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Biology and genetics of prions

Henry G Brown, MD, PhD
John M Lee, MD, PhD
Section Editors
Steven T DeKosky, MD, FAAN, FACP, FANA
Benjamin A Raby, MD, MPH
Deputy Editor
Janet L Wilterdink, MD


Prion diseases are neurodegenerative diseases that have long incubation periods and progress inexorably once clinical symptoms appear. Five human prion diseases are currently recognized: kuru, Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob disease (vCJD also known as new variant CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI) [1-4]. Bovine spongiform encephalopathy (BSE), one of a number of prion infections affecting animals, has helped to focus more widespread public attention on these diseases with its possible link to vCJD [5,6].

These human prion diseases share certain common neuropathologic features including neuronal loss, proliferation of glial cells, absence of an inflammatory response, and the presence of small vacuoles within the neuropil which produces a spongiform appearance. Current evidence indicates that prion diseases are associated with the accumulation of an abnormal form of a host cell protein, designated the prion protein (PrP) [7].

The biology of prions will be reviewed here. The clinical manifestations, genetics, and diagnosis of prion diseases are discussed separately. (See "Diseases of the central nervous system caused by prions" and "Creutzfeldt-Jakob disease" and "Variant Creutzfeldt-Jakob disease".)


Dr. Stanley Prusiner coined the term "prion" in 1982 which he defined as a small infectious pathogen containing protein but apparently lacking nucleic acid [8]. The prion protein (PrP) is the critical component of these agents and may, in fact, be its exclusive constituent.

One of the characteristic features of prions is their resistance to a number of normal decontaminating procedures. These pathogens are resistant to processes affecting nucleic acids, such as hydrolysis or shearing [9]. However, agents that digest, denature or modify proteins do have activity against prions [7]. The prion protein purified from the brains of scrapie-infected animals (PrPSc) can be inactivated by prolonged autoclaving (at 121ºC and 15 psi for 4.5 h), or immersion in 1N NaOH (for 30 min, repeat three times), or in concentrated (>3 M) solutions of guanidine thiocyanate [10]. However, certain cautions prevail; it appears that inadequate autoclaving can establish heat resistant subpopulations which fail to diminish with a further cycle of autoclaving [11]. Stainless steel instruments also may retain infectivity even after treatment with 10 percent formaldehyde [12,13].

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Literature review current through: Nov 2017. | This topic last updated: Jul 26, 2013.
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  1. Prusiner SB. Shattuck lecture--neurodegenerative diseases and prions. N Engl J Med 2001; 344:1516.
  2. McKintosh E, Tabrizi SJ, Collinge J. Prion diseases. J Neurovirol 2003; 9:183.
  3. Sy MS, Gambetti P, Wong BS. Human prion diseases. Med Clin North Am 2002; 86:551.
  4. Glatzel M, Stoeck K, Seeger H, et al. Human prion diseases: molecular and clinical aspects. Arch Neurol 2005; 62:545.
  5. O'Brien C. Mad cow disease. Scant data cause widespread concern. Science 1996; 271:1798.
  6. Collinge J. Variant Creutzfeldt-Jakob disease. Lancet 1999; 354:317.
  7. Prusiner SB. The prion hypothesis. In: Prions, Prusiner, SB, McKinley, MP (Eds), Academic Press, San Diego 1987. p.17.
  8. Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science 1982; 216:136.
  9. Bellinger-Kawahara C, Diener TO, McKinley MP, et al. Purified scrapie prions resist inactivation by procedures that hydrolyze, modify, or shear nucleic acids. Virology 1987; 160:271.
  10. Manuelidis L. Decontamination of Creutzfeldt-Jakob disease and other transmissible agents. J Neurovirol 1997; 3:62.
  11. Taylor DM, Fernie K, McConnell I, Steele PJ. Observations on thermostable subpopulations of the unconventional agents that cause transmissible degenerative encephalopathies. Vet Microbiol 1998; 64:33.
  12. Zobeley E, Flechsig E, Cozzio A, et al. Infectivity of scrapie prions bound to a stainless steel surface. Mol Med 1999; 5:240.
  13. Flechsig E, Hegyi I, Enari M, et al. Transmission of scrapie by steel-surface-bound prions. Mol Med 2001; 7:679.
  14. Jackson GS, McKintosh E, Flechsig E, et al. An enzyme-detergent method for effective prion decontamination of surgical steel. J Gen Virol 2005; 86:869.
  15. Baxter HC, Campbell GA, Whittaker AG, et al. Elimination of transmissible spongiform encephalopathy infectivity and decontamination of surgical instruments by using radio-frequency gas-plasma treatment. J Gen Virol 2005; 86:2393.
  16. Solassol J, Pastore M, Crozet C, et al. A novel copper-hydrogen peroxide formulation for prion decontamination. J Infect Dis 2006; 194:865.
  17. Harris DA. Cellular biology of prion diseases. Clin Microbiol Rev 1999; 12:429.
  18. Stahl N, Borchelt DR, Hsiao K, Prusiner SB. Scrapie prion protein contains a phosphatidylinositol glycolipid. Cell 1987; 51:229.
  19. Caughey B. Transmissible spongiform encephalopathies, amyloidoses and yeast prions: common threads? Nat Med 2000; 6:751.
  20. Toni M, Massimino ML, Griffoni C, et al. Extracellular copper ions regulate cellular prion protein (PrPC) expression and metabolism in neuronal cells. FEBS Lett 2005; 579:741.
  21. Brown DR, Wong BS, Hafiz F, et al. Normal prion protein has an activity like that of superoxide dismutase. Biochem J 1999; 344 Pt 1:1.
  22. Sakudo A, Lee DC, Nishimura T, et al. Octapeptide repeat region and N-terminal half of hydrophobic region of prion protein (PrP) mediate PrP-dependent activation of superoxide dismutase. Biochem Biophys Res Commun 2005; 326:600.
  23. Solforosi L, Criado JR, McGavern DB, et al. Cross-linking cellular prion protein triggers neuronal apoptosis in vivo. Science 2004; 303:1514.
  24. Robertson C, Booth SA, Beniac DR, et al. Cellular prion protein is released on exosomes from activated platelets. Blood 2006; 107:3907.
  25. Isaacs JD, Jackson GS, Altmann DM. The role of the cellular prion protein in the immune system. Clin Exp Immunol 2006; 146:1.
  26. Downing DT, Lazo ND. Molecular modelling indicates that the pathological conformations of prion proteins might be beta-helical. Biochem J 1999; 343 Pt 2:453.
  27. Harrison PM, Chan HS, Prusiner SB, Cohen FE. Thermodynamics of model prions and its implications for the problem of prion protein folding. J Mol Biol 1999; 286:593.
  28. Morillas M, Swietnicki W, Gambetti P, Surewicz WK. Membrane environment alters the conformational structure of the recombinant human prion protein. J Biol Chem 1999; 274:36859.
  29. Pierce MM, Baxa U, Steven AC, et al. Is the prion domain of soluble Ure2p unstructured? Biochemistry 2005; 44:321.
  30. Prusiner SB, McKinley MP, Bowman KA, et al. Scrapie prions aggregate to form amyloid-like birefringent rods. Cell 1983; 35:349.
  31. Merz PA, Kascsak RJ, Rubenstein R, et al. Antisera to scrapie-associated fibril protein and prion protein decorate scrapie-associated fibrils. J Virol 1987; 61:42.
  32. Jobling MF, Stewart LR, White AR, et al. The hydrophobic core sequence modulates the neurotoxic and secondary structure properties of the prion peptide 106-126. J Neurochem 1999; 73:1557.
  33. Ritter C, Maddelein ML, Siemer AB, et al. Correlation of structural elements and infectivity of the HET-s prion. Nature 2005; 435:844.
  34. Harris DA, Huber MT, van Dijken P, et al. Processing of a cellular prion protein: identification of N- and C-terminal cleavage sites. Biochemistry 1993; 32:1009.
  35. Narwa R, Harris DA. Prion proteins carrying pathogenic mutations are resistant to phospholipase cleavage of their glycolipid anchors. Biochemistry 1999; 38:8770.
  36. Herms J, Tings T, Gall S, et al. Evidence of presynaptic location and function of the prion protein. J Neurosci 1999; 19:8866.
  37. Shyng SL, Huber MT, Harris DA. A prion protein cycles between the cell surface and an endocytic compartment in cultured neuroblastoma cells. J Biol Chem 1993; 268:15922.
  38. Hay B, Prusiner SB, Lingappa VR. Evidence for a secretory form of the cellular prion protein. Biochemistry 1987; 26:8110.
  39. Parchi P, Chen SG, Brown P, et al. Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann-Sträussler-Scheinker disease. Proc Natl Acad Sci U S A 1998; 95:8322.
  40. Hill AF, Joiner S, Beck JA, et al. Distinct glycoform ratios of protease resistant prion protein associated with PRNP point mutations. Brain 2006; 129:676.
  41. Lawson VA, Collins SJ, Masters CL, Hill AF. Prion protein glycosylation. J Neurochem 2005; 93:793.
  42. Borchelt DR, Taraboulos A, Prusiner SB. Evidence for synthesis of scrapie prion proteins in the endocytic pathway. J Biol Chem 1992; 267:16188.
  43. Vey M, Pilkuhn S, Wille H, et al. Subcellular colocalization of the cellular and scrapie prion proteins in caveolae-like membranous domains. Proc Natl Acad Sci U S A 1996; 93:14945.
  44. Büeler H, Aguzzi A, Sailer A, et al. Mice devoid of PrP are resistant to scrapie. Cell 1993; 73:1339.
  45. Büeler H, Fischer M, Lang Y, et al. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 1992; 356:577.
  46. Soto C, Kascsak RJ, Saborío GP, et al. Reversion of prion protein conformational changes by synthetic beta-sheet breaker peptides. Lancet 2000; 355:192.
  47. Kaneko K, Zulianello L, Scott M, et al. 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 1997; 94:10069.
  48. Chesebro B, Trifilo M, Race R, et al. Anchorless prion protein results in infectious amyloid disease without clinical scrapie. Science 2005; 308:1435.
  49. Telling G. Anchors away--of plaques and pathology in prion disease. N Engl J Med 2005; 353:1177.
  50. Cohen FE, Prusiner SB. Pathologic conformations of prion proteins. Annu Rev Biochem 1998; 67:793.
  51. Tessier PM, Lindquist S. Prion recognition elements govern nucleation, strain specificity and species barriers. Nature 2007; 447:556.
  52. Mabbott NA, Bruce ME, Botto M, et al. Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie. Nat Med 2001; 7:485.
  53. Klein MA, Kaeser PS, Schwarz P, et al. Complement facilitates early prion pathogenesis. Nat Med 2001; 7:488.
  54. Khalili-Shirazi A, Quaratino S, Londei M, et al. Protein conformation significantly influences immune responses to prion protein. J Immunol 2005; 174:3256.
  55. Kimberlin RH, Walker CA. Pathogenesis of mouse scrapie: evidence for neural spread of infection to the CNS. J Gen Virol 1980; 51:183.
  56. Fraser H, Dickinson AG. Targeting of scrapie lesions and spread of agent via the retino-tectal projection. Brain Res 1985; 346:32.
  57. Borchelt DR, Koliatsos VE, Guarnieri M, et al. Rapid anterograde axonal transport of the cellular prion glycoprotein in the peripheral and central nervous systems. J Biol Chem 1994; 269:14711.
  58. Rodolfo K, Hässig R, Moya KL, et al. A novel cellular prion protein isoform present in rapid anterograde axonal transport. Neuroreport 1999; 10:3639.
  59. Zanusso G, Ferrari S, Cardone F, et al. Detection of pathologic prion protein in the olfactory epithelium in sporadic Creutzfeldt-Jakob disease. N Engl J Med 2003; 348:711.
  60. Klein MA, Frigg R, Flechsig E, et al. A crucial role for B cells in neuroinvasive scrapie. Nature 1997; 390:687.
  61. Crozet C, Lezmi S, Flamant F, et al. Peripheral circulation of the prion infectious agent in transgenic mice expressing the ovine prion protein gene in neurons only. J Infect Dis 2007; 195:997.
  62. Kincaid AE, Bartz JC. The nasal cavity is a route for prion infection in hamsters. J Virol 2007; 81:4482.
  63. Forloni G, Angeretti N, Chiesa R, et al. Neurotoxicity of a prion protein fragment. Nature 1993; 362:543.
  64. Brown DR, Schmidt B, Kretzschmar HA. Role of microglia and host prion protein in neurotoxicity of a prion protein fragment. Nature 1996; 380:345.
  65. Jeffrey M, Goodsir CM, Race RE, Chesebro B. Scrapie-specific neuronal lesions are independent of neuronal PrP expression. Ann Neurol 2004; 55:781.
  66. Ma J, Wollmann R, Lindquist S. Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol. Science 2002; 298:1781.
  67. Hegde RS, Rane NS. Prion protein trafficking and the development of neurodegeneration. Trends Neurosci 2003; 26:337.
  68. Serban D, Taraboulos A, DeArmond SJ, Prusiner SB. Rapid detection of Creutzfeldt-Jakob disease and scrapie prion proteins. Neurology 1990; 40:110.
  69. Safar J, Wille H, Itri V, et al. Eight prion strains have PrP(Sc) molecules with different conformations. Nat Med 1998; 4:1157.
  70. Safar JG, Geschwind MD, Deering C, et al. Diagnosis of human prion disease. Proc Natl Acad Sci U S A 2005; 102:3501.
  71. Castilla J, Saá P, Soto C. Detection of prions in blood. Nat Med 2005; 11:982.
  72. Saá P, Castilla J, Soto C. Presymptomatic detection of prions in blood. Science 2006; 313:92.
  73. Paramithiotis E, Pinard M, Lawton T, et al. A prion protein epitope selective for the pathologically misfolded conformation. Nat Med 2003; 9:893.
  74. Yang WC, Schmerr MJ, Jackman R, et al. Capillary electrophoresis-based noncompetitive immunoassay for the prion protein using fluorescein-labeled protein A as a fluorescent probe. Anal Chem 2005; 77:4489.
  75. Gofflot S, Deprez M, el Moualij B, et al. Immunoquantitative PCR for prion protein detection in sporadic Creutzfeldt-Jakob disease. Clin Chem 2005; 51:1605.
  76. Tcherkasskaya O, Davidson EA, Schmerr MJ, Orser CS. Conformational biosensor for diagnosis of prion diseases. Biotechnol Lett 2005; 27:671.
  77. Birkmann E, Schäfer O, Weinmann N, et al. Detection of prion particles in samples of BSE and scrapie by fluorescence correlation spectroscopy without proteinase K digestion. Biol Chem 2006; 387:95.
  78. Sakudo A, Nakamura I, Ikuta K, Onodera T. Recent developments in prion disease research: diagnostic tools and in vitro cell culture models. J Vet Med Sci 2007; 69:329.
  79. Atarashi R, Satoh K, Sano K, et al. Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion. Nat Med 2011; 17:175.
  80. Sparkes RS, Simon M, Cohn VH, et al. Assignment of the human and mouse prion protein genes to homologous chromosomes. Proc Natl Acad Sci U S A 1986; 83:7358.
  81. Wadsworth JD, Hill AF, Beck JA, Collinge J. Molecular and clinical classification of human prion disease. Br Med Bull 2003; 66:241.
  82. Kong Q, Surewicz WK, Petersen RB, et al. Inherited prion diseases. In: Prion biology and disease, 2nd, Prusiner SB (Ed), Cold Spring Harbor Laboratory Press, New York 2004. p.673.
  83. Saitoh Y, Ogawa M, Naito Y, et al. Discordant clinicopathologic phenotypes in a Japanese kindred of fatal familial insomnia. Neurology 2010; 74:86.
  84. Synofzik M, Bauer P, Schöls L. Prion mutation D178N with highly variable disease onset and phenotype. J Neurol Neurosurg Psychiatry 2009; 80:345.
  85. Mallucci GR, Campbell TA, Dickinson A, et al. Inherited prion disease with an alanine to valine mutation at codon 117 in the prion protein gene. Brain 1999; 122 ( Pt 10):1823.
  86. McLean CA, Storey E, Gardner RJ, et al. The D178N (cis-129M) "fatal familial insomnia" mutation associated with diverse clinicopathologic phenotypes in an Australian kindred. Neurology 1997; 49:552.
  87. Gambetti P. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: a tale of two diseases with the same genetic mutation. Curr Top Microbiol Immunol 1996; 207:19.
  88. Zarranz JJ, Digon A, Atarés B, et al. Phenotypic variability in familial prion diseases due to the D178N mutation. J Neurol Neurosurg Psychiatry 2005; 76:1491.
  89. Mead S, Poulter M, Beck J, et al. Inherited prion disease with six octapeptide repeat insertional mutation--molecular analysis of phenotypic heterogeneity. Brain 2006; 129:2297.
  90. Monari L, Chen SG, Brown P, et al. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism. Proc Natl Acad Sci U S A 1994; 91:2839.
  91. Meiner Z, Gabizon R, Prusiner SB. Familial Creutzfeldt-Jakob disease. Codon 200 prion disease in Libyan Jews. Medicine (Baltimore) 1997; 76:227.
  92. Brown P, Gálvez S, Goldfarb LG, et al. Familial Creutzfeldt-Jakob disease in Chile is associated with the codon 200 mutation of the PRNP amyloid precursor gene on chromosome 20. J Neurol Sci 1992; 112:65.
  93. Kovács GG, László L, Bakos A, et al. Increased incidence of genetic human prion disease in Hungary. Neurology 2005; 65:1666.
  94. Mitrová E, Belay G. Creutzfeldt-Jakob disease with E200K mutation in Slovakia: characterization and development. Acta Virol 2002; 46:31.
  95. Hainfellner JA, Parchi P, Kitamoto T, et al. A novel phenotype in familial Creutzfeldt-Jakob disease: prion protein gene E200K mutation coupled with valine at codon 129 and type 2 protease-resistant prion protein. Ann Neurol 1999; 45:812.
  96. Prusiner SB. Prion diseases and the BSE crisis. Science 1997; 278:245.
  97. Ladogana A, Puopolo M, Poleggi A, et al. High incidence of genetic human transmissible spongiform encephalopathies in Italy. Neurology 2005; 64:1592.
  98. Basset-Leobon C, Uro-Coste E, Peoc'h K, et al. Familial Creutzfeldt-Jakob disease with an R208H-129V haplotype and Kuru plaques. Arch Neurol 2006; 63:449.
  99. Wang XF, Guo YJ, Zhang BY, et al. Creutzfeldt-Jakob disease in a Chinese patient with a novel seven extra-repeat insertion in PRNP. J Neurol Neurosurg Psychiatry 2007; 78:201.
  100. Kovács T, Beck JA, Papp MI, et al. Familial prion disease in a Hungarian family with a novel 144-base pair insertion in the prion protein gene. J Neurol Neurosurg Psychiatry 2007; 78:321.
  101. Sánchez-Valle R, Aróstegui JI, Yagüe J, et al. First demonstrated de novo insertion in the prion protein gene in a young patient with dementia. J Neurol Neurosurg Psychiatry 2008; 79:845.
  102. Jansen C, van Swieten JC, Capellari S, et al. Inherited Creutzfeldt-Jakob disease in a Dutch patient with a novel five octapeptide repeat insertion and unusual cerebellar morphology. J Neurol Neurosurg Psychiatry 2009; 80:1386.
  103. Palmer MS, Dryden AJ, Hughes JT, Collinge J. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature 1991; 352:340.
  104. Collinge J, Palmer MS, Dryden AJ. Genetic predisposition to iatrogenic Creutzfeldt-Jakob disease. Lancet 1991; 337:1441.
  105. Parchi P, Giese A, Capellari S, et al. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999; 46:224.
  106. Hsiao K, Baker HF, Crow TJ, et al. Linkage of a prion protein missense variant to Gerstmann-Sträussler syndrome. Nature 1989; 338:342.
  107. Kretzschmar HA, Kufer P, Riethmüller G, et al. Prion protein mutation at codon 102 in an Italian family with Gerstmann-Sträussler-Scheinker syndrome. Neurology 1992; 42:809.
  108. Hainfellner JA, Brantner-Inthaler S, Cervenáková L, et al. The original Gerstmann-Sträussler-Scheinker family of Austria: divergent clinicopathological phenotypes but constant PrP genotype. Brain Pathol 1995; 5:201.
  109. Gajdusek DC. Infectious amyloids: Subacute spongiform encephalopathies as transmissible cerebral amyloidoses. In: Fields Virology, 3rd, Fields, BN, Knipe, DM, Howley, PM (Eds), Lippincott-Raven, New York 1996. p.2851.
  110. Collinge J. Inherited prion diseases. Adv Neurol 1993; 61:155.
  111. Panegyres PK, Toufexis K, Kakulas BA, et al. A new PRNP mutation (G131V) associated with Gerstmann-Sträussler-Scheinker disease. Arch Neurol 2001; 58:1899.
  112. Piccardo P, Liepnieks JJ, William A, et al. Prion proteins with different conformations accumulate in Gerstmann-Sträussler-Scheinker disease caused by A117V and F198S mutations. Am J Pathol 2001; 158:2201.
  113. Rowe DB, Lewis V, Needham M, et al. Novel prion protein gene mutation presenting with subacute PSP-like syndrome. Neurology 2007; 68:868.
  114. Hinnell C, Coulthart MB, Jansen GH, et al. Gerstmann-Straussler-Scheinker disease due to a novel prion protein gene mutation. Neurology 2011; 76:485.
  115. Webb TE, Poulter M, Beck J, et al. Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series. Brain 2008; 131:2632.
  116. Young K, Jones CK, Piccardo P, et al. Gerstmann-Sträussler-Scheinker disease with mutation at codon 102 and methionine at codon 129 of PRNP in previously unreported patients. Neurology 1995; 45:1127.
  117. Barbanti P, Fabbrini G, Salvatore M, et al. Polymorphism at codon 129 or codon 219 of PRNP and clinical heterogeneity in a previously unreported family with Gerstmann-Sträussler-Scheinker disease (PrP-P102L mutation). Neurology 1996; 47:734.
  118. Tanaka Y, Minematsu K, Moriyasu H, et al. A Japanese family with a variant of Gerstmann-Sträussler-Scheinker disease. J Neurol Neurosurg Psychiatry 1997; 62:454.
  119. Wadsworth JD, Joiner S, Linehan JM, et al. Phenotypic heterogeneity in inherited prion disease (P102L) is associated with differential propagation of protease-resistant wild-type and mutant prion protein. Brain 2006; 129:1557.
  120. Medori R, Tritschler HJ, LeBlanc A, et al. Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. N Engl J Med 1992; 326:444.
  121. Krasnianski A, Bartl M, Sanchez Juan PJ, et al. Fatal familial insomnia: Clinical features and early identification. Ann Neurol 2008; 63:658.