Spontaneous Generation of Infectious Amyloid Nucleants in the Transmissible and Nontransmissible Brain Amyloidoses

  • D. Carleton Gajdusek
Part of the Advances in Research on Neurodegeneration book series (ARN, volume 2)


In recent years we have become aware that the unconventional or atypical slow virus diseases of kuru-Creutzfeldt-Jacob syndrome (CJD) — Gerstmann Sträussler syndrome (GSS) and scrapie-bovine spongiform encephalopathy (BSE) are cerebral amyloidoses (Gajdusek, 1986, 1988a, 1988b, 1989, 1990, 1991a, 1991b, 1991c; Gajdusek and Gibbs, 1990; Gajdusek et al., 1991). As with most amyloidoses, the spontaneous de novo generation of amyloid fibrils is under genetic control, although in many susceptible hosts all individuals are susceptible to even a minimal intracerebral infective dose; thus, for such inoculation there is no genetic control other than the species barrier.


Spontaneous Generation Familial Fatal Insomnia Cerebral Amyloidosis Octapeptide Repeat Transthyretin Amyloidosis 
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  1. Axelrad MA, Kisilevsky R (1980): Biological characterization of amyloid enhancing factor. In: Amyloid and Amyloidosis, Glenner GG, Costa PP, de Freitas AF, eds., pp. 527–533. Amsterdam: Excerpta MedicaGoogle Scholar
  2. Axelrad MA, Kisilevsky R, Wilmer J, Chen SJ, Skinner M (1982): Further characterization of amyloid-enhancing factor. Lab Invest 47:139–146PubMedGoogle Scholar
  3. Blake CCF, Oatley SJ (1977): Protein-DNA and protein-hormone interactions in prealbumin: a model of the thyroid hormone nuclear receptor? Nature 268:115–120PubMedCrossRefGoogle Scholar
  4. Blake CCF, Geisow MJ, Oatley, SJ, Rerat B, Rerat C (1978): Structure of prealbumin: secondary, tertiary and quaternary interactions determined by Fourier refinement at 1.8 Å. J Mol Biol 121:339–356PubMedCrossRefGoogle Scholar
  5. Blake CCF, Geisow MJ, Swan IDA, Rerat C, Rerat B (1974): Structure of human plasma prealbumin at 2.6 A resolution: a preliminary report on the polypeptide chain conformation, quaternary structure and thyroxine binding. J Mol Biol 88:1–12PubMedCrossRefGoogle Scholar
  6. Blake CCF, Swan IDA, Rerat C, Berthou J, Laurent A, Rerat B (1971): An X-ray study of the subunit structure of prealbumin. J Mol Biol 61:217–224PubMedCrossRefGoogle Scholar
  7. Brown P, Gálvez S, Goldfarb LG, Nieto A, Cartier L, Gibbs CJ Jr, Gajdusek DC (1992): Familial Creutzfeldt-Jakob disease in Chile is associated with the codon 200Asn mutation of the chromosome 20 amyloid precursor gene. J Neurol Sci 112:65–67PubMedCrossRefGoogle Scholar
  8. Brown P, Goldfarb LG, Cathala F, Vrbovská A, Sulima M, Nieto A, Gibbs CJ Jr, Gajdusek DC (1991a): The molecular genetics of familial Creutzfeldt-Jakob disease in France. J Neurol Sci 105:240–246PubMedCrossRefGoogle Scholar
  9. Brown P, Goldfarb LG, Gajdusek DC (1991b): The new biology of spongiform encephalopathy: infectious amyloidoses with a genetic twist. Lancet 337:1019–1022PubMedCrossRefGoogle Scholar
  10. Brown P, Goldfarb LG, Gibbs CJ Jr, Gajdusek DC (1991c): The phenotypic expression of different mutations in transmissible familial Creutzfeldt-Jakob disease. Eur J Epidemiol 7(5):469–476PubMedCrossRefGoogle Scholar
  11. Brown P, Goldfarb LG, Kovanen J, Haltia M, Cathala F, Sulima M, Gibbs CJ Jr, Gajdusek DC (1992a): Phenotypic characteristics of familial Creutzfeldt-Jakob disease associated with the codon 178Asn PPNP mutation. Ann Neurol 31:282–285PubMedCrossRefGoogle Scholar
  12. Brown P, Goldfarb LG, McCombie WR, Nieto A, Squillacote D, Sheremata W, Little BW, Godec MS, Gibbs CJ Jr, Gajdusek DC (1992b): Atypical Creutzfeldt-Jakob disease in an American family with an insert mutation in the PRNP amyloid precursor gene. Neurology 42:422–427PubMedCrossRefGoogle Scholar
  13. Cohen AS (1965): The constitution and genesis of amyloid. Int Rev Exp Pathol 4:159–243PubMedGoogle Scholar
  14. Costa PP, de Freitas AF, Saraiva MJM, eds. (1990): Familial Amyloidotic Polyneuropathy and Other Transthyretin Related Disorders. Porto: Archives de MedicinaGoogle Scholar
  15. Dloughy SI, Hsiao K, Farlow MR, Foroud T, Conneally PM, Johnson P, Prusiner SB, Hodes ME, Ghetti B (1992): Linkage of the Indiana kindred of Gerstmann-Sträussler-Scheinker disease to the prion protein gene. Nature Genet 1:64–67CrossRefGoogle Scholar
  16. Dohura K, Tateishi J, Sasaki H, Kitamoto T, Sakaki Y (1989): Protein change at position 102 of prion gene is the most common but not the sole mutation related to Gerstmann-Sträussler syndrome. Biochem Biophys Res Commun 163:974–979CrossRefGoogle Scholar
  17. Frangione B, Wisniewski T, Ghiso J (1992): Accelerated instructive fibrillogenesis. J Cell Biochem Suppl 16E:200 (abstr.)Google Scholar
  18. Gajdusek DC (1986): Unconventional virus infections as cerebral amyloidoses. In: Unconventional Virus Diseases of the Central Nervous System, Court LA, Dormont D, Brown P, eds. [Proceedings of Conference, Paris, December 2–6, 1986], pp. 641–659. Fontenay-aux-Roses, France: Commissariat a l’Energie Atomique (CEA), Service de DocumentationGoogle Scholar
  19. Gajdusek DC (1988a): Transmissible and non-transmissible amyloidoses: autocatalytic post-translational conversion of host precursor to β-pleated configurations. J Neuroimmunol 20:95–110PubMedCrossRefGoogle Scholar
  20. Gajdusek DC (1988b): Etiology versus pathogenesis: the causes of post-translational modifications of host specified brain proteins to amyloid configuration. In: Genetics and Alzheimer’s Disease, Proceedings of a meeting held by the Foundation IPSEN pour la Recherche Thérapeutique, Paris, March 25, Sinet PM, Lamour Y, Christen Y, eds., pp. 174–176. Berlin: Springer-VerlagGoogle Scholar
  21. Gajdusek DC (1989): Fantasy of a “virus” from the inorganic world: pathogenesis of cerebral amyloidoses by polymer nucleating agents and/or “viruses.” In: Modern Trends in Human Leukemia, Vol VIII, Neth R, Gallo RC, Greaves M, Gaedicke G, Gohla S, Mannweiller K, Ritter J., eds., pp. 481–499. New York: Springer-VerlagCrossRefGoogle Scholar
  22. Gajdusek DC (1990): Subacute spongiform encephalopathies: transmissible cerebral amyloidoses caused by unconventional viruses. In: Virology, 2nd Ed., Fields BN, Knipe DM, Chanock RM, Hirsch MS, Melnick JL, Monath TP, Roizman B, eds., pp. 2289–2324. New York: Raven PressGoogle Scholar
  23. Gajdusek DC (1991a): Genetic control of de novo conversion to infectious amyloids of host precursor proteins: Kuru-CJD-scrape. In: Concepts in Biomedical Research, Proceedings of paul Ehrlich Institute Scientific Conference. New York: Springer-VerlagGoogle Scholar
  24. Gajdusek DC (1991b): Transthyretin amyloidoses of familial amyloidotic polyneuropathy as a paradigm for the genetic control of de novo generation of Creutzfeldt-Jakob disease infectious amyloid by a spontaneous change in the configuration of the host precursor protein. In: Sub-Acute Spongiform Encephalopathies, Current Topics of Veterinary and Animal Science, Vol. 55, Bradley R, Savey M, Marchant BA, eds., pp. 91–114. Kluwer Academic PublishersGoogle Scholar
  25. Gajdusek DC (1991c): The transmissible amyloidoses: genetic control of spontaneous generation of infectious amyloid proteins by nucleation of configurational change in host precursors kuru-CJD-Scrapie-BSE. Eur J Epidemiol 7:567–577PubMedCrossRefGoogle Scholar
  26. Gajdusek DC, Gibbs CJ Jr, (1991): Brain amyloidoses: precursor proteins and the amyloids of transmissible and nontransmissible dementias: scrapie-kuru-CJD viruses as infectious polypeptides or amyloid-enhancing factors. In: Biomedical Advances in Aging, Goldstein AL, ed., pp. 3–24. New York: Plenum PublishingGoogle Scholar
  27. Gajdusek DC, Beyreuther K, Brown P, Cork LC, Cunningham DD, Frangione B, Gibbs CJ Jr, Goldfarb LG, Goldgaber D, Hsiao KK, Koo EH, Martin LJ, Masters CL, Odenwald WF, Price DL, Prusiner SB, Ruddle FH, Safar J, Scangos G, Schmechel DE, Shashikant CS, Shlichta PJ, Sisodia SS, Trapp BD, Unterbeck A, Van Nostrand WE, Violette SM, Walker LC, Wirak D (1991): Regulation and genetic control of brain amyloid. Brain Res Rev 16:83–114PubMedCrossRefGoogle Scholar
  28. Goldfarb LG, Brown P, Goldgaber D, Asher D, Rubenstein R, Brown WT, Piccardo P, Kasasak J, Boellaard JW, Gajdusek DC (1990c): Creutzfeldt-Jakob disease and kuru patients lack a mutation consistently found in Gerstmann-Sträussler-Scheinker syndrome. Exp Neurol 108:247–250PubMedCrossRefGoogle Scholar
  29. Goldfarb LG, Brown P, Goldgaber D, Garruto RM, Yanagihara R, Asher DM, Gajdusek DC 91990b): Identical mutation in unrelated patients with Creutzfeldt-Jakob disease. Lancet 336:174–175PubMedCrossRefGoogle Scholar
  30. Goldfarb LG, Korczyn AO, Brown P, Chapman J, Gajdusek DC (1990c): Mutation in codon 200 of scrapie amyloid precursor gene linked to CJD in Sephardic Jews. Lancet 336:637PubMedCrossRefGoogle Scholar
  31. Goldfarb LG, Mitrová E, Brown P, Toh BH, Gajdusek DC (1990d): Mutation in codon 200 of scrapie amyloid protein gene in two clusters of Creutzfeldt-Jakob disease in Slovakia. Lancet 336:514–515PubMedCrossRefGoogle Scholar
  32. Goldfarb LG, Brown P, Mitrová E, Cervenakova L, Goldin L, Korczyn AD, Chapman I, Gálvez S, Carder L, Rubenstein R, Gajdusek DC (1991a): Creutzfeldt-Jakob disease associated with the PRNP codon 200lys mutation: an analysis of 45 families. Eur J Epidemiol 7:477–86PubMedCrossRefGoogle Scholar
  33. Goldfarb LG, Haltia M, Brown P, Nieto A, Kovanen J, McCombie WR, Trapp S, Gajdusek DC (1991b): New mutation in scrapie amyloid precursor gene (at codon 178) in Finnish Creutzfeldt-Jakob kindred. Lancet 337:425PubMedCrossRefGoogle Scholar
  34. Goldfarb LG, Brown P, McCombie WR, Goldgaber D, Swergold GD, Wills PR, Cervenakova L, Baron H, Gibbs CJ Jr, Gajdusek DC (1991c): Transmissible familial Creutzfeldt-Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene. Proc Natl Acad Sci USA 88:10926–10930PubMedCrossRefGoogle Scholar
  35. Goldfarb LG, Brown P, Haltia M, Cathala F, McCombie WR, Kovanen J, Cervenakova L, Goldin L, Nieto A, Godec M, Asher DM, Gajdusek DC (1992a): Creutzfeldt-Jakob disease associated with the codon 178ASN PRNP mutation in families of European origin. Ann Neurol 31(3):274–281PubMedCrossRefGoogle Scholar
  36. Goldfarb LG, Brown P, Vrbovska A, Baron H, McCombie WR, Cathala F, Gibbs CJ Jr, Gajdusek DC (1992b): An insert mutation in the chromosome 20 amyloid precursor gene in a Gerstmann-Sträussler-Scheinker family. J Neurol Sci 111:189–194PubMedCrossRefGoogle Scholar
  37. Goldfarb LG, Brown P, Haltia M, Ghiso J, Frangione B, Gajdusek DC (1993a): Synthetic peptides corresponding to different mutated regions of the amyloid gene in familial Creutzfeldt-Jakob disease show enhanced in vitro formation of morphologically distinct amyloid fibrils. Proc Natl Acad Sci USA 90:4451–4454PubMedCrossRefGoogle Scholar
  38. Goldfarb LG, Brown P, Little BW, Cervenáková L, Kenney K, Gibbs CJ Jr, Gajdusek DC (1993b): A new (2-repeat) octapeptide coding insert mutation in Creutzfeldt-Jakob disease. Neurology 43:2392–2394PubMedCrossRefGoogle Scholar
  39. Goldgaber D, Goldfarb LG, Brown P, Asher DM, Brown WT, Lin S, Teener JW, Feinstone SM, Rubenstein B, Kascsak R, Boellaard JW, Gajdusek DC (1989): Mutations in familial Creutzfeldt-Jakob disease and Gerstmann-Sträussler syndrome. Exp Neurol 106:204–206PubMedCrossRefGoogle Scholar
  40. Guiroy DC, Gajdusek DC (1988): Fibril-derived amyloid enhancing factors as nucleating agents in Alzheimer’s disease and transmissible virus dementia. In: Molecular Genetic Mechanisms in Neurodegenerative Disorders, Brown P, Bolis L, Gajdusek DC, eds., Discussions in Neuroscience, Geneva: FESN Vol. 5, pp. 69–73Google Scholar
  41. Haltia M, Kovanen J, van Crevel H, Bots GTAM, Stefanko S (1979): Familial Creutzfeldt-Jakob disease. J Neurol Sci 42:381–389PubMedCrossRefGoogle Scholar
  42. Haltia M, Kovanen J, Goldfarb LG, Brown P, Gajdusek DC (1991): Familial Creutzfeldt-Jakob disease in Finland: epidemiological, clinical, pathological and molecular genetic studies. Eur J Epidemiol 7(5):494–500PubMedCrossRefGoogle Scholar
  43. Hol PR, van Andel ACJ, van Ederen AM, Draäyer J, Gruys E (1985): Amyloid enhancing factor in hamster. Br J Exp Pathol 66:689–697PubMedGoogle Scholar
  44. Hsiao K, Baker HF, Crow TJ, Poulter M, Owen E, Terwilliger JD, Westaway D, Ott J, Prusiner SB (1989): Linkage of prion protein missense variant to Gerstmann-Sträussler syndrome. Nature 338:342–345PubMedCrossRefGoogle Scholar
  45. Hsiao K, Cass C, Conneally PM, Dloughy SR, Hodes ME, Farlow MR, Ghetti B, Prusiner SB (1990a): Atypical Gerstmann-Sträussler-Scheinker syndrome with neurofibrillary tangles: no mutations in the prion protein open-reading-frame in a portion of the Indiana kindred. Neurobiol Aging 11:3, 302Google Scholar
  46. Hsiao K, Cass C, Schellenberg G, Bird T, Devine-Gage E, Wisniewski M, Prusiner SB (1990b): A prion protein variant in a family with a telencephalic form of Gerstmann-Sträussler-Scheinker syndrome. Neurology 41:681–684CrossRefGoogle Scholar
  47. Hsiao K, Dloughy SR, Farlow MR, Cass C, Da Costa M, Conneally PM, Hodes ME, Ghetti B, Prusiner SB (1992a): Mutant prion proteins in Gerstmann-Sträussler-Scheinker disease with neurofibrillary tangles. Nature Genet 1:68–71PubMedCrossRefGoogle Scholar
  48. Hsiao KK, Dohura K, Kitamoto T, Tateishi J, Prusiner SB (1990c): A prion protein amino acid substitution in ataxic Gerstmann-Sträussler syndrome. Ann Neurol 26:137Google Scholar
  49. Janigan DT (1965): Experimental amyloidoses. Am J Pathol 47:159–171PubMedGoogle Scholar
  50. Janigan DT (1969): Pathogenetic mechanisms in protein-induced amyloidosis. Am J Pathol 55:379–393PubMedGoogle Scholar
  51. Janigan DT, Druet RL (1968): Experimental murine amyloidosis in X-irradiated recipients of spleen homogenates or serum from sensitized donors. Am J Pathol 52:381–390PubMedGoogle Scholar
  52. Kitamoto T, Ohta M, Dohura K, Hitash S, Tarao Y, Tateishi J (1993a): Novel missvariants of prion protein in Creutzfeldt-Jakob disease or Gertsmann-Sträussler syndrome. Biochem Biophys Res Commun 191:709PubMedCrossRefGoogle Scholar
  53. Kitamoto T, Iizuka R, Tateishi J (1993b): An amber mutation of prion protein in Gertsmann-Sträussler syndrome with mutant PrP plaques. Biochem Biophys Res Commun 192:525–531PubMedCrossRefGoogle Scholar
  54. Kretzschmar HA, Kufer P, Riethmüller G, Dearmond S, Prusiner SB, Schiffer D (1992): Prion protein mutation at codon 102 in an Italian family with Gerst-mann-Sträussler-Scheinker syndrome. Neurology 42:809–810PubMedCrossRefGoogle Scholar
  55. Mitrová E (1980): Focal accumulation of Creutzfeldt-Jakob disease in Slovakia. In: Search for the Cause of Multiple Sclerosis and Other Chronic Disease of the Central Nervous System, Boese A, ed., pp. 356–366. Weinheim: Verlag ChemieGoogle Scholar
  56. Mitrová E (1990): Analytical epidemiology and risk factors of CJD. In Unconventional Virus Diseases of the Central Nervous System, Court LA, Dormont D, Brown P, Kingsbury DT, eds. Paris: Commissanat á l’Energie Atomique, Service de DocumentationGoogle Scholar
  57. Mitrová E, Brown P, Hroncová D, Tatara M, Zilák J (1991): Focal accumulation of CJD in Slovakia: retrospective investigation of a new rural familial cluster. Eur J Epidemiol 7:487–489PubMedCrossRefGoogle Scholar
  58. Nieto A, Goldfarb LG, Brown P, Wexler P, Chodosh HL, McCombie WR, Trapp S (1991): Mutation in codon 178 of amyloid precursor gene occurs in Creutzfeldt-Jakob disease families of diverse ethnic origins. Lancet 337:622–623PubMedCrossRefGoogle Scholar
  59. Niewold TA, Hol PR, van Andel ACJ, Lutz ETG, Gruys E (1987): Enhancement of amyloid induction by amyloid fibril fragments in hamster. Lab Invest 56:544–549PubMedGoogle Scholar
  60. Owen F, Poulter M, Collinge J, Crow T (1990a): Codon 129 changes in the prion protein gene in Caucasians. Am J Hum Genet 46:1215–1216PubMedGoogle Scholar
  61. Owen F, Poulter M, Lofthouse R, Collinge J, Crow TJ, Risby D, Baker HF, Ridley RM, Hsiao K, Prusiner SB (1989): Insertion in prion protein gene in familial Creutzfeldt-Jakob disease. Lancet i:51–52CrossRefGoogle Scholar
  62. Owen F, Poulter M, Shah T, Collinge J, Lofthaus R, Baker H, Ridley R, McVey J, Crow TJ (1990b): An in-frame insertion in the prion protein gene in familial Creutzfeldt-Jakob disease. Mol Brain Res 7:273–276PubMedCrossRefGoogle Scholar
  63. Ranlov P (1967): The adoptive transfer of experimental mouse amyloidosis by intravenous injection of spleen cell extracts from casein-treated syngeneic donor mice. Acta Pathol Microbiol Scand 70:321–335PubMedCrossRefGoogle Scholar
  64. Safar J: Infectious amyloid, prions, unconventional viruses and disease, review. Neurobiol Aging (in press, a)Google Scholar
  65. Safar J, Wang W, Padgett MP, Ceroni M, Piccardo P, Zopf D, Gajdusek DC, Gibbs CJ Jr (1990): Molecular mass, biochemical composition and physicochemical behavior of the infectious form of the scrapie precursor protein monomer. Proc Natl Acad Sci USA 87:6373–6377PubMedCrossRefGoogle Scholar
  66. Safar J, Roller PP, Ruben GC, Gajdusek DC, Gibbs CJ Jr (1993a): Secondary structure of proteins associated in thin films. Biopolymers 33:1461–1476PubMedCrossRefGoogle Scholar
  67. Safar J, Roller PP, Gajdusek DC, Gibbs CJ Jr (1993b): Confirmational transitions, dissociation, and unfolding of scrapie amyloid (prion) proteins. J Biol Chem 268:20276–20284PubMedGoogle Scholar
  68. Sasaki H, Yoshioka N, Takagi Y, Sakaki Y (1985): Structure of the chromosomal gene for human serum prealbumin. Gene 37:191–197PubMedCrossRefGoogle Scholar
  69. Tsuzuki T, Mita S, Maede S, Araki S, Shimada KJ (1985): Structure of the human prealbumin gene. Biol Chem 260:12224–12227Google Scholar
  70. Wakasugi S, Inomoto T, Yi S, Naito M, Ushira M, Iwanaga T, Maeda S, Araki K, Miyasaki J, Takahashi K, Shimada K, Yamamure K (1988): A potential animal model for familial amyloidotic polyneuropathy through introduction of human mutant transthyretin gene into mice. In: Amyloid and Amyloidoses, Takashi I, Shakuro A, Fumike O, Shozo K, Eiro T, eds., pp. 393–398. New York: Plenum PressGoogle Scholar
  71. Yi S, Tadahashi K, Tashiro F, Wakasugi S, Yamamura K, Araki S (1990): Pathological similarity to human familial amyloidotic polyneuropathy (FAP) type 1 in transgenic mice carrying the human mutant transthyretin gene. In: Program and Abstracts of the VIth International Symposium on Amyloidosis, Oslo, Norway, August 5–9, 1990, p. 58, Abstr. 07/5Google Scholar

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© Birkhäuser Boston 1994

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  • D. Carleton Gajdusek

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