Chapter 71 : Diagnosis of Prion Diseases

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Diagnosis of Prion Diseases, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555818722/9781555818715_CH71-1.gif /docserver/preview/fulltext/10.1128/9781555818722/9781555818715_CH71-2.gif


Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a large group of transmissible, progressive, and invariably fatal neurodegenerative conditions that affect both animals and humans (1–5). Prion diseases are unique in that they can be inherited, occur sporadically, or can be acquired by infection (1, 3–5). As described below, the infectious agent in the prion disease is composed mainly or entirely of an abnormal conformation of a host-encoded glycoprotein called the cellular prion protein (PrP). The replication of prions involves the recruitment of the normally expressed prion protein (PrP) structure, which is largely alpha-helical, into a disease-specific conformation (PrP) that is rich in beta-sheets and that can adopt a fibrillar aggregated structure that is characteristic of many of the deposits found in the brains of TSE-affected species. In contrast to the protease-sensitive PrP, the beta-sheet conformation along with the aggregation properties of PrP makes this protein partially resistant to proteolytic digestion (6). Furthermore, this posttranslational modification of PrP into the abnormal, infection-associated isoform, PrP, is believed to be the principal molecular basis underlying prion diseases. Animal prion diseases include scrapie of sheep and goats, bovine spongiform encephalopathy (BSE) or mad cow disease, chronic wasting disease (CWD) of cervids (predominantly mule deer and elk), transmissible mink encephalopathy (TME), feline spongiform encephalopathy, exotic ungulate spongiform encephalopathy, and spongiform encephalopathy of nonhuman primates. Although some cases of sporadic atypical scrapie and BSE have also been reported, most animal prion diseases occur via the acquisition of infection from contaminated feed or via exposure to environmental contaminants. Scrapie and CWD are naturally sustaining epidemics. The human prion diseases can be sporadic, inherited, or acquired. Sporadic human prion diseases include Creutzfeldt-Jakob disease (sCJD), fatal insomnia, and variably protease-sensitive prionopathy (VPSPr) (3, 4). Genetic prion diseases are caused by inheritance of autosomal dominant mutations in the host gene, which encodes the normal cellular PrP and includes genetic CJD (gCJD), fatal familial insomnia (FFI), and Gerstmann-Sträussler-Scheinker syndrome (GSS) (3, 4). Acquired human prion diseases account for only 5% of cases of human prion disease. They include kuru, iatrogenic CJD (iCJD), and variant CJD (vCJD) (3, 4), which was transmitted to humans from affected cattle via meat consumption. The transmission of BSE to humans has resulted in more than 200 cases of vCJD and has raised serious public health concerns. All prion diseases have long incubation periods but are typically rapidly progressive once clinical symptoms begin. Currently, there are no effective treatments for prion diseases, although increased understanding of their pathogenesis has recently led to the promise of effective therapeutic interventions. Numerous therapeutic approaches are under development both for the prevention of prion disease prior to or shortly after exposure and for treatment of already symptomatic disease (2, 7–10).

Citation: Rubenstein R, Petersen R, Wisniewski T. 2016. Diagnosis of Prion Diseases, p 682-702. In Detrick B, Schmitz J, Hamilton R (ed), Manual of Molecular and Clinical Laboratory Immunology, Eighth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818722.ch71
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


1. Colby DW, Prusiner SB. 2011. Prions. Cold Spring Harb Perspect Biol 3:a006833.[CrossRef].[PubMed]
2. Wisniewski T, Goñi F. 2012. Could immunomodulation be used to prevent prion diseases? Expert Rev Anti Infect Ther 10:307317.[CrossRef].[PubMed]
3. Takada LT, Geschwind MD. 2013. Prion diseases. Semin Neurol 33:348356.[CrossRef].[PubMed]
4. Head MW. 2013. Human prion diseases: molecular, cellular and population biology. Neuropathology 33:221236.[CrossRef].[PubMed]
5. Kretzschmar H, Tatzelt J. 2013. Prion disease: a tale of folds and strains. Brain Pathol 23:321332.[CrossRef].[PubMed]
6. DeArmond SJ, Bouzamondo E. 2002. Fundamentals of prion biology and diseases. Toxicology 181-182:916.[PubMed].[CrossRef]
7. Forloni G, Artuso V, Roiter I, Morbin M, Tagliavini F. 2013. Therapy in prion diseases. Curr Top Med Chem 13:24652476.[PubMed].[CrossRef]
8. Roettger Y, Du Y, Bacher M, Zerr I, Dodel R, Bach J-P. 2013. Immunotherapy in prion disease. Nat Rev Neurol 9:98105.[CrossRef].[PubMed]
9. Sim VL. 2012. Prion disease: chemotherapeutic strategies. Infect Disord Drug Targets 12:144160.[PubMed].[CrossRef]
10. Trevitt CR, Collinge J. 2006. A systematic review of prion therapeutics in experimental models. Brain 129:22412265.[CrossRef].[PubMed]
11. Griffith JS. 1967. Self-replication and scrapie. Nature 215:10431044.[PubMed].[CrossRef]
12. Prusiner SB, Scott MR, DeArmond SJ, Cohen FE. 1998. Prion protein biology. Cell 93:337348.[PubMed].[CrossRef]
13. Prusiner SB. 1982. Novel proteinaceous infectious particles cause scrapie. Science 216:136144.[PubMed].[CrossRef]
14. Prusiner SB. 2012. Cell biology. A unifying role for prions in neurodegenerative diseases. Science 336:15111513.[CrossRef].[PubMed]
15. Prusiner SB. 2013. Biology and genetics of prions causing neurodegeneration. Annu Rev Genet 47:601623.[CrossRef].[PubMed]
16. Wickner RB, Edskes HK, Kryndushkin D, McGlinchey R, Bateman D, Kelly A. 2011. Prion diseases of yeast: amyloid structure and biology. Semin Cell Dev Biol 22:469475.[CrossRef].[PubMed]
17. Wickner RB, Edskes HK, Bateman DA, Kelly AC, Gorkovskiy A, Dayani Y, Zhou A. 2013. Amyloids and yeast prion biology. Biochemistry 52:15141527.[CrossRef].[PubMed]
18. Si K, Choi YB, White-Grindley E, Majumdar A, Kandel ER. 2010. Aplysia CPEB can form prion-like multimers in sensory neurons that contribute to long-term facilitation. Cell 140:421435.[CrossRef].[PubMed]
19. Raveendra BL, Siemer AB, Puthanveettil SV, Hendrickson WA, Kandel ER, McDermott AE. 2013. Characterization of prion-like conformational changes of the neuronal isoform of Aplysia CPEB. Nat Struct Mol Biol 20:495501.[CrossRef].[PubMed]
20. Halfmann R, Jarosz DF, Jones SK, Chang A, Lancaster AK, Lindquist S. 2012. Prions are a common mechanism for phenotypic inheritance in wild yeasts. Nature 482:363368.[CrossRef].[PubMed]
21. Newby GA, Lindquist S. 2013. Blessings in disguise: biological benefits of prion-like mechanisms. Trends Cell Biol 23:251259.[CrossRef].[PubMed]
22. Goñi F, Herline K, Peyser D, Wong K, Ji Y, Sun Y, Mehta P, Wisniewski T. 2013. Immunomodulation targeting of both Aβ and tau pathological conformers ameliorates Alzheimer's disease pathology in TgSwDI and 3xTg mouse models. J Neuroinflammation 10:150.[CrossRef].[PubMed]
23. Wisniewski T, Goñi F. 2014. Immunotherapy for Alzheimer's disease. Biochem Pharmacol 88:499507.[CrossRef].[PubMed]
24. Goñi F, Prelli F, Ji Y, Scholtzova H, Yang J, Sun Y, Liang F-X, Kascsak R, Kascsak R, Mehta P, Wisniewski T. 2010. Immunomodulation targeting abnormal protein conformation reduces pathology in a mouse model of Alzheimer's disease. PLoS One 5:e13391.[CrossRef].[PubMed]
25. Rasool S, Martinez-Coria H, Milton S, Glabe CG. 2013. Nonhuman amyloid oligomer epitope reduces Alzheimer's-like neuropathology in 3xTg-AD transgenic mice. Mol Neurobiol 48:931940.[CrossRef].[PubMed]
26. Brandner S, Raeber A, Sailer A, Blättler T, Fischer M, Weissmann C, Aguzzi A. 1996. Normal host prion protein (PrPC) is required for scrapie spread within the central nervous system. Proc Natl Acad Sci USA 93:1314813151.[PubMed].[CrossRef]
27. Brown DR. 2011. Prions and manganese: A maddening beast. Metallomics 3:229238.[CrossRef].[PubMed]
28. Watt NT, Taylor DR, Kerrigan TL, Griffiths HH, Rushworth JV, Whitehouse IJ, Hooper NM. 2012. Prion protein facilitates uptake of zinc into neuronal cells. Nat Commun 3:1134.[CrossRef].[PubMed]
29. Watt NT, Griffiths HH, Hooper NM. 2013. Neuronal zinc regulation and the prion protein. Prion 7:203208.[CrossRef].[PubMed]
30. Thackray AM, Knight R, Haswell SJ, Bujdoso R, Brown DR. 2002. Metal imbalance and compromised antioxidant function are early changes in prion disease. Biochem J 362:253258.[PubMed].[CrossRef]
31. Singh A, Haldar S, Horback K, Tom C, Zhou L, Meyerson H, Singh N. 2013. Prion protein regulates iron transport by functioning as a ferrireductase. J Alzheimers Dis 35:541552.[CrossRef].[PubMed]
32. Sigurdsson EM, Brown DR, Alim MA, Scholtzova H, Carp R, Meeker HC, Prelli F, Frangione B, Wisniewski T. 2003. Copper chelation delays the onset of prion disease. J Biol Chem 278:4619946202.[CrossRef].[PubMed]
33. Brazier MW, Volitakis I, Kvasnicka M, White AR, Underwood JR, Green JE, Han S, Hill AF, Masters CL, Collins SJ. 2010. Manganese chelation therapy extends survival in a mouse model of M1000 prion disease. J Neurochem 114:440451.[CrossRef].[PubMed]
34. Linden R, Martins VR, Prado MA, Cammarota M, Izquierdo I, Brentani RR. 2008. Physiology of the prion protein. Physiol Rev 88:673728.[CrossRef].[PubMed]
35. Young R, Passet B, Vilotte M, Cribiu EP, Béringue V, Le Provost F, Laude H, Vilotte J-L. 2009. The prion or the related Shadoo protein is required for early mouse embryogenesis. FEBS Lett 583:32963300.[CrossRef].[PubMed]
36. Passet B, Young R, Makhzami S, Vilotte M, Jaffrezic F, Halliez S, Bouet S, Marthey S, Khalifé M, Kanellopoulos-Langevin C, Béringue V, Le Provost F, Laude H, Vilotte JL. 2012. Prion protein and Shadoo are involved in overlapping embryonic pathways and trophoblastic development. PLoS One 7:e41959.[CrossRef].[PubMed]
37. Um JW, Nygaard HB, Heiss JK, Kostylev MA, Stagi M, Vortmeyer A, Wisniewski T, Gunther EC, Strittmatter SM. 2012. Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat Neurosci 15:12271235.[CrossRef].[PubMed]
38. Chung E, Ji Y, Sun Y, Kascsak R, Kascsak RB, Mehta PD, Strittmatter SM, Wisniewski T. 2010. Anti-PrPC monoclonal antibody infusion as a novel treatment for Aβ oligomer cognitive deficits. BMC Neurosci 11:130.[CrossRef].[PubMed]
39. Um JW, Kaufman AC, Kostylev MA, Heiss JK, Stagi M, Takahashi H, Kerrisk ME, Vortmeyer A, Wisniewski T, Koleske AJ, Gunther EC, Nygaard HB, Strittmatter SM. 2013. Metabotropic glutamate receptor 5 mediates signaling from Alzheimer Aβ oligomer bound to prion protein. Neuron 79:887902.[CrossRef].[PubMed]
40. Harris DA, Huber MT, van Dijken P, Shyng SL, Chait BT, Wang R. 1993. Processing of a cellular prion protein: identification of N- and C-terminal cleavage sites. Biochemistry 32:10091016.[PubMed].[CrossRef]
41. Windl O, Dempster M, Estibeiro P, Lathe R. 1995. A candidate marsupial PrP gene reveals two domains conserved in mammalian PrP proteins. Gene 159:181186.[PubMed].[CrossRef]
42. Büeler H, Aguzzi A, Sailer A, Greiner RA, Autenried P, Aguet M, Weissmann C. 1993. Mice devoid of PrP are resistant to scrapie. Cell 73:13391347.[PubMed].[CrossRef]
43. Collinge J, Whittington MA, Sidle KC, Smith CJ, Palmer MS, Clarke AR, Jefferys JGR. 1994. Prion protein is necessary for normal synaptic function. Nature 370:295297.[CrossRef].[PubMed]
44. Tobler I, Gaus SE, Deboer T, Achermann P, Fischer M, Rülicke T, Moser M, Oesch B, McBride PA, Manson JC. 1996. Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature 380:639642.[CrossRef].[PubMed]
45. 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 98:259264.[PubMed].[CrossRef]
46. Windl O, Giese A, Schulz-Schaeffer W, Zerr I, Skworc K, Arendt S, Oberdieck C, Bodemer M, Poser S, Kretzschmar HA. 1999. Molecular genetics of human prion diseases in Germany. Hum Genet 105:244252.[PubMed].[CrossRef]
47. 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 46:224233.[PubMed].[CrossRef]
48. Ironside JW. 2012. Variant Creutzfeldt-Jakob disease: an update. Folia Neuropathol 50:5056.[PubMed]
49. Riek R, Hornemann S, Wider G, Billeter M, Glockshuber R, Wüthrich K. 1996. NMR structure of the mouse prion protein domain PrP(121-231). Nature 382:180182.[CrossRef].[PubMed]
50. Riek R, Hornemann S, Wider G, Glockshuber R, Wüthrich K. 1997. NMR characterization of the full-length recombinant murine prion protein, mPrP(23-231). FEBS Lett 413:282288.[PubMed].[CrossRef]
51. Hosszu LLP, Baxter NJ, Jackson GS, Power A, Clarke AR, Waltho JP, Craven CJ, Collinge J. 1999. Structural mobility of the human prion protein probed by backbone hydrogen exchange. Nat Struct Biol 6:740743.[CrossRef].[PubMed]
52. James TL, Liu H, Ulyanov NB, Farr-Jones S, Zhang H, Donne DG, Kaneko K, Groth D, Mehlhorn I, Prusiner SB, Cohen FE. 1997. Solution structure of a 142-residue recombinant prion protein corresponding to the infectious fragment of the scrapie isoform. Proc Natl Acad Sci USA 94:1008610091.[PubMed].[CrossRef]
53. Knaus KJ, Morillas M, Swietnicki W, Malone M, Surewicz WK, Yee VC. 2001. Crystal structure of the human prion protein reveals a mechanism for oligomerization. Nat Struct Biol 8:770774.[CrossRef].[PubMed]
54. Diaz-Espinoza R, Soto C. 2012. High-resolution structure of infectious prion protein: the final frontier. Nat Struct Mol Biol 19:370377.[CrossRef].[PubMed]
55. Pan KM , et al. 1993. Conversion of alpha-helices into β-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci USA 90:1096210966.[PubMed].[CrossRef]
56. Aucouturier P, Kascsak RJ, Frangione B, Wisniewski T. 1999. Biochemical and conformational variability of human prion strains in sporadic Creutzfeldt-Jakob disease. Neurosci Lett 274:3336.[PubMed].[CrossRef]
57. Baron T. 2002. Identification of inter-species transmission of prion strains. J Neuropathol Exp Neurol 61:377383.[PubMed].[CrossRef]
58. Kascsak RJ, Rubenstein R, Merz PA, Carp RI, Robakis NK, Wisniewski HM, Diringer H. 1986. Immunological comparison of scrapie-associated fibrils isolated from animals infected with four different scrapie strains. J Virol 59:676683.[PubMed]
59. Carp RI, Rubenstein R. 1991. Diversity and significance of scrapie strains. Semin Virol 2:203213.
60. Kimberlin RH, Walker CA. 1978. Evidence that the transmission of one source of scrapie agent to hamsters involves separation of agent strains from a mixture. J Gen Virol 39:487496.[CrossRef].[PubMed]
61. Bessen RA, Marsh RF. 1994. Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J Virol 68:78597868.[PubMed]
62. Caughey B, Raymond GJ, Bessen RA. 1998. Strain-dependent differences in β-sheet conformations of abnormal prion protein. J Biol Chem 273:3223032235.[PubMed].[CrossRef]
63. Schutt CR, Bartz JC. 2008. Prion interference with multiple prion isolates. Prion 2:6163.[PubMed].[CrossRef]
64. Shikiya RA, Ayers JI, Schutt CR, Kincaid AE, Bartz JC. 2010. Coinfecting prion strains compete for a limiting cellular resource. J Virol 84:57065714.[CrossRef].[PubMed]
65. Parchi P, Castellani R, Capellari S, Ghetti B, Young K, Chen SG, Farlow M, Dickson DW, Sima AAF, Trojanowski JQ, Petersen RB, Gambetti P. 1996. Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann Neurol 39:767778.[CrossRef].[PubMed]
66. Parchi P, de Boni L, Saverioni D, Cohen ML, Ferrer I, Gambetti P, Gelpi E, Giaccone G, Hauw JJ, Höftberger R, Ironside JW, Jansen C, Kovacs GG, Rozemuller A, Seilhean D, Tagliavini F, Giese A, Kretzschmar HA. 2012. Consensus classification of human prion disease histotypes allows reliable identification of molecular subtypes: an inter-rater study among surveillance centres in Europe and USA. Acta Neuropathol 124:517529.[CrossRef].[PubMed]
67. Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF. 1996. Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature 383:685690.[CrossRef].[PubMed]
68. Wadsworth JD, Powell C, Beck JA, Joiner S, Linehan JM, Brandner S, Mead S, Collinge J. 2008. Molecular diagnosis of human prion disease. Methods Mol Biol 459:197227.[CrossRef].[PubMed]
69. Kimberlin RH, Walker CA. 1989. Pathogenesis of scrapie in mice after intragastric infection. Virus Res 12:213220.[PubMed].[CrossRef]
70. Carp RI. 1982. Transmission of scrapie by oral route: effect of gingival scarification. Lancet 1:170171.[PubMed].[CrossRef]
71. Mohan J, Brown KL, Farquhar CF, Bruce ME, Mabbott NA. 2004. Scrapie transmission following exposure through the skin is dependent on follicular dendritic cells in lymphoid tissues. J Dermatol Sci 35:101111.[CrossRef].[PubMed]
72. Glaysher BR, Mabbott NA. 2007. Role of the draining lymph node in scrapie agent transmission from the skin. Immunol Lett 109:6471.[CrossRef].[PubMed]
73. Denkers ND, Telling GC, Hoover EA. 2011. Minor oral lesions facilitate transmission of chronic wasting disease. J Virol 85:13961399.[CrossRef].[PubMed]
74. Denkers ND, Seelig DM, Telling GC, Hoover EA. 2010. Aerosol and nasal transmission of chronic wasting disease in cervidized mice. J Gen Virol 91:16511658.[CrossRef].[PubMed]
75. Denkers ND, Hayes-Klug J, Anderson KR, Seelig DM, Haley NJ, Dahmes SJ, Osborn DA, Miller KV, Warren RJ, Mathiason CK, Hoover EA. 2013. Aerosol transmission of chronic wasting disease in white-tailed deer. J Virol 87:18901892.[CrossRef].[PubMed]
76. Haybaeck J, Heikenwalder M, Klevenz B, Schwarz P, Margalith I, Bridel C, Mertz K, Zirdum E, Petsch B, Fuchs TJ, Stitz L, Aguzzi A. 2011. Aerosols transmit prions to immunocompetent and immunodeficient mice. PLoS Pathog 7:e1001257.[CrossRef].[PubMed]
77. Nichols TA, Spraker TR, Rigg TD, Meyerett-Reid C, Hoover C, Michel B, Bian J, Hoover E, Gidlewski T, Balachandran A, O'Rourke K, Telling GC, Bowen R, Zabel MD, VerCauteren KC. 2013. Intranasal inoculation of white-tailed deer (Odocoileus virginianus) with lyophilized chronic wasting disease prion particulate complexed to montmorillonite clay. PLoS One 8:e62455.[CrossRef].[PubMed]
78. Saunders SE, Bartelt-Hunt SL, Bartz JC. 2012. Occurrence, transmission, and zoonotic potential of chronic wasting disease. Emerg Infect Dis 18:369376.[CrossRef].[PubMed]
79. Daus ML, Beekes M. 2012. Chronic wasting disease: fingerprinting the culprit in risk assessments. Prion 6:1722.[CrossRef].[PubMed]
80. Aucouturier P, Carp RI, Carnaud C, Wisniewski T. 2000. Prion diseases and the immune system. Clin Immunol 96:7985.[CrossRef].[PubMed]
81. Mabbott NA, MacPherson GG. 2006. Prions and their lethal journey to the brain. Nat Rev Microbiol 4:201211.[CrossRef].[PubMed]
82. Natale G, Ferrucci M, Lazzeri G, Paparelli A, Fornai F. 2011. Transmission of prions within the gut and towards the central nervous system. Prion 5:142149.[CrossRef].[PubMed]
83. Aguzzi A, Nuvolone M, Zhu C. 2013. The immunobiology of prion diseases. Nat Rev Immunol 13:888902.[CrossRef].[PubMed]
84. Eklund CM, Kennedy RC, Hadlow WJ. 1967. Pathogenesis of scrapie virus infection in the mouse. J Infect Dis 117:1522.[PubMed].[CrossRef]
85. Fraser H, Dickinson AG. 1978. Studies of the lymphoreticular system in the pathogenesis of scrapie: the role of spleen and thymus. J Comp Pathol 88:563573.[PubMed].[CrossRef]
86. Kimberlin RH, Walker CA. 1979. Pathogenesis of mouse scrapie: dynamics of agent replication in spleen, spinal cord and brain after infection by different routes. J Comp Pathol 89:551562.[PubMed].[CrossRef]
87. Fraser H, Dickinson AG. 1970. Pathogenesis of scrapie in the mouse: the role of the spleen. Nature 226:462463.[PubMed].[CrossRef]
88. Kimberlin RH, Walker CA. 1989. The role of the spleen in the neuroinvasion of scrapie in mice. Virus Res 12:201211.[PubMed].[CrossRef]
89. Pattison IH, Millson GC. 1960. Further observations on the experimental production of scrapie in goats and sheep. J Comp Pathol 70:182193.[PubMed].[CrossRef]
90. Sigurdson CJ, Williams ES, Miller MW, Spraker TR, O'Rourke KI, Hoover EA. 1999. Oral transmission and early lymphoid tropism of chronic wasting disease PrPres in mule deer fawns (Odocoileus hemionus). J Gen Virol 80:27572764.[CrossRef].[PubMed]
91. Espinosa JC, Morales M, Castilla J, Rogers M, Torres JM. 2007. Progression of prion infectivity in asymptomatic cattle after oral bovine spongiform encephalopathy challenge. J Gen Virol 88:13791383.[CrossRef].[PubMed]
92. Hilton DA, Sutak J, Smith ME, Penney M, Conyers L, Edwards P, McCardle L, Ritchie D, Head MW, Wiley CA, Ironside JW. 2004. Specificity of lymphoreticular accumulation of prion protein for variant Creutzfeldt-Jakob disease. J Clin Pathol 57:300302.[PubMed].[CrossRef]
93. Hill AF, Zeidler M, Ironside J, Collinge J. 1997. Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy. Lancet 349:99100.[CrossRef].[PubMed]
94. Hilton DA, Ghani AC, Conyers L, Edwards P, McCardle L, Ritchie D, Penney M, Hegazy D, Ironside JW. 2004. Prevalence of lymphoreticular prion protein accumulation in UK tissue samples. J Pathol 203:733739.[CrossRef].[PubMed]
95. Gill ON, Spencer Y, Richard-Loendt A, Kelly C, Dabaghian R, Boyes L, Linehan J, Simmons M, Webb P, Bellerby P, Andrews N, Hilton DA, Ironside JW, Beck J, Poulter M, Mead S, Brandner S. 2013. Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey. BMJ 347:f5675.[PubMed].[CrossRef]
96. Prinz M, Huber G, Macpherson AJ, Heppner FL, Glatzel M, Eugster HP, Wagner N, Aguzzi A. 2003. Oral prion infection requires normal numbers of Peyer's patches but not of enteric lymphocytes. Am J Pathol 162:11031111.[CrossRef].[PubMed]
97. Rieger R, Edenhofer F, Lasmézas CI, Weiss S. 1997. The human 37-kDa laminin receptor precursor interacts with the prion protein in eukaryotic cells. Nat Med 3:13831388.[PubMed].[CrossRef]
98. Shmakov AN, Ghosh S. 2001. Prion proteins and the gut: une liaison dangereuse? Gut 48:443447.[PubMed].[CrossRef]
99. Morel E, Andrieu T, Casagrande F, Gauczynski S, Weiss S, Grassi J, Rousset M, Dormont D, Chambaz J. 2005. Bovine prion is endocytosed by human enterocytes via the 37 kDa/67 kDa laminin receptor. Am J Pathol 167:10331042.[CrossRef].[PubMed]
100. Heppner FL, Christ AD, Klein MA, Prinz M, Fried M, Kraehenbuhl JP, Aguzzi A. 2001. Transepithelial prion transport by M cells. Nat Med 7:976977.[CrossRef].[PubMed]
101. Donaldson DS, Kobayashi A, Ohno H, Yagita H, Williams IR, Mabbott NA. 2012. M cell-depletion blocks oral prion disease pathogenesis. Mucosal Immunol 5:216225.[CrossRef].[PubMed]
102. Raymond CR, Aucouturier P, Mabbott NA. 2007. In vivo depletion of CD11c+ cells impairs scrapie agent neuroinvasion from the intestine. J Immunol 179:77587766.[PubMed].[CrossRef]
103. Beekes M, McBride PA, Baldauf E. 1998. Cerebral targeting indicates vagal spread of infection in hamsters fed with scrapie. J Gen Virol 79:601607.[CrossRef].[PubMed]
104. Glatzel M, Heppner FL, Albers KM, Aguzzi A. 2001. Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron 31:2534.[PubMed].[CrossRef]
105. Houston F, Foster JD, Chong A, Hunter N, Bostock CJ. 2000. Transmission of BSE by blood transfusion in sheep. Lancet 356:9991000.[PubMed].[CrossRef]
106. Mathiason CK, Powers JG, Dahmes SJ, Osborn DA, Miller KV, Warren RJ, Mason GL, Hays SA, Hayes-Klug J, Seelig DM, Wild MA, Wolfe LL, Spraker TR, Miller MW, Sigurdson CJ, Telling GC, Hoover EA. 2006. Infectious prions in the saliva and blood of deer with chronic wasting disease. Science 314:133136.[CrossRef].[PubMed]
107. Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. 2004. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 364:527529.[CrossRef].[PubMed]
108. Klein MA, Frigg R, Flechsig E, Raeber AJ, Kalinke U, Bluethmann H, Bootz F, Suter M, Zinkernagel RM, Aguzzi A. 1997. A crucial role for B cells in neuroinvasive scrapie. Nature 390:687690.[CrossRef].[PubMed]
109. Montrasio F, Frigg R, Glatzel M, Klein MA, Mackay F, Aguzzi A, Weissmann C. 2000. Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science 288:12571259.[PubMed].[CrossRef]
110. Aucouturier P, Geissmann F, Damotte D, Saborio GP, Meeker HC, Kascsak R, Kascsak R, Carp RI, Wisniewski T. 2001. Infected splenic dendritic cells are sufficient for prion transmission to the CNS in mouse scrapie. J Clin Invest 108:703708.[CrossRef].[PubMed]
111. Goñi F, Prelli F, Schreiber F, Scholtzova H, Chung E, Kascsak R, Brown DR, Sigurdsson EM, Chabalgoity JA, Wisniewski T. 2008. High titers of mucosal and systemic anti-PrP antibodies abrogate oral prion infection in mucosal-vaccinated mice. Neuroscience 153:679686.[CrossRef].[PubMed]
112. Goni F, Mathiason CK, Yim L, Wong K, Hayes-Klug J, Nalls A, Peyser D, Estevez V, Denkers N, Xu J, Osborn DA, Miller KV, Warren RJ, Brown DR, Chabalgoity JA, Hoover EA, Wisniewski T. 2015. Mucosal immunization with an attenuated Salmonella vaccine partially protects white-tailed deer from chronic wasting disease. Vaccine 33:726733.[CrossRef].[PubMed]
113. M'Gowan JP. 1914. Investigation into the disease of sheep called scrapie (Traberkrankheit, La Tremblante) with a special reference to its association with Sarcosporidiosas. William Blackwood & Sons, Edinburgh, Scotland.
114. Cuillé J, Chelle PL. 1939. Experimental transmission of trembling to the goat. CR Seances Acad Sci 208:10581060.
115. Parry HB. 1962. Scrapie: a transmissible and hereditary disease of sheep. Hered Edinb 17:75105.[CrossRef]
116. Marsh R, Hanson RP,. 1979. On the origin of transmissible mink encephalopathy, p 451460. In Prusiner SB, Hadlow WJ (ed), Slow Transmissible Disease of the Nervous System. Academic Press, New York.
117. Baron T, Bencsik A, Biacabe AG, Morignat E, Bessen RA. 2007. Phenotypic similarity of transmissible mink encephalopathy in cattle and L-type bovine spongiform encephalopathy in a mouse model. Emerg Infect Dis 13:18871894.[CrossRef].[PubMed]
118. Prusiner SB. 1991. Molecular biology and transgenetics of prion diseases. Crit Rev Biochem Mol Biol 26:397438.[CrossRef].[PubMed]
119. Prusiner SB. 1993. Transgenetics and cell biology of prion diseases: investigations of PrPSc synthesis and diversity. Br Med Bull 49:873912.[PubMed]
120. Hope J, Reekie LJ, Hunter N, Multhaup G, Beyreuther K, White H, Scott AC, Stack MJ, Dawson M, Wells GA. 1988. Fibrils from brains of cows with new cattle disease contain scrapie-associated protein. Nature 336:390392.[CrossRef].[PubMed]
121. Wilesmith JW, Wells GAH, Cranwell MP, Ryan JBM. 1988. Bovine spongiform encephalopathy: epidemiological studies. Vet Rec 123:638644.[PubMed]
122. Miller MW, Williams ES. 2004. Chronic wasting disease of cervids. Curr Top Microbiol Immunol 284:193214.[PubMed]
123. Gajdusek DC. 1977. Unconventional viruses and the origin and disappearance of kuru. Science 197:943960.[PubMed].[CrossRef]
124. Safar J, Roller PP, Gajdusek DC, Gibbs CJ Jr. 1993. Thermal stability and conformational transitions of scrapie amyloid (prion) protein correlate with infectivity. Protein Sci 2:22062216.[CrossRef].[PubMed]
125. Prusiner SB, Groth DF, Bolton DC, Kent SB, Hood LE. 1984. Purification and structural studies of a major scrapie prion protein. Cell 38:127134.[PubMed].[CrossRef]
126. Palmer AC. 1957. Vacuolated neurones in sheep affected with scrapie. Nature 179:480481.[PubMed].[CrossRef]
127. Merz PA, Somerville RA, Wisniewski HM, Iqbal K. 1981. Abnormal fibrils from scrapie-infected brain. Acta Neuropathol 54:6374.[PubMed].[CrossRef]
128. Oesch B, Westaway D, Wälchli M, McKinley MP, Kent SBH, Aebersold R, Barry RA, Tempst P, Teplow DB, Hood LE, Prusiner SB, Weissmann C. 1985. A cellular gene encodes scrapie PrP 27-30 protein. Cell 40:735746.[PubMed].[CrossRef]
129. Chesebro B, Race R, Wehrly K, Nishio J, Bloom M, Lechner D, Bergstrom S, Robbins K, Mayer L, Keith JM, Garon C, Haase A. 1985. Identification of scrapie prion protein-specific mRNA in scrapie-infected and uninfected brain. Nature 315:331333.[PubMed].[CrossRef]
130. Bendheim PE, Barry RA, DeArmond SJ, Stites DP, Prusiner SB. 1984. Antibodies to a scrapie prion protein. Nature 310:418421.[PubMed].[CrossRef]
131. Kascsak RJ, Rubenstein R, Merz PA, Tonna-DeMasi M, Fersko R, Carp RI, Wisniewski HM, Diringer H. 1987. Mouse polyclonal and monoclonal antibody to scrapie-associated fibril proteins. J Virol 61:36883693.[PubMed]
132. Rubenstein R, Kascsak RJ, Merz PA, Papini MC, Carp RI, Robakis NK, Wisniewski HM. 1986. Detection of scrapie-associated fibril (SAF) proteins using anti-SAF antibody in non-purified tissue preparations. J Gen Virol 67:671681.[CrossRef].[PubMed]
133. Miller JM, Jenny AL, Taylor WD, Marsh RF, Rubenstein R, Race RE. 1993. Immunohistochemical detection of prion protein in sheep with scrapie. J Vet Diagn Invest 5:309316.[PubMed].[CrossRef]
134. Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, Poser S, Pocchiari M, Hofman A, Smith PG. 1996. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 347:921925.[PubMed].[CrossRef]
135. Korth C, Stierli B, Streit P, Moser M, Schaller O, Fischer R, Schulz-Schaeffer W, Kretzschmar H, Raeber A, Braun U, Ehrensperger F, Hornemann S, Glockshuber R, Riek R, Billeter M, Wüthrich K, Oesch B. 1997. Prion (PrPSc)-specific epitope defined by a monoclonal antibody. Nature 390:7477.[CrossRef].[PubMed]
136. Paramithiotis E, Pinard M, Lawton T, LaBoissiere S, Leathers VL, Zou WQ, Estey LA, Lamontagne J, Lehto MT, Kondejewski LH, Francoeur GP, Papadopoulos M, Haghighat A, Spatz SJ, Head M, Will R, Ironside J, O'Rourke K, Tonelli Q, Ledebur HC, Chakrabartty A, Cashman NR. 2003. A prion protein epitope selective for the pathologically misfolded conformation. Nat Med 9:893899.[CrossRef].[PubMed]
137. 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 386:232234.[CrossRef].[PubMed]
138. Thuring CM, Erkens JH, Jacobs JG, Bossers A, Van Keulen LJ, Garssen GJ, Van Zijderveld FG, Ryder SJ, Groschup MH, Sweeney T, Langeveld JP. 2004. Discrimination between scrapie and bovine spongiform encephalopathy in sheep by molecular size, immunoreactivity, and glycoprofile of prion protein. J Clin Microbiol 42:972980.[PubMed].[CrossRef]
139. Caughey B, Kocisko DA, Raymond GJ, Lansbury PT Jr. 1995. Aggregates of scrapie-associated prion protein induce the cell-free conversion of protease-sensitive prion protein to the protease-resistant state. Chem Biol 2:807817.[PubMed].[CrossRef]
140. Saá P, Castilla J, Soto C. 2006. Ultra-efficient replication of infectious prions by automated protein misfolding cyclic amplification. J Biol Chem 281:3524535252.[CrossRef].[PubMed]
141. Atarashi R, Wilham JM, Christensen L, Hughson AG, Moore RA, Johnson LM, Onwubiko HA, Priola SA, Caughey B. 2008. Simplified ultrasensitive prion detection by recombinant PrP conversion with shaking. Nat Methods 5:211212.[CrossRef].[PubMed]
142. Wilham JM, Orrú CD, Bessen RA, Atarashi R, Sano K, Race B, Meade-White KD, Taubner LM, Timmes A, Caughey B. 2010. Rapid end-point quantitation of prion seeding activity with sensitivity comparable to bioassays. PLoS Pathog 6:e1001217.[CrossRef].[PubMed]
143. Orrú CD, Wilham JM, Raymond LD, Kuhn F, Schroeder B, Raeber AJ, Caughey B. 2011. Prion disease blood test using immunoprecipitation and improved quaking-induced conversion. MBio 2:e00078e11.[CrossRef].[PubMed]
144. Chang B, Gray P, Piltch M, Bulgin MS, Sorensen-Melson S, Miller MW, Davies P, Brown DR, Coughlin DR, Rubenstein R. 2009. Surround optical fiber immunoassay (SOFIA): an ultra-sensitive assay for prion protein detection. J Virol Methods 159:1522.[CrossRef].[PubMed]
145. Rubenstein R, Chang B, Gray P, Piltch M, Bulgin MS, Sorensen-Melson S, Miller MW. 2010. A novel method for preclinical detection of PrPSc in blood. J Gen Virol 91:18831892.[CrossRef].[PubMed]
146. Rubenstein R, Chang B, Gray P, Piltch M, Bulgin MS, Sorensen-Melson S, Miller MW. 2011. Prion disease detection, PMCA kinetics, and IgG in urine from sheep naturally/experimentally infected with scrapie and deer with preclinical/clinical chronic wasting disease. J Virol 85:90319038.[CrossRef].[PubMed]
147. Rubenstein R, Bulgin MS, Chang B, Sorensen-Melson S, Petersen RB, LaFauci G. 2012. PrP(Sc) detection and infectivity in semen from scrapie-infected sheep. J Gen Virol 93:13751383.[CrossRef].[PubMed]
148. Fujihara A, Atarashi R, Fuse T, Ubagai K, Nakagaki T, Yamaguchi N, Ishibashi D, Katamine S, Nishida N. 2009. Hyperefficient PrP Sc amplification of mouse-adapted BSE and scrapie strain by protein misfolding cyclic amplification technique. FEBS J 276:28412848.[CrossRef].[PubMed]
149. Safar J, Cohen FE, Prusiner SB. 2000. Quantitative traits of prion strains are enciphered in the conformation of the prion protein. Arch Virol Suppl 16:227235.[PubMed]
150. 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 4:11571165.[CrossRef].[PubMed]
151. 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 68:162172.[CrossRef].[PubMed]
152. Kim C, Haldiman T, Cohen Y, Chen W, Blevins J, Sy MS, Cohen M, Safar JG. 2011. Protease-sensitive conformers in broad spectrum of distinct PrPSc structures in sporadic Creutzfeldt-Jakob disease are indicator of progression rate. PLoS Pathog 7:e1002242.[CrossRef].[PubMed]
153. Pirisinu L, Nonno R, Esposito E, Benestad SL, Gambetti P, Agrimi U, Zou WQ. 2013. Small ruminant nor98 prions share biochemical features with human gerstmann-sträussler-scheinker disease and variably protease-sensitive prionopathy. PLoS One 8:e66405.[CrossRef].[PubMed]
154. Gajdusek DC, Zigas V. 1957. Degenerative disease of the central nervous system in New Guinea; the endemic occurrence of kuru in the native population. N Engl J Med 257:974978.[CrossRef].[PubMed]
155. Gajdusek DC, Zigas V. 1959. Kuru; clinical, pathological and epidemiological study of an acute progressive degenerative disease of the central nervous system among natives of the Eastern Highlands of New Guinea. Am J Med 26:442469.[PubMed].[CrossRef]
156. Mead S, Whitfield J, Poulter M, Shah P, Uphill J, Campbell T, Al-Dujaily H, Hummerich H, Beck J, Mein CA, Verzilli C, Whittaker J, Alpers MP, Collinge J. 2009. A novel protective prion protein variant that colocalizes with kuru exposure. N Engl J Med 361:20562065.[CrossRef].[PubMed]
157. Collinge J, Whitfield J, McKintosh E, Beck J, Mead S, Thomas DJ, Alpers MP. 2006. Kuru in the 21st century—an acquired human prion disease with very long incubation periods. Lancet 367:20682074.[CrossRef].[PubMed]
158. Hadlow WJ. 1959. Scrapie and kuru. Lancet 11:289290.[CrossRef]