SG, Gambetti P (2004) Sensitivity of 14-3-3 protein test varies in subtypes of sporadic Creutzfeldt–Jakob disease. Neurology 63:436–442

    CAS  PubMed  Google Scholar 

  20. Caughey B, Raymond GJ, Kocisko DA, Lansbury PT Jr (1997) Scrapie infectivity correlates with converting activity, protease resistance, and aggregation of scrapie-associated prion protein in guanidine denaturation studies. J Virol 71:4107–4110

    CAS  PubMed  Google Scholar 

  21. Chou SM, Martin JD (1971) Kuru-plaques in a case of Creutzfeldt–Jakob disease. Acta Neuropathol 17:150–155

    Article  CAS  PubMed  Google Scholar 

  22. 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 383:685–690

    Article  CAS  PubMed  Google Scholar 

  23. Collins SJ, Sanchez-Juan P, Masters CL, Klug GM, van Duijn C, Poleggi A, Pocchiari M, Almonti S, Cuadrado-Corrales N, de Pedro-Cuesta J, Budka H, Gelpi E, Glatzel M, Tolnay M, Hewer E, Zerr I, Heinemann U, Kretszchmar HA, Jansen GH, Olsen E, Mitrova E, Alperovitch A, Brandel JP, Mackenzie J, Murray K, Will RG (2006) Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt–Jakob disease. Brain 129:2278–2287

    Article  CAS  PubMed  Google Scholar 

  24. Cruz-Sanchez F, Lafuente J, Gertz HJ, Stoltenburg-Didinger G (1987) Spongiform encephalopathy with extensive involvement of white matter. J Neurol Sci 82:81–87

    Article  CAS  PubMed  Google Scholar 

  25. de Silva R, Ironside JW, McCardle L, Esmonde T, Bell J, Will R, Windl O, Dempster M, Estibeiro P, Lathe R (1994) Neuropathological phenotype and ‘prion protein’ genotype correlation in sporadic Creutzfeldt–Jakob disease. Neurosci Lett 179:50–52

    Article  PubMed  Google Scholar 

  26. DeArmond SJ, Sanchez H, Yehiely F, Qiu Y, Ninchak-Casey A, Daggett V, Camerino AP, Cayetano J, Rogers M, Groth D, Torchia M, Tremblay P, Scott MR, Cohen FE, Prusiner SB (1997) Selective neuronal targeting in prion disease. Neuron 19:1337–1348

    Article  CAS  PubMed  Google Scholar 

  27. Doh-ura K, Kitamoto T, Sakaki Y, Tateishi J (1991) CJD discrepancy. Nature 353:801–802

    Article  CAS  PubMed  Google Scholar 

  28. Endo T, Groth D, Prusiner SB, Kobata A (1989) Diversity of oligosaccharide structures linked to asparagines of the scrapie prion protein. Biochemistry 28:8380–8388

    Article  CAS  PubMed  Google Scholar 

  29. Garcin RBS, Khochneviss AA (1963) Le syndrome de Creutzfeldt–Jakob et les syndromes corticotrices du presenium (à l’occasion d’ observations anatomo-cliniques). Rev Neurol (Paris) 109:419–441

    Google Scholar 

  30. Giese A, Brown DR, Groschup MH, Feldmann C, Haist I, Kretzschmar HA (1998) Role of microglia in neuronal cell death in prion disease. Brain Pathol 8:449–457

    Article  CAS  PubMed  Google Scholar 

  31. Gmitterova K, Heinemann U, Bodemer M, Krasnianski A, Meissner B, Kretzschmar HA, Zerr I (2009) 14-3-3 CSF levels in sporadic Creutzfeldt–Jakob disease differ across molecular subtypes. Neurobiol Aging 30:1842–1850

    Article  CAS  PubMed  Google Scholar 

  32. Gomori AJ, Partnow MJ, Horoupian DS, Hirano A (1973) The ataxic form of Creutzfeldt–Jakob disease. Arch Neurol 29:318–323

    CAS  PubMed  Google Scholar 

  33. Graeber MB, Streit WJ (2010) Microglia: biology and pathology. Acta Neuropathol 119:89–105

    Article  PubMed  Google Scholar 

  34. Haik S, Galanaud D, Linguraru MG, Peoc’h K, Privat N, Faucheux BA, Ayache N, Hauw JJ, Dormont D, Brandel JP (2008) In vivo detection of thalamic gliosis: a pathoradiologic demonstration in familial fatal insomnia. Arch Neurol 65:545–549

    Article  PubMed  Google Scholar 

  35. Hamaguchi T, Kitamoto T, Sato T, Mizusawa H, Nakamura Y, Noguchi M, Furukawa Y, Ishida C, Kuji I, Mitani K, Murayama S, Kohriyama T, Katayama S, Yamashita M, Yamamoto T, Udaka F, Kawakami A, Ihara Y, Nishinaka T, Kuroda S, Suzuki N, Shiga Y, Arai H, Maruyama M, Yamada M (2005) Clinical diagnosis of MM2-type sporadic Creutzfeldt–Jakob disease. Neurology 64:643–648

    CAS  PubMed  Google Scholar 

  36. Head MW, Bunn TJ, Bishop MT, McLoughlin V, Lowrie S, McKimmie CS, Williams MC, McCardle L, MacKenzie J, Knight R, Will RG, Ironside JW (2004) Prion protein heterogeneity in sporadic but not variant Creutzfeldt–Jakob disease: UK cases 1991–2002. Ann Neurol 55:851–859

    Article  CAS  PubMed  Google Scholar 

  37. Head MW, Ironside JW (2009) Sporadic Creutzfeldt–Jakob disease: discrete subtypes or a spectrum of disease? Brain 132:2627–2629

    Article  PubMed  Google Scholar 

  38. Heidenhain A (1929) Klinische und anatomische Untersuchungen über eine eigenartige organische Erkrankung des Zentralnervensystems im Praesenium. Z Ges Neurol Psychiatr 118:49–114

    Article  Google Scholar 

  39. Herms J, Tings T, Gall S, Madlung A, Giese A, Siebert H, Schurmann P, Windl O, Brose N, Kretzschmar H (1999) Evidence of presynaptic location and function of the prion protein. J Neurosci 19:8866–8875

    CAS  PubMed  Google Scholar 

  40. Hill AF, Desbruslais M, Joiner S, Sidle KC, Gowland I, Collinge J, Doey LJ, Lantos P (1997) The same prion strain causes vCJD and BSE. Nature 389:448–450, 526

    Google Scholar 

  41. Hill AF, Joiner S, Beck JA, Campbell TA, Dickinson A, Poulter M, Wadsworth JD, Collinge J (2006) Distinct glycoform ratios of protease resistant prion protein associated with PRNP point mutations. Brain 129:676–685

    Article  PubMed  Google Scholar 

  42. Hornshaw MP, McDermott JR, Candy JM, Lakey JH (1995) Copper binding to the N-terminal tandem repeat region of mammalian and avian prion protein: structural studies using synthetic peptides. Biochem Biophys Res Commun 214:993–999

    Article  CAS  PubMed  Google Scholar 

  43. Hsiao K, Dlouhy SR, Farlow MR, Cass C, Da Costa M, Conneally PM, Hodes ME, Ghetti B, Prusiner SB (1992) Mutant prion proteins in Gerstmann-Straussler-Scheinker disease with neurofibrillary tangles. Nat Genet 1:68–71

    Article  CAS  PubMed  Google Scholar 

  44. Jakob A (1921) Über eigenartige Erkrankungen des Zentralnervensystems mit bemerkenswertem anatomischem Befunde (spastische Pseurosklerose-Encephalomyelopathie mit disseminierten Degenerationsherden). Dtsch Z Nervenheilkd 70:132–146

    Google Scholar 

  45. Jellinger K, Heiss WD, Deisenhammer E (1974) The ataxic (cerebellar) form of Creutzfeldt–Jakob disease. J Neurol 207:289–305

    Article  CAS  PubMed  Google Scholar 

  46. Jeong BH, Nam JH, Lee YJ, Lee KH, Jang MK, Carp RI, Lee HD, Ju YR, Ahn Jo S, Park KY, Kim YS (2004) Polymorphisms of the prion protein gene (PRNP) in a Korean population. J Hum Genet 49:319–324

    Article  CAS  PubMed  Google Scholar 

  47. Jones HR Jr, Hedley-Whyte ET, Freidberg SR, Baker RA (1985) Ataxic Creutzfeldt–Jakob disease: diagnostic techniques and neuropathologic observations in early disease. Neurology 35:254–257

    PubMed  Google Scholar 

  48. Kitamoto T, Mohri S, Ironside JW, Miyoshi I, Tanaka T, Kitamoto N, Itohara S, Kasai N, Katsuki M, Higuchi J, Muramoto T, Shin RW (2002) Follicular dendritic cell of the knock-in mouse provides a new bioassay for human prions. Biochem Biophys Res Commun 294:280–286

    Article  CAS  PubMed  Google Scholar 

  49. Kitamoto T, Ogomori K, Tateishi J, Prusiner SB (1987) Formic acid pretreatment enhances immunostaining of cerebral and systemic amyloids. Lab Invest 57:230–236

    CAS  PubMed  Google Scholar 

  50. Kitamoto T, Shin RW, Doh-ura K, Tomokane N, Miyazono M, Muramoto T, Tateishi J (1992) Abnormal isoform of prion proteins accumulates in the synaptic structures of the central nervous system in patients with Creutzfeldt–Jakob disease. Am J Pathol 140:1285–1294

    CAS  PubMed  Google Scholar 

  51. Kitamoto T, Tateishi J (1994) Human prion diseases with variant prion protein. Philos Trans R Soc Lond B Biol Sci 343:391–398

    Article  CAS  PubMed  Google Scholar 

  52. Kobayashi A, Arima K, Ogawa M, Murata M, Fukuda T, Kitamoto T (2008) Plaque-type deposition of prion protein in the damaged white matter of sporadic Creutzfeldt–Jakob disease MM1 patients. Acta Neuropathol 116:561–566

    Article  CAS  PubMed  Google Scholar 

  53. Kobayashi A, Sakuma N, Matsuura Y, Mohri S, Aguzzi A, Kitamoto T (2010) Experimental verification of a traceback phenomenon in prion infection. J Virol 84:3230–3238

    Article  CAS  PubMed  Google Scholar 

  54. 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 86:237–240

    Article  CAS  PubMed  Google Scholar 

  55. Korth C, Kaneko K, Groth D, Heye N, Telling G, Mastrianni J, Parchi P, Gambetti P, Will R, Ironside J, Heinrich C, Tremblay P, DeArmond SJ, Prusiner SB (2003) Abbreviated incubation times for human prions in mice expressing a chimeric mouse–human prion protein transgene. Proc Natl Acad Sci USA 100:4784–4789

    Article  CAS  PubMed  Google Scholar 

  56. Kott E, Bornstein B, Sandbank U (1967) Ataxic form of Creutzfeldt–Jakob disease. Its relation to subacute spongiform encephalopathy. J Neurol Sci 5:107–113

    Article  CAS  PubMed  Google Scholar 

  57. Krebs B, Bader B, Klehmet J, Grasbon-Frodl E, Oertel WH, Zerr I, Stricker S, Zschenderlein R, Kretzschmar HA (2007) A novel subtype of Creutzfeldt–Jakob disease characterized by a small 6 kDa PrP fragment. Acta Neuropathol 114:195–199

    Article  PubMed  Google Scholar 

  58. Kretzschmar HA, Prusiner SB, Stowring LE, DeArmond SJ (1986) Scrapie prion proteins are synthesized in neurons. Am J Pathol 122:1–5

    CAS  PubMed  Google Scholar 

  59. Kretzschmar HA, Stowring LE, Westaway D, Stubblebine WH, Prusiner SB, Dearmond SJ (1986) Molecular cloning of a human prion protein cDNA. DNA 5:315–324

    CAS  PubMed  Google Scholar 

  60. Krucke W, Beck E, Vitzthum HG (1973) Creutzfeldt–Jakob disease. Some unusual morphological features reminiscent of kuru. Z Neurol 206:1–24

    Article  CAS  PubMed  Google Scholar 

  61. Kuczius T, Koch R, Keyvani K, Karch H, Grassi J, Groschup MH (2007) Regional and phenotype heterogeneity of cellular prion proteins in the human brain. Eur J Neurosci 25:2649–2655

    Article  PubMed  Google Scholar 

  62. Laplanche JL, Delasnerie-Laupretre N, Brandel JP, Chatelain J, Beaudry P, Alperovitch A, Launay JM (1994) Molecular genetics of prion diseases in France. French Research Group on Epidemiology of Human Spongiform Encephalopathies. Neurology 44:2347–2351

    CAS  PubMed  Google Scholar 

  63. Lasmezas CI, Fournier JG, Nouvel V, Boe H, Marce D, Lamoury F, Kopp N, Hauw JJ, Ironside J, Bruce M, Dormont D, Deslys JP (2001) Adaptation of the bovine spongiform encephalopathy agent to primates and comparison with Creutzfeldt–Jakob disease: implications for human health. Proc Natl Acad Sci USA 98:4142–4147

    Article  CAS  PubMed  Google Scholar 

  64. Legname G, Baskakov IV, Nguyen HO, Riesner D, Cohen FE, DeArmond SJ, Prusiner SB (2004) Synthetic mammalian prions. Science 305:673–676

    Article  CAS  PubMed  Google Scholar 

  65. Levavasseur E, Laffont-Proust I, Morain E, Faucheux BA, Privat N, Peoc’h K, Sazdovitch V, Brandel JP, Hauw JJ, Haik S (2008) Regulating factors of PrP glycosylation in Creutzfeldt–Jakob disease—implications for the dissemination and the diagnosis of human prion strains. PLoS One 3:e2786

    Article  PubMed  CAS  Google Scholar 

  66. Lewis V, Hill AF, Klug GM, Boyd A, Masters CL, Collins SJ (2005) Australian sporadic CJD analysis supports endogenous determinants of molecular-clinical profiles. Neurology 65:113–118

    Article  CAS  PubMed  Google Scholar 

  67. Lodi R, Parchi P, Tonon C, Manners D, Capellari S, Strammiello R, Rinaldi R, Testa C, Malucelli E, Mostacci B, Rizzo G, Pierangeli G, Cortelli P, Montagna P, Barbiroli B (2009) Magnetic resonance diagnostic markers in clinically sporadic prion disease: a combined brain magnetic resonance imaging and spectroscopy study. Brain 132:2669–2679

    Article  PubMed  Google Scholar 

  68. Manners DN, Parchi P, Tonon C, Capellari S, Strammiello R, Testa C, Tani G, Malucelli E, Spagnolo C, Cortelli P, Montagna P, Lodi R, Barbiroli B (2009) Pathologic correlates of diffusion MRI changes in Creutzfeldt–Jakob disease. Neurology 72:1425–1431

    Article  CAS  PubMed  Google Scholar 

  69. Masters CL, Richardson EP Jr (1978) Subacute spongiform encephalopathy (Creutzfeldt–Jakob disease). The nature and progression of spongiform change. Brain 101:333–344

    Article  CAS  PubMed  Google Scholar 

  70. Mastrianni JA, Nixon R, Layzer R, Telling GC, Han D, DeArmond SJ, Prusiner SB (1999) Prion protein conformation in a patient with sporadic fatal insomnia. N Engl J Med 340:1630–1638

    Article  CAS  PubMed  Google Scholar 

  71. McCormack JE, Baybutt HN, Everington D, Will RG, Ironside JW, Manson JC (2002) PRNP contains both intronic and upstream regulatory regions that may influence susceptibility to Creutzfeldt–Jakob Disease. Gene 288:139–146

    Article  CAS  PubMed  Google Scholar 

  72. Mead S, Mahal SP, Beck J, Campbell T, Farrall M, Fisher E, Collinge J (2001) Sporadic—but not variant—Creutzfeldt–Jakob disease is associated with polymorphisms upstream of PRNP exon 1. Am J Hum Genet 69:1225–1235

    Article  CAS  PubMed  Google Scholar 

  73. Meissner B, Kallenberg K, Sanchez-Juan P, Collie D, Summers DM, Almonti S, Collins SJ, Smith P, Cras P, Jansen GH, Brandel JP, Coulthart MB, Roberts H, Van Everbroeck B, Galanaud D, Mellina V, Will RG, Zerr I (2009) MRI lesion profiles in sporadic Creutzfeldt–Jakob disease. Neurology 72:1994–2001

    Article  CAS  PubMed  Google Scholar 

  74. Meyer A, Leigh D, Bagg CE (1954) A rare presenile dementia associated with cortical blindness (Heidenhain’s syndrome). J Neurol Neurosurg Psychiatry 17:129–133

    Article  CAS  PubMed  Google Scholar 

  75. Mitteregger G, Vosko M, Krebs B, Xiang W, Kohlmannsperger V, Nolting S, Hamann GF, Kretzschmar HA (2007) The role of the octarepeat region in neuroprotective function of the cellular prion protein. Brain Pathol 17:174–183

    Article  CAS  PubMed  Google Scholar 

  76. Miyazono M, Kitamoto T, Doh-ura K, Iwaki T, Tateishi J (1992) Creutzfeldt–Jakob disease with codon 129 polymorphism (valine): a comparative study of patients with codon 102 point mutation or without mutations. Acta Neuropathol 84:349–354

    CAS  PubMed  Google Scholar 

  77. Mizutani T, Okumura A, Oda M, Shiraki H (1981) Panencephalopathic type of Creutzfeldt–Jakob disease: primary involvement of the cerebral white matter. J Neurol Neurosurg Psychiatry 44:103–115

    Article  CAS  PubMed  Google Scholar 

  78. Monari L, Chen SG, Brown P, Parchi P, Petersen RB, Mikol J, Gray F, Cortelli P, Montagna P, Ghetti B et al (1994) Fatal familial insomnia and familial Creutzfeldt–Jakob disease: different prion proteins determined by a DNA polymorphism. Proc Natl Acad Sci USA 91:2839–2842

    Article  CAS  PubMed  Google Scholar 

  79. Montagna P, Gambetti P, Cortelli P, Lugaresi E (2003) Familial and sporadic fatal insomnia. Lancet Neurol 2:167–176

    Article  CAS  PubMed  Google Scholar 

  80. Moser M, Colello RJ, Pott U, Oesch B (1995) Developmental expression of the prion protein gene in glial cells. Neuron 14:509–517

    Article  CAS  PubMed  Google Scholar 

  81. Nevin S, Mc MW, Behrman S, Jones DP (1960) Subacute spongiform encephalopathy—a subacute form of encephalopathy attributable to vascular dysfunction (spongiform cerebral atrophy). Brain 83:519–564

    Article  CAS  PubMed  Google Scholar 

  82. Nonno R, Di Bari MA, Cardone F, Vaccari G, Fazzi P, Dell’Omo G, Cartoni C, Ingrosso L, Boyle A, Galeno R, Sbriccoli M, Lipp HP, Bruce M, Pocchiari M, Agrimi U (2006) Efficient transmission and characterization of Creutzfeldt–Jakob disease strains in bank voles. PLoS Pathog 2:e12

    Article  PubMed  CAS  Google Scholar 

  83. Notari S, Capellari S, Giese A, Westner I, Baruzzi A, Ghetti B, Gambetti P, Kretzschmar HA, Parchi P (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 279:16797–16804

    Article  CAS  PubMed  Google Scholar 

  84. Notari S, Capellari S, Langeveld J, Giese A, Strammiello R, Gambetti P, Kretzschmar HA, Parchi P (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 87:1103–1112

    Article  CAS  PubMed  Google Scholar 

  85. Notari S, Strammiello R, Capellari S, Giese A, Cescatti M, Grassi J, Ghetti B, Langeveld JP, Zou WQ, Gambetti P, Kretzschmar HA, Parchi P (2008) Characterization of truncated forms of abnormal prion protein in Creutzfeldt–Jakob disease. J Biol Chem 283:30557–30565

    Article  CAS  PubMed  Google Scholar 

  86. Palmer MS, Dryden AJ, Hughes JT, Collinge J (1991) Homozygous prion protein genotype predisposes to sporadic Creutzfeldt–Jakob disease. Nature 352:340–342

    Article  CAS  PubMed  Google Scholar 

  87. Palmer MS, Mahal SP, Campbell TA, Hill AF, Sidle KC, Laplanche JL, Collinge J (1993) Deletions in the prion protein gene are not associated with CJD. Hum Mol Genet 2:541–544

    Article  CAS  PubMed  Google Scholar 

  88. Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, Mehlhorn I, Huang Z, Fletterick RJ, Cohen FE et al (1993) Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci USA 90:10962–10966

    Article  CAS  PubMed  Google Scholar 

  89. Pan T, Colucci M, Wong BS, Li R, Liu T, Petersen RB, Chen S, Gambetti P, Sy MS (2001) Novel differences between two human prion strains revealed by two-dimensional gel electrophoresis. J Biol Chem 276:37284–37288

    Article  CAS  PubMed  Google Scholar 

  90. Parchi P, Capellari S, Chen SG, Petersen RB, Gambetti P, Kopp N, Brown P, Kitamoto T, Tateishi J, Giese A, Kretzschmar H (1997) Typing prion isoforms. Nature 386:232–234

    Article  CAS  PubMed  Google Scholar 

  91. Parchi P, Castellani R, Capellari S, Ghetti B, Young K, Chen SG, Farlow M, Dickson DW, Sima AA, Trojanowski JQ, Petersen RB, Gambetti P (1996) Molecular basis of phenotypic variability in sporadic Creutzfeldt–Jakob disease. Ann Neurol 39:767–778

    Article  CAS  PubMed  Google Scholar 

  92. Parchi P, Cescatti M, Notari S, Schulz-Schaeffer WJ, Capellari S, Giese A, Zou WQ, Kretzschmar H, Ghetti B, Brown P (2010) Agent strain variation in human prion disease: insights from a molecular and pathological review of the National Institutes of Health series of experimentally transmitted disease. Brain 133:3030–3042

    Article  PubMed  Google Scholar 

  93. Parchi P, Chen SG, Brown P, Zou W, Capellari S, Budka H, Hainfellner J, Reyes PF, Golden GT, Hauw JJ, Gajdusek DC, Gambetti P (1998) Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann-Straussler-Scheinker disease. Proc Natl Acad Sci USA 95:8322–8327

    Article  CAS  PubMed  Google Scholar 

  94. Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I, Budka H, Kopp N, Piccardo P, Poser S, Rojiani A, Streichemberger N, Julien J, Vital C, Ghetti B, Gambetti P, Kretzschmar H (1999) Classification of sporadic Creutzfeldt–Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 46:224–233

    Article  CAS  PubMed  Google Scholar 

  95. Parchi P, Notari S, Weber P, Schimmel H, Budka H, Ferrer I, Haik S, Hauw JJ, Head MW, Ironside JW, Limido L, Rodriguez A, Strobel T, Tagliavini F, Kretzschmar HA (2009) Inter-laboratory assessment of PrPSc typing in Creutzfeldt–Jakob disease: a Western blot study within the NeuroPrion Consortium. Brain Pathol 19:384–391

    Article  CAS  PubMed  Google Scholar 

  96. Parchi P, Strammiello R, Notari S, Giese A, Langeveld JP, Ladogana A, Zerr I, Roncaroli F, Cras P, Ghetti B, Pocchiari M, Kretzschmar H, Capellari S (2009) Incidence and spectrum of sporadic Creutzfeldt–Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification. Acta Neuropathol 118:659–671

    Article  CAS  PubMed  Google Scholar 

  97. Parchi P, Zou W, Wang W, Brown P, Capellari S, Ghetti B, Kopp N, Schulz-Schaeffer WJ, Kretzschmar HA, Head MW, Ironside JW, Gambetti P, Chen SG (2000) Genetic influence on the structural variations of the abnormal prion protein. Proc Natl Acad Sci USA 97:10168–10172

    Article  CAS  PubMed  Google Scholar 

  98. Park TS, Kleinman GM, Richardson EP (1980) Creutzfeldt–Jakob disease with extensive degeneration of white matter. Acta Neuropathol 52:239–242

    Article  CAS  PubMed  Google Scholar 

  99. Peretz D, Scott MR, Groth D, Williamson RA, Burton DR, Cohen FE, Prusiner SB (2001) Strain-specified relative conformational stability of the scrapie prion protein. Protein Sci 10:854–863

    Article  CAS  PubMed  Google Scholar 

  100. Petersen RB, Parchi P, Richardson SL, Urig CB, Gambetti P (1996) Effect of the D178N mutation and the codon 129 polymorphism on the metabolism of the prion protein. J Biol Chem 271:12661–12668

    Article  CAS  PubMed  Google Scholar 

  101. Piccardo P, Dlouhy SR, Lievens PM, Young K, Bird TD, Nochlin D, Dickson DW, Vinters HV, Zimmerman TR, Mackenzie IR, Kish SJ, Ang LC, De Carli C, Pocchiari M, Brown P, Gibbs CJ Jr, Gajdusek DC, Bugiani O, Ironside J, Tagliavini F, Ghetti B (1998) Phenotypic variability of Gerstmann-Straussler-Scheinker disease is associated with prion protein heterogeneity. J Neuropathol Exp Neurol 57:979–988

    Article  CAS  PubMed  Google Scholar 

  102. Piro JR, Harris BT, Nishina K, Soto C, Morales R, Rees JR, Supattapone S (2009) Prion protein glycosylation is not required for strain-specific neurotropism. J Virol 83:5321–5328

    Article  CAS  PubMed  Google Scholar 

  103. Polymenidou M, Stoeck K, Glatzel M, Vey M, Bellon A, Aguzzi A (2005) Coexistence of multiple PrPSc types in individuals with Creutzfeldt–Jakob disease. Lancet Neurol 4:805–814

    Article  CAS  PubMed  Google Scholar 

  104. Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95:13363–13383

    Article  CAS  PubMed  Google Scholar 

  105. Puoti G, Giaccone G, Rossi G, Canciani B, Bugiani O, Tagliavini F (1999) Sporadic Creutzfeldt–Jakob disease: co-occurrence of different types of PrP(Sc) in the same brain. Neurology 53:2173–2176

    CAS  PubMed  Google Scholar 

  106. Riek R, Hornemann S, Wider G, Billeter M, Glockshuber R, Wuthrich K (1996) NMR structure of the mouse prion protein domain PrP(121-321). Nature 382:180–182

    Article  CAS  PubMed  Google Scholar 

  107. Safar J, Wille H, Itri V, Groth D, Serban H, Torchia M, Cohen FE, Prusiner SB (1998) Eight prion strains have PrP(Sc) molecules with different conformations. Nat Med 4:1157–1165

    Article  CAS  PubMed  Google Scholar 

  108. Salvatore M, Genuardi M, Petraroli R, Masullo C, D’Alessandro M, Pocchiari M (1994) Polymorphisms of the prion protein gene in Italian patients with Creutzfeldt–Jakob disease. Hum Genet 94:375–379

    Article  CAS  PubMed  Google Scholar 

  109. Sanchez-Juan P, Green A, Ladogana A, Cuadrado-Corrales N, Saanchez-Valle R, Mitrovaa E, Stoeck K, Sklaviadis T, Kulczycki J, Hess K, Bodemer M, Slivarichova D, Saiz A, Calero M, Ingrosso L, Knight R, Janssens AC, van Duijn CM, Zerr I (2006) CSF tests in the differential diagnosis of Creutzfeldt–Jakob disease. Neurology 67:637–643

    Article  CAS  PubMed  Google Scholar 

  110. Schoch G, Seeger H, Bogousslavsky J, Tolnay M, Janzer RC, Aguzzi A, Glatzel M (2006) Analysis of prion strains by PrPSc profiling in sporadic Creutzfeldt–Jakob disease. PLoS Med 3:e14

    Article  PubMed  CAS  Google Scholar 

  111. Schoene WC, Masters CL, Gibbs CJ Jr, Gajdusek DC, Tyler HR, Moore FD, Dammin GJ (1981) Transmissible spongiform encephalopathy (Creutzfeldt–Jakob disease). Atypical clinical and pathological findings. Arch Neurol 38:473–477

    CAS  PubMed  Google Scholar 

  112. Schulman S (1957) Bilateral symmetrical degeneration of the thalamus: a clinicopathological study. J Neuropathol Exp Neurol 16:446–470

    Article  CAS  PubMed  Google Scholar 

  113. Schulz-Schaeffer WJ, Giese A, Windl O, Kretzschmar HA (1996) Polymorphism at codon 129 of the prion protein gene determines cerebellar pathology in Creutzfeldt–Jakob disease. Clin Neuropathol 15:353–357

    CAS  PubMed  Google Scholar 

  114. 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 156:51–56

    CAS  PubMed  Google Scholar 

  115. Shibuya S, Higuchi J, Shin RW, Tateishi J, Kitamoto T (1998) Protective prion protein polymorphisms against sporadic Creutzfeldt–Jakob disease. Lancet 351:419

    Article  CAS  PubMed  Google Scholar 

  116. Somerville RA, Hamilton S, Fernie K (2005) Transmissible spongiform encephalopathy strain, PrP genotype and brain region all affect the degree of glycosylation of PrPSc. J Gen Virol 86:241–246

    Article  CAS  PubMed  Google Scholar 

  117. Stack MJ, Chaplin MJ, Clark J (2002) Differentiation of prion protein glycoforms from naturally occurring sheep scrapie, sheep-passaged scrapie strains (CH1641 and SSBP1), bovine spongiform encephalopathy (BSE) cases and Romney and Cheviot breed sheep experimentally inoculated with BSE using two monoclonal antibodies. Acta Neuropathol 104:279–286

    CAS  PubMed  Google Scholar 

  118. Stahl N, Baldwin MA, Hecker R, Pan KM, Burlingame AL, Prusiner SB (1992) Glycosylinositol phospholipid anchors of the scrapie and cellular prion proteins contain sialic acid. Biochemistry 31:5043–5053

    Article  CAS  PubMed  Google Scholar 

  119. Stern K (1939) Severe dementia associated with bilateral symmetrical degeneration of the thalamus. Brain 62:157–171

    Article  Google Scholar 

  120. Stimson E, Hope J, Chong A, Burlingame AL (1999) Site-specific characterization of the N-linked glycans of murine prion protein by high-performance liquid chromatography/electrospray mass spectrometry and exoglycosidase digestions. Biochemistry 38:4885–4895

    Article  CAS  PubMed  Google Scholar 

  121. Tagliavini F, Prelli F, Ghiso J, Bugiani O, Serban D, Prusiner SB, Farlow MR, Ghetti B, Frangione B (1991) Amyloid protein of Gerstmann-Straussler-Scheinker disease (Indiana kindred) is an 11 kDa fragment of prion protein with an N-terminal glycine at codon 58. EMBO J 10:513–519

    CAS  PubMed  Google Scholar 

  122. Thackray AM, Hopkins L, Klein MA, Bujdoso R (2007) Mouse-adapted ovine scrapie prion strains are characterized by different conformers of PrPSc. J Virol 81:12119–12127

    Article  CAS  PubMed  Google Scholar 

  123. Tixador P, Herzog L, Reine F, Jaumain E, Chapuis J, Le Dur A, Laude H, Beringue V (2010) The physical relationship between infectivity and prion protein aggregates is strain-dependent. PLoS Pathog 6:e1000859

    Article  PubMed  CAS  Google Scholar 

  124. Uro-Coste E, Cassard H, Simon S, Lugan S, Bilheude JM, Perret-Liaudet A, Ironside JW, Haik S, Basset-Leobon C, Lacroux C, Peoch K, Streichenberger N, Langeveld J, Head MW, Grassi J, Hauw JJ, Schelcher F, Delisle MB, Andreoletti O (2008) Beyond PrP res type 1/type 2 dichotomy in Creutzfeldt–Jakob disease. PLoS Pathog 4:e1000029

    Article  CAS  Google Scholar 

  125. Van Rossum A (1968) Spastic pseudosclerosis (Creutzfeldt–Jakob disease). In: Vinken PJ, Bruyn GW (eds) Handbook of clinical neurology. North Holland, Amsterdam, pp 726–760

    Google Scholar 

  126. Wadsworth JD, Hill AF, Joiner S, Jackson GS, Clarke AR, Collinge J (1999) Strain-specific prion-protein conformation determined by metal ions. Nat Cell Biol 1:55–59

    Article  CAS  PubMed  Google Scholar 

  127. Will RG, Matthews WB (1984) A retrospective study of Creutzfeldt–Jakob disease in England and Wales 1970–79. I. Clinical features. J Neurol Neurosurg Psychiatry 47:134–140

    Article  CAS  PubMed  Google Scholar 

  128. Williams A, Lucassen PJ, Ritchie D, Bruce M (1997) PrP deposition, microglial activation, and neuronal apoptosis in murine scrapie. Exp Neurol 144:433–438

    Article  CAS  PubMed  Google Scholar 

  129. Williams AE, Lawson LJ, Perry VH, Fraser H (1994) Characterization of the microglial response in murine scrapie. Neuropathol Appl Neurobiol 20:47–55

    Article  CAS  PubMed  Google Scholar 

  130. Windl O, Dempster M, Estibeiro JP, Lathe R, de Silva R, Esmonde T, Will R, Springbett A, Campbell TA, Sidle KC, Palmer MS, Collinge J (1996) Genetic basis of Creutzfeldt–Jakob disease in the United Kingdom: a systematic analysis of predisposing mutations and allelic variation in the PRNP gene. Hum Genet 98:259–264

    Article  CAS  PubMed  Google Scholar 

  131. Wu Y, Brown WT, Robakis NK, Dobkin C, Devine-Gage E, Merz P, Wisniewski HM (1987) A PvuII RFLP detected in the human prion protein (PrP) gene. Nucleic Acids Res 15:3191

    Article  CAS  PubMed  Google Scholar 

  132. Yull HM, Ironside JW, Head MW (2009) Further characterisation of the prion protein molecular types detectable in the NIBSC Creutzfeldt–Jakob disease brain reference materials. Biologicals 37:210–215

    Article  CAS  PubMed  Google Scholar 

  133. Zanusso G, Farinazzo A, Fiorini M, Gelati M, Castagna A, Righetti PG, Rizzuto N, Monaco S (2001) pH-dependent prion protein conformation in classical Creutzfeldt–Jakob disease. J Biol Chem 276:40377–40380

    Article  CAS  PubMed  Google Scholar 

  134. Zanusso G, Ferrari S, Conte S, Mellina V, Sacchi V, Rizzuto N, Monaco S (2006) A 49-year-old man with neuropsychiatric symptoms followed by progressive cognitive decline. Brain Pathol 16:237–238

    Article  PubMed  Google Scholar 

  135. Zeidler M, Sellar RJ, Collie DA, Knight R, Stewart G, Macleod MA, Ironside JW, Cousens S, Colchester AC, Hadley DM, Will RG (2000) The pulvinar sign on magnetic resonance imaging in variant Creutzfeldt–Jakob disease. Lancet 355:1412–1418

    Article  CAS  PubMed  Google Scholar 

  136. Zou WQ, Capellari S, Parchi P, Sy MS, Gambetti P, Chen SG (2003) Identification of novel proteinase K-resistant C-terminal fragments of PrP in Creutzfeldt–Jakob disease. J Biol Chem 278:40429–40436

    Article  CAS  PubMed  Google Scholar 

  137. Zou WQ, Puoti G, Xiao X, Yuan J, Qing L, Cali I, Shimoji M, Langeveld JP, Castellani R, Notari S, Crain B, Schmidt RE, Geschwind M, Dearmond SJ, Cairns NJ, Dickson D, Honig L, Torres JM, Mastrianni J, Capellari S, Giaccone G, Belay ED, Schonberger LB, Cohen M, Perry G, Kong Q, Parchi P, Tagliavini F, Gambetti P (2010) Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein. Ann Neurol 68:162–172

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the RFO of the University of Bologna, the Gino Galletti Foundation and the Robert-Koch Institut (Berlin).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hans Kretzschmar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Parchi, P., Strammiello, R., Giese, A. et al. Phenotypic variability of sporadic human prion disease and its molecular basis: past, present, and future. Acta Neuropathol 121, 91–112 (2011). https://doi.org/10.1007/s00401-010-0779-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-010-0779-6

Keywords

Navigation