Chapter 59 : 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

Prion Diseases, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555819439/9781555819422.ch59-1.gif /docserver/preview/fulltext/10.1128/9781555819439/9781555819422.ch59-2.gif


Prion diseases are infectious and fatal neurodegenerative disorders of humans and animals caused by the accumulation of a misfolded and aggregated form of the cellular prion protein (1, 2). The term “prion” was coined by Stanley Prusiner and is derived from the words “proteinaceous infectious particle” (2). Prions are misfolded forms of a normal protein called the “prion protein” and by definition are infectious. In most prion diseases, prions are abundant in the brain and spinal cord and can spread between patients iatrogenically, for example, through neurosurgical procedures or grafts of prion-contaminated dura mater (3). The classic neuropathologic lesion neuropatholog in the brain of a prion-infected patient is spongiform degeneration with neuronal loss, activated astrocytes and microglia, and a notable lack of peripheral inflammatory cells (4).

Citation: Sigurdson C, Kim M, Geschwind M. 2017. Prion Diseases, p 1425-1448. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch59
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1

(A) The structure of mouse PrP solved by NMR spectroscopy ( ) shows an unstructured amino terminal domain (blue) and a well-ordered C-terminal domain with three α-helices (green) and an anti-parallel β-sheet (red). A disulfide bond links α2 to α3 (yellow). (B) A long straight fibril from PrP derived from a prion-infected brain shows a single twist (arrowhead) ( ). A model of the fibril composed of multimeric PrP is shown that accounts for available biophysical measurements ( ). Note that all α-helices have been converted to β-sheets, and PrP molecules are stacked. Each PrP molecule is represented by a different color and molecules are aligned parallel and in-register. The locations of the glycans are shown in orange. (C) Model for the conformational conversion of PrP into PrP. The “seeding” or nucleated polymerization model proposes that PrP forms a highly ordered nucleus, which requires overcoming a high-energy barrier. Further monomeric PrP is recruited into the growing PrP aggregate. Fragmentation of PrP aggregates increases the number of nuclei, which each recruit PrP monomers, resulting in amplification of the prion aggregates. (Modified from references [ ] and [ ]).

Citation: Sigurdson C, Kim M, Geschwind M. 2017. Prion Diseases, p 1425-1448. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch59
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2

Schematic representation of human PrP showing the known mutations and polymorphisms. The cleaved signal sequences are shown in dark gray and the octapeptide repeat region in purple. Shown are the pathogenic mutations (red) and the nonpathogenic variants (green). OPRD: octapeptide repeat deletion; OPRI: octapeptide repeat insertion. (Modified from reference [ ]).

Citation: Sigurdson C, Kim M, Geschwind M. 2017. Prion Diseases, p 1425-1448. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch59
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3

A typical electroencephalogram in a sporadic Creutzfeldt–Jakob disease patient, with diffuse slowing and 1-Hz periodic sharp wave complexes (PSWCs). (

Citation: Sigurdson C, Kim M, Geschwind M. 2017. Prion Diseases, p 1425-1448. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch59
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 4

Diffusion-weighted (dw) and fluid-attenuated inversion recovery (flair) magnetic resonance imaging (MRI) in sporadic Creutzfeldt–Jakob disease (sCJD) and variant (v)CJD. Three common MRI patterns in sCJD are predominantly subcortical (A, B), both cortical and subcortical (C, D), and predominantly cortical (E, F). A patient with probable vCJD is shown in G and H. Note that in sCJD, the abnormalities are more evident on DWI (A, C, E) than on FLAIR (B, D, F) images. The three sCJD cases (A-F) are verified by pathology. A, B: A 52-year-old woman with MRI showing strong hyperintensity in bilateral caudate (solid arrow) and putamen (dashed arrow) and slight hyperintensity in bilateral mesial and posterior thalamus (dotted arrow). C, D: A 68-year-old man with MRI showing hyperintensity in bilateral caudate and putamen (note anteroposterior gradient in the putamen, which is commonly seen in CJD), thalamus, right insula (dotted arrow), anterior and posterior cingulate gyrus (solid arrow), and left temporal-parietal-occipital junction (dashed arrow). E, F: A 76-year-old woman with MRI showing diffuse hyperintense signal, mainly in bilateral temporoparietal (solid arrows) and occipital cortex (dotted arrow), right posterior insula (dashed arrow), and left inferior frontal cortex (arrowhead) but no significant subcortical abnormalities. G, H: A 21-year-old woman with probable vCJD, with MRI showing bilateral thalamic hyperintensity in the mesial pars (mainly dorsomedian nucleus) and posterior pars (pulvinar) of the thalamus, called the double hockey stick sign. Also note the pulvinar sign, with the posterior thalamus (pulvinar; arrow) being more hyperintense than the anterior putamen. (Modified from references [ ] and [ ]).

Citation: Sigurdson C, Kim M, Geschwind M. 2017. Prion Diseases, p 1425-1448. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch59
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 5

Histological features of prion diseases. CNS parenchyma of sCJD (A and B) and vCJD (C and D) showing astrogliosis and widespread spongiform changes. PrP depositions are synaptic (A and B) and in the form of florid plaques (asterisk, C and D). A and C are hematoxylin and eosin stains, B and D are immunohistochemically labeled for PrP (scale bar = 50 micrometers). (Note: from previous version of this chapter.)

Citation: Sigurdson C, Kim M, Geschwind M. 2017. Prion Diseases, p 1425-1448. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch59
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 6

Western blot analysis of PrP. The classification schemes for CJD discriminate PrP types based on the mobility of the unglycosylated band of PrP and the signal intensity of di-, mono-, and unglycosylated PrP forms. Types 1 and 2 PrP have distinct electrophoretic mobilities due to different sizes of their respective protease-resistant fragments (type 2 is smaller than type 1). The PrP types are distinguished by their different migration on electrophoresis, particularly after cleavage of the sugars by the enzyme peptide N glycosidase F (PNGase). (Modified from Puotri GP et al. ( )).

Citation: Sigurdson C, Kim M, Geschwind M. 2017. Prion Diseases, p 1425-1448. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch59
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 7

Olfactory mucosa brushing and RT-QuIC assay for PrP. (A) To collect olfactory neurons, the operator inserts a rigid fiberoptic rhinoscope and a sterile brush into the nasal cavity and gently rolls the brush on the mucosal surface. (B) Nasal brush cells were immunostained with antiolfactory marker protein (OMP) antibody to show clusters of OMP positive olfactory neurons (40X). (C) A cytocentrifuged sample of the OM pellet was stained immunocytochemically for an olfactory marker protein to detect olfactory neurons. (D) The average percent thioflavin T (ThT) fluorescence readings from four replicate reactions in samples of OM and CSF from patients with possible, probable, or definite Creutzfeldt–Jakob disease and from controls without Creutzfeldt–Jakob disease. The means (thick lines) with standard deviations (thin lines) of those averages are shown as a function of RT-QuIC reaction time. (E) The final average relative ThT fluorescence readings for each person with Creutzfeldt–Jakob disease (CJD) and for each control with either a neurologic disease other than Creutzfeldt–Jakob disease (other neurologic disease (OND) or no neurologic disease (NND)) are shown. Inherited CJD refers to patients with the E200K genetic mutation causing CJD. (Modified from reference [ ]).

Citation: Sigurdson C, Kim M, Geschwind M. 2017. Prion Diseases, p 1425-1448. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch59
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Bolton DC, McKinley MP, Prusiner SB . 1982. Identification of a protein that purifies with the scrapie prion. Science 218 : 1309 1311.[PubMed]
2. Prusiner SB . 1982. Novel proteinaceous infectious particles cause scrapie. Science 216 : 136 144.[PubMed]
3. Brown P, Preece M, Brandel JP, Sato T, McShane L, Zerr I, Fletcher A, Will RG, Pocchiari M, Cashman NR, d'Aignaux JH, Cervenáková L, Fradkin J, Schonberger LB, Collins SJ . 2000. Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology 55 : 1075 1081.[PubMed]
4. DeArmond SJ, Prusiner SB . 1995. Etiology and pathogenesis of prion diseases. Am J Pathol 146 : 785 811.[PubMed]
5. Cuille J, Chelle PL . 1939. Experimental transmission of trembling to the goat. C R Seances Acad Sci 208 : 1058 1160.[PubMed]
6. Jakob A . 1921. Über eigenartige erkrankungen des zentralnervensystems mit bemerkenswertem anatomischem befunde (Spastische pseudosklerose-encephalomyelopathie mit disseminierten degenerationsherden). Z Gesamte Neurol Psychiatr (Bucur) 64 : 147 228.[PubMed]
7. Creutzfeldt HG . 1920. Über eine eigenartige herdförmige erkrankung des zentralnervensystems. Z Gesamte Neurol Psychiatr (Bucur) 57 : 1 19.
8. Gibbs CJ Jr, Gajdusek DC, Asher DM, Alpers MP, Beck E, Daniel PM, Matthews WB . 1968. Creutzfeldt-Jakob disease (spongiform encephalopathy): transmission to the chimpanzee. Science 161 : 388 389.[PubMed]
9. Gajdusek DC, Gibbs CJ, Alpers M . 1966. Experimental transmission of a Kuru-like syndrome to chimpanzees. Nature 209 : 794 796.[PubMed]
10. 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 : 442 469.[PubMed]
11. Hadlow WJ . 1959. Scrapie and kuru. Lancet 2 : 289 290.[PubMed]
12. Gibbs CJ Jr, . 1992. Spongiform encephalopathies—slow, latent, and temperate virus infections—in retrospect, p 53 62. In Prusiner JCSB, Powell J, Anderton B (ed), Prion Diseases of Humans and Animals. Ellis Horwood, London.
13. Katscher F . 1998. It's Jakob's disease, not Creutzfeldt's. Nature 393 : 11.[PubMed]
14. Wells GA, Scott AC, Johnson CT, Gunning RF, Hancock RD, Jeffrey M, Dawson M, Bradley R . 1987. A novel progressive spongiform encephalopathy in cattle. Vet Rec 121 : 419 420.[PubMed]
15. Anderson RM, Donnelly CA, Ferguson NM, Woolhouse ME, Watt CJ, Udy HJ, MaWhinney S, Dunstan SP, Southwood TR, Wilesmith JW, Ryan JB, Hoinville LJ, Hillerton JE, Austin AR, Wells GA . 1996. Transmission dynamics and epidemiology of BSE in British cattle. Nature 382 : 779 788.[PubMed]
16. 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.[PubMed]
17. 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.[PubMed]
18. Legname G, Baskakov IV, Nguyen HO, Riesner D, Cohen FE, DeArmond SJ, Prusiner SB . 2004. Synthetic mammalian prions. Science 305 : 673 676[CrossRef].[PubMed]
19. Deleault NR, Harris BT, Rees JR, Supattapone S . 2007. Formation of native prions from minimal components in vitro. Proc Natl Acad Sci USA 104 : 9741 9746.[PubMed]
20. Wang F, Wang X, Yuan CG, Ma J . 2010. Generating a prion with bacterially expressed recombinant prion protein. Science 327 : 1132 1135.[PubMed]
21. 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.[PubMed]
22. Alper T, Haig DA . 1968. Protection by anoxia of the scrapie agent and some DNA and RNA viruses irradiated as dry preparations. J Gen Virol 3 : 157 166.[PubMed]
23. Alper T, Haig DA, Clarke MC . 1966. The exceptionally small size of the scrapie agent. Biochem Biophys Res Commun 22 : 278 284.[PubMed]
24. Alper T, Haig DA, Clarke MC . 1978. The scrapie agent: evidence against its dependence for replication on intrinsic nucleic acid. J Gen Virol 41 : 503 516.[PubMed]
25. 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.[PubMed]
26. Prusiner SB . 1989. Creutzfeldt-Jakob disease and scrapie prions. Alzheimer Dis Assoc Disord 3 : 52 78.[PubMed]
27. Takada LT, Geschwind MD . 2013. Prion diseases. Semin Neurol 33 : 348 356.[PubMed]
28. Scott MR, Will R, Ironside J, Nguyen HO, Tremblay P, DeArmond SJ, Prusiner SB . 1999. Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans. Proc Natl Acad Sci USA 96 : 15137 15142.[PubMed]
29. Baron T, Biacabe AG, Arsac JN, Benestad S, Groschup MH . 2007. Atypical transmissible spongiform encephalopathies (TSEs) in ruminants. Vaccine 25 : 5625 5630.[PubMed]
30. Benestad SL, Arsac JN, Goldmann W, Nöremark M . 2008. Atypical/Nor98 scrapie: properties of the agent, genetics, and epidemiology. Vet Res 39 : 19.[PubMed]
31. Biacabe AG, Morignat E, Vulin J, Calavas D, Baron TG . 2008. Atypical bovine spongiform encephalopathies, France, 2001–2007. Emerg Infect Dis 14 : 298 300.[PubMed]
32. Detwiler LA . 1992. Scrapie. Rev Sci Tech 11 : 491 537.[PubMed]
33. Wells GA, Wilesmith JW . 1995. The neuropathology and epidemiology of bovine spongiform encephalopathy. Brain Pathol 5 : 91 103.[PubMed]
34. Bons N, Mestre-Frances N, Belli P, Cathala F, Gajdusek DC, Brown P . 1999. Natural and experimental oral infection of nonhuman primates by bovine spongiform encephalopathy agents. Proc Natl Acad Sci USA 96 : 4046 4051.[PubMed]
35. Bons N, Mestre-Frances N, Guiraud I, Charnay Y . 1997. Prion immunoreactivity in brain, tonsil, gastrointestinal epithelial cells, and blood and lymph vessels in lemurian zoo primates with spongiform encephalopathy. C R Acad Sci III 320 : 971 979.[PubMed]
36. Ryder SJ, Wells GA, Bradshaw JM, Pearson GR . 2001. Inconsistent detection of PrP in extraneural tissues of cats with feline spongiform encephalopathy. Vet Rec 148 : 437 441.[PubMed]
37. Cunningham AA, Kirkwood JK, Dawson M, Spencer YI, Green RB, Wells GA . 2004. Bovine spongiform encephalopathy infectivity in greater kudu (Tragelaphus strepsiceros). Emerg Infect Dis 10 : 1044 1049.[PubMed]
38. Lezmi S, Bencsik A, Monks E, Petit T, Baron T . 2003. First case of feline spongiform encephalopathy in a captive cheetah born in France: PrP(sc) analysis in various tissues revealed unexpected targeting of kidney and adrenal gland. Histochem Cell Biol 119 : 415 422.[PubMed]
39. Young S, Slocombe RF . 2003. Prion-associated spongiform encephalopathy in an imported Asiatic golden cat (Catopuma temmincki). Aust Vet J 81 : 295 296.[PubMed]
40. Williams ES, Young S . 1980. Chronic wasting disease of captive mule deer: a spongiform encephalopathy. J Wildl Dis 16 : 89 98.[PubMed]
41. Sigurdson CJ . 2008. A prion disease of cervids: chronic wasting disease. Vet Res 39 : 41.[PubMed]
42. Marsh RF, Hadlow WJ . 1992. Transmissible mink encephalopathy. Rev Sci Tech 11 : 539 550.[PubMed]
43. Bessen RA, Marsh RF . 1992. Biochemical and physical properties of the prion protein from two strains of the transmissible mink encephalopathy agent. J Virol 66 : 2096 2101.[PubMed]
44. Telling GC, Parchi P, DeArmond SJ, Cortelli P, Montagna P, Gabizon R, Mastrianni J, Lugaresi E, Gambetti P, Prusiner SB . 1996. Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274 : 2079 2082.[PubMed]
45. 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.[PubMed]
46. 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.[PubMed]
47. Peretz D, Williamson RA, Legname G, Matsunaga Y, Vergara J, Burton DR, DeArmond SJ, Prusiner SB, Scott MR . 2002. A change in the conformation of prions accompanies the emergence of a new prion strain. Neuron 34 : 921 932.[PubMed]
48. Bruce ME, McBride PA, Farquhar CF . 1989. Precise targeting of the pathology of the sialoglycoprotein, PrP, and vacuolar degeneration in mouse scrapie. Neurosci Lett 102 : 1 6.[PubMed]
49. Fraser H, Dickinson AG . 1968. The sequential development of the brain lesion of scrapie in three strains of mice. J Comp Pathol 78 : 301 311.[PubMed]
50. Fraser H, Dickinson AG . 1973. Scrapie in mice. Agent-strain differences in the distribution and intensity of grey matter vacuolation. J Comp Pathol 83 : 29 40.[PubMed]
51. Smirnovas V, Kim JI, Lu X, Atarashi R, Caughey B, Surewicz WK . 2009. Distinct structures of scrapie prion protein (PrPSc)-seeded versus spontaneous recombinant prion protein fibrils revealed by hydrogen/deuterium exchange. J Biol Chem 284 : 24233 24241.[PubMed]
52. Smirnovas V, Baron GS, Offerdahl DK, Raymond GJ, Caughey B, Surewicz WK . 2011. Structural organization of brain-derived mammalian prions examined by hydrogen-deuterium exchange. Nat Struct Mol Biol 18 : 504 506.[PubMed]
53. 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 : 180 182.[PubMed]
54. 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 : 282 288.[PubMed]
55. Pan KM , 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.[PubMed]
56. Bolton DC, Meyer RK, Prusiner SB . 1985. Scrapie PrP 27–30 is a sialoglycoprotein. J Virol 53 : 596 606.[PubMed]
57. Stahl N, Borchelt DR, Hsiao K, Prusiner SB . 1987. Scrapie prion protein contains a phosphatidylinositol glycolipid. Cell 51 : 229 240.[PubMed]
58. Stahl N, Baldwin MA, Burlingame AL, Prusiner SB . 1990. Identification of glycoinositol phospholipid linked and truncated forms of the scrapie prion protein. Biochemistry 29 : 8879 8884.[PubMed]
59. Caughey BW, Dong A, Bhat KS, Ernst D, Hayes SF, Caughey WS . 1991. Secondary structure analysis of the scrapie-associated protein PrP 27–30 in water by infrared spectroscopy. Biochemistry 30 : 7672 7680.[PubMed]
60. Apostol MI, Wiltzius JJ, Sawaya MR, Cascio D, Eisenberg D . 2011. Atomic structures suggest determinants of transmission barriers in mammalian prion disease. Biochemistry 50 : 2456 2463.[PubMed]
61. Sawaya MR, Sambashivan S, Nelson R, Ivanova MI, Sievers SA, Apostol MI, Thompson MJ, Balbirnie M, Wiltzius JJ, McFarlane HT, Madsen , Riekel C, Eisenberg D . 2007. Atomic structures of amyloid cross-beta spines reveal varied steric zippers. Nature 447 : 453 457.[PubMed]
62. Bremer J, Baumann F, Tiberi C, Wessig C, Fischer H, Schwarz P, Steele AD, Toyka KV, Nave KA, Weis J, Aguzzi A . 2010. Axonal prion protein is required for peripheral myelin maintenance. Nat Neurosci 13 : 310 318.[PubMed]
63. 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 : 662 663.[PubMed]
64. Viles JH, Cohen FE, Prusiner SB, Goodin DB, Wright PE, Dyson HJ . 1999. Copper binding to the prion protein: structural implications of four identical cooperative binding sites. Proc Natl Acad Sci USA 96 : 2042 2047.[PubMed]
65. Grant SG, O'Dell TJ, Karl KA, Stein PL, Soriano P, Kandel ER . 1992. Impaired long-term potentiation, spatial learning, and hippocampal development in Fyn mutant mice. Science 258 : 1903 1910.[PubMed]
66. Um JW, Kaufman AC, Kostylev M, 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 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein. Neuron 79 : 887 902.[PubMed]
67. Bounhar Y, Zhang Y, Goodyer CG, LeBlanc A . 2001. Prion protein protects human neurons against Bax-mediated apoptosis. J Biol Chem 276 : 39145 39149.[PubMed]
68. Kurschner C, Morgan JI . 1995. The cellular prion protein (PrP) selectively binds to Bcl-2 in the yeast two-hybrid system. Brain Res Mol Brain Res 30 : 165 168.[PubMed]
69. Shmerling D, Hegyi I, Fischer M, Blättler T, Brandner S, Götz J, Rülicke T, Flechsig E, Cozzio A, von Mering C, Hangartner C, Aguzzi A, Weissmann C . 1998. Expression of amino-terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions. Cell 93 : 203 214.[PubMed]
70. Nishida N, Tremblay P, Sugimoto T, Shigematsu K, Shirabe S, Petromilli C, Erpel SP, Nakaoke R, Atarashi R, Houtani T, Torchia M, Sakaguchi S, DeArmond SJ, Prusiner SB, Katamine S . 1999. A mouse prion protein transgene rescues mice deficient for the prion protein gene from purkinje cell degeneration and demyelination. Lab Invest 79 : 689 697.[PubMed]
71. Tobler I, Deboer T, Fischer M . 1997. Sleep and sleep regulation in normal and prion protein-deficient mice. J Neurosci 17 : 1869 1879.[PubMed]
72. 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 : 639 642.[PubMed]
73. 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 : 770 774.[PubMed]
74. Wille H, Bian W, McDonald M, Kendall A, Colby DW, Bloch L, Ollesch J, Borovinskiy AL, Cohen FE, Prusiner SB, Stubbs G . 2009. Natural and synthetic prion structure from X-ray fiber diffraction. Proc Natl Acad Sci USA 106 : 16990 16995.[PubMed]
75. Groveman BR, Dolan MA, Taubner LM, Kraus A, Wickner RB, Caughey B . 2014. Parallel in-register intermolecular β-sheet architectures for prion-seeded prion protein (PrP) amyloids. J Biol Chem 289 : 24129 24142.[PubMed]
76. Wille H, Michelitsch MD, Guenebaut V, Supattapone S, Serban A, Cohen FE, Agard DA, Prusiner SB . 2002. Structural studies of the scrapie prion protein by electron crystallography. Proc Natl Acad Sci USA 99 : 3563 3568.[PubMed]
77. Prusiner SB, Cochran SP, Groth DF, Downey DE, Bowman KA, Martinez HM . 1982. Measurement of the scrapie agent using an incubation time interval assay. Ann Neurol 11 : 353 358.[PubMed]
78. Sklaviadis T, Dreyer R, Manuelidis L . 1992. Analysis of Creutzfeldt-Jakob disease infectious fractions by gel permeation chromatography and sedimentation field flow fractionation. Virus Res 26 : 241 254.[PubMed]
79. Silveira JR, Raymond GJ, Hughson AG, Race RE, Sim VL, Hayes SF, Caughey B . 2005. The most infectious prion protein particles. Nature 437 : 257 261.[PubMed]
80. McKinley MP, Braunfeld MB, Bellinger CG, Prusiner SB . 1986. Molecular characteristics of prion rods purified from scrapie-infected hamster brains. J Infect Dis 154 : 110 120.[PubMed]
81. Prusiner SB, Groth D, Serban A, Koehler R, Foster D, Torchia M, Burton D, Yang SL, DeArmond SJ . 1993. Ablation of the prion protein (PrP) gene in mice prevents scrapie and facilitates production of anti-PrP antibodies. Proc Natl Acad Sci USA 90 : 10608 10612.[PubMed]
82. Williamson RA, Peretz D, Smorodinsky N, Bastidas R, Serban H, Mehlhorn I, DeArmond SJ, Prusiner SB, Burton DR . 1996. Circumventing tolerance to generate autologous monoclonal antibodies to the prion protein. Proc Natl Acad Sci USA 93 : 7279 7282.[PubMed]
83. Fischer M, Rülicke T, Raeber A, Sailer A, Moser M, Oesch B, Brandner S, Aguzzi A, Weissmann C . 1996. Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO J 15 : 1255 1264.[PubMed]
84. Flechsig E, Shmerling D, Hegyi I, Raeber AJ, Fischer M, Cozzio A, von Mering C, Aguzzi A, Weissmann C . 2000. Prion protein devoid of the octapeptide repeat region restores susceptibility to scrapie in PrP knockout mice. Neuron 27 : 399 408.[PubMed]
85. Supattapone S, Bosque P, Muramoto T, Wille H, Aagaard C, Peretz D, Nguyen HO, Heinrich C, Torchia M, Safar J, Cohen FE, DeArmond SJ, Prusiner SB, Scott M . 1999. Prion protein of 106 residues creates an artifical transmission barrier for prion replication in transgenic mice. Cell 96 : 869 878.[PubMed]
86. Supattapone S . 2014. Synthesis of high titer infectious prions with cofactor molecules. J Biol Chem 289 : 19850 1985.[PubMed]
87. Tanaka M, Collins SR, Toyama BH, Weissman JS . 2006. The physical basis of how prion conformations determine strain phenotypes. Nature 442 : 585 589.[PubMed]
88. Castilla J, Saá P, Hetz C, Soto C . 2005. In vitro generation of infectious scrapie prions. Cell 121 : 195 206.[PubMed]
89. Prusiner SB, Scott M, Foster D, Pan K-M, Groth D, Mirenda C, Torchia M, Yang S-L, Serban D, Carlson GA, Hoppe PC, Westaway D, DeArmond SJ . 1990. Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell 63 : 673 686.[PubMed]
90. Scott M, Groth D, Foster D, Torchia M, Yang SL, DeArmond SJ, Prusiner SB . 1993. Propagation of prions with artificial properties in transgenic mice expressing chimeric PrP genes. Cell 73 : 979 988.[PubMed]
91. Hamir AN, Miller JM, Cutlip RC, Kunkle RA, Jenny AL, Stack MJ, Chaplin MJ, Richt JA . 2004. Transmission of sheep scrapie to elk (Cervus elaphus nelsoni) by intracerebral inoculation: final outcome of the experiment. J Vet Diagn Invest 16 : 316 321.[PubMed]
92. 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.[PubMed]
93. Piening N, Nonno R, Di Bari M, Walter S, Windl O, Agrimi U, Kretzschmar HA, Bertsch U . 2006. Conversion efficiency of bank vole prion protein in vitro is determined by residues 155 and 170, but does not correlate with the high susceptibility of bank voles to sheep scrapie in vivo. J Biol Chem 281 : 9373 9384.[PubMed]
94. Watts JC, Giles K, Patel S, Oehler A, DeArmond SJ, Prusiner SB . 2014. Evidence that bank vole PrP is a universal acceptor for prions. PLoS Pathog 10 : e1003990.[PubMed]
95. Kurt TD, Seelig DM, Schneider JR, Johnson CJ, Telling GC, Heisey DM, Hoover EA . 2011. Alteration of the chronic wasting disease species barrier by in vitro prion amplification. J Virol 85 : 8528 8537.[PubMed]
96. Heisey DM, Mickelsen NA, Schneider JR, Johnson CJ, Johnson CJ, Langenberg JA, Bochsler PN, Keane DP, Barr DJ . 2010. Chronic wasting disease (CWD) susceptibility of several North American rodents that are sympatric with cervid CWD epidemics. J Virol 84 : 210 215.[PubMed]
97. Kurt TD, Jiang L, Fernández-Borges N, Bett C, Liu J, Yang T, Spraker TR, Castilla J, Eisenberg D, Kong Q, Sigurdson CJ . 2015. Human prion protein sequence elements impede cross-species chronic wasting disease transmission. J Clin Invest 125 : 1485 1496.
98. Collinge J, Palmer MS, Dryden AJ . 1991. Genetic predisposition to iatrogenic Creutzfeldt-Jakob disease. Lancet 337 : 1441 1442.[PubMed]
99. Ironside JW . 2012. Variant Creutzfeldt-Jakob disease: an update. Folia Neuropathol 50 : 50 56.[PubMed]
100. Kaski D, Mead S, Hyare H, Cooper S, Jampana R, Overell J, Knight R, Collinge J, Rudge P . 2009. Variant CJD in an individual heterozygous for PRNP codon 129. Lancet 374 : 2128.[PubMed]
101. Peden A, McCardle L, Head MW, Love S, Ward HJ, Cousens SN, Keeling DM, Millar CM, Hill FG, Ironside JW . 2010. Variant CJD infection in the spleen of a neurologically asymptomatic UK adult patient with haemophilia. Haemophilia 16 : 296 304.[PubMed]
102. 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]
103. Ghaemmaghami S, May BC, Renslo AR, Prusiner SB . 2010. Discovery of 2-aminothiazoles as potent antiprion compounds. J Virol 84 : 3408 3412.[PubMed]
104. Giri RK, Young R, Pitstick R, DeArmond SJ, Prusiner SB, Carlson GA . 2006. Prion infection of mouse neurospheres. Proc Natl Acad Sci USA 103 : 3875 3880.[PubMed]
105. Cronier S, Laude H, Peyrin JM . 2004. Prions can infect primary cultured neurons and astrocytes and promote neuronal cell death. Proc Natl Acad Sci USA 101 : 12271 12276.[PubMed]
106. Brandel JP, Delasnerie-Lauprêtre N, Laplanche JL, Hauw JJ, Alpérovitch A . 2000. Diagnosis of Creutzfeldt-Jakob disease: effect of clinical criteria on incidence estimates. Neurology 54 : 1095 1099.[PubMed]
107. Aguzzi A , et al . Rapport des activitées 1996–1999. Hôpital universitaire de Zurich. Département de pathologie. Institut de neuropathologie. Centre nationale de référence pour les prionoses (NRPE). (Acrobat file) 2000; Available from: www.unizh.ch/pathol/neuropathologie/d/ptn_prionen_index.html.[PubMed]
108. Glatzel M, Ott PM, Linder T, Gebbers JO, Gmür A, Wüst W, Huber G, Moch H, Podvinec M, Stamm B, Aguzzi A . 2003. Human prion diseases: epidemiology and integrated risk assessment. Lancet Neurol 2 : 757 763.[PubMed]
109. Brown P, Cathala F, Raubertas RF, Gajdusek DC, Castaigne P . 1987. The epidemiology of Creutzfeldt-Jakob disease: conclusion of a 15-year investigation in France and review of the world literature. Neurology 37 : 895 904.[PubMed]
110. Palmer MS, Dryden AJ, Hughes JT, Collinge J . 1991. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature 352 : 340 342.[PubMed]
111. 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, Alpérovitch 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.[PubMed]
112. 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.[PubMed]
113. 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.[PubMed]
114. 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.[PubMed]
115. 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.[PubMed]
116. 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.[PubMed]
117. 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.[PubMed]
118. Harries-Jones R, Knight R, Will RG, Cousens S, Smith PG, Matthews WB . 1988. Creutzfeldt-Jakob disease in England and Wales, 1980–1984: a case-control study of potential risk factors. J Neurol Neurosurg Psychiatry 51 : 1113 1119.[PubMed]
119. van Duijn CM, Delasnerie-Lauprêtre N, Masullo C, Zerr I, de Silva R, Wientjens DP, Brandel JP, Weber T, Bonavita V, Zeidler M, Alpérovitch A, Poser S, Granieri E, Hofman A, Will RG . 1998. Case-control study of risk factors of Creutzfeldt-Jakob disease in Europe during 1993–95. European Union (EU) Collaborative Study Group of Creutzfeldt-Jakob disease (CJD). Lancet 351 : 1081 1085.[PubMed]
120. Collins S, Law MG, Fletcher A, Boyd A, Kaldor J, Masters CL . 1999. Surgical treatment and risk of sporadic Creutzfeldt-Jakob disease: a case-control study. Lancet 353 : 693 697.[PubMed]
121. Ward HJ, Everington D, Cousens SN, Smith-Bathgate B, Gillies M, Murray K, Knight RS, Smith PG, Will RG . 2008. Risk factors for sporadic Creutzfeldt-Jakob disease. Ann Neurol 63 : 347 354.[PubMed]
122. Mahillo-Fernandez I, de Pedro-Cuesta J, Bleda MJ, Cruz M, Mølbak K, Laursen H, Falkenhorst G, Martínez-Martín P, Siden A EUROSURGYCJD Research Group . 2008. Surgery and risk of sporadic Creutzfeldt-Jakob disease in Denmark and Sweden: registry-based case-control studies. Neuroepidemiology 31 : 229 240.[PubMed]
123. Harder A, Jendroska K, Kreuz F, Wirth T, Schafranka C, Karnatz N, Théallier-Janko A, Dreier J, Lohan K, Emmerich D, Cervós-Navarro J, Windl O, Kretzschmar HA, Nürnberg P, Witkowski R . 1999. Novel twelve-generation kindred of fatal familial insomnia from germany representing the entire spectrum of disease expression. Am J Med Genet 87 : 311 316.[PubMed]
124. Kong Q, . 2004. W.K.S., Robert B. Petersen, Wenquan Zou, Shu G. Chen, Pierluigi Gambetti, Piero Parchi, Sabina Capellari, Lev Goldfarb, Pasquale Montagna, Elio Lugaresi, Pedro Piccardo, Bernadino Ghetti, p 673 776. In Prusiner SB (ed), Prion Biology and Diseases. Cold Spring Harbor Laboratory Press, Cold Spring Harbor.
125. Kahana E, Zilber N, Abraham M . 1991. Do Creutzfeldt-Jakob disease patients of Jewish Libyan origin have unique clinical features? Neurology 41 : 1390 1392.[PubMed]
126. Simon ES, Kahana E, Chapman J, Treves TA, Gabizon R, Rosenmann H, Zilber N, Korczyn AD . 2000. Creutzfeldt-Jakob disease profile in patients homozygous for the PRNP E200K mutation. Ann Neurol 47 : 257 260.[PubMed]
127. Roos R, Gajdusek DC, Gibbs CJ Jr . 1973. The clinical characteristics of transmissible Creutzfeldt-Jakob disease. Brain 96 : 1 20.[PubMed]
128. Brown P, Gibbs CJ Jr, Rodgers-Johnson P, Asher DM, Sulima MP, Bacote A, Goldfarb LG, Gajdusek DC . 1994. Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol 35 : 513 529.[PubMed]
129. Sigurdson CJ, Nilsson KP, Hornemann S, Heikenwalder M, Manco G, Schwarz P, Ott D, Rülicke T, Liberski PP, Julius C, Falsig J, Stitz L, Wüthrich K, Aguzzi A . 2009. De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis. Proc Natl Acad Sci USA 106 : 304 309.[PubMed]
130. Jackson WS, Borkowski AW, Faas H, Steele AD, King OD, Watson N, Jasanoff A, Lindquist S . 2009. Spontaneous generation of prion infectivity in fatal familial insomnia knockin mice. Neuron 63 : 438 450.[PubMed]
131. Hsiao KK, Scott M, Foster D, Groth DF, DeArmond SJ, Prusiner SB . 1990. Spontaneous neurodegeneration in transgenic mice with mutant prion protein. Science 250 : 1587 1590.[PubMed]
132. Will RG, . 2003. Acquired prion disease: iatrogenic CJD, variant CJD, kuru, p 255 265. In Weissmann C, Aguzzi A, Dormont D, Hunter N (ed), Prions for Physicians. Oxford University Press.[PubMed]
133. Hoshi K, Yoshino H, Urata J, Nakamura Y, Yanagawa H, Sato T . 2000. Creutzfeldt-Jakob disease associated with cadaveric dura mater grafts in Japan. Neurology 55 : 718 721.[PubMed]
134. Dorsey K, Zou S, Schonberger LB, Sullivan M, Kessler D, Notari E IV, Fang CT, Dodd RY . 2009. Lack of evidence of transfusion transmission of Creutzfeldt-Jakob disease in a US surveillance study. Transfusion 49 : 977 984.[PubMed]
135. Urwin PJ, Mackenzie JM, Llewelyn CA, Will RG, Hewitt PE . 2015. Creutzfeldt-Jakob disease and blood transfusion: updated results of the UK Transfusion Medicine Epidemiology Review Study. Vox Sang.[PubMed]
136. Llewelyn CA, Hewitt PE, Knight RS, Amar K, Cousens S, Mackenzie J, Will RG . 2004. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 363 : 417 421.[PubMed]
137. Wroe SJ, Pal S, Siddique D, Hyare H, Macfarlane R, Joiner S, Linehan JM, Brandner S, Wadsworth JD, Hewitt P, Collinge J . 2006. Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt-Jakob disease associated with blood transfusion: a case report. Lancet 368 : 2061 2067.[PubMed]
138. 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 : 527 529.[PubMed]
139. Houston F, McCutcheon S, Goldmann W, Chong A, Foster J, Sisó S, González L, Jeffrey M, Hunter N . 2008. Prion diseases are efficiently transmitted by blood transfusion in sheep. Blood 112 : 4739 4745.[PubMed]
140. Knight R . 2010. The risk of transmitting prion disease by blood or plasma products. Transfus Apheresis Sci 43 : 387 391.[PubMed]
141. Murray K, Peters J, Stellitano L, Winstone AM, Verity C, Will RG . 2011. Is there evidence of vertical transmission of variant Creutzfeldt-Jakob disease? J Neurol Neurosurg Psychiatry 82 : 729 731.[PubMed]
142. 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 : 2056 2065.[PubMed]
143. Asante EA, Smidak M, Grimshaw A, Houghton R, Tomlinson A, Jeelani A, Jakubcova T, Hamdan S, Richard-Londt A, Linehan JM, Brandner S, Alpers M, Whitfield J, Mead S, Wadsworth JD, Collinge J . 2015. A naturally occurring variant of the human prion protein completely prevents prion disease. Nature 522 : 478 481[PubMed]
144. Collinge J . 1999. Variant Creutzfeldt-Jakob disease. Lancet 354 : 317 323.[PubMed]
145. Brown KL, Wathne GJ, Sales J, Bruce ME, Mabbott NA . 2009. The effects of host age on follicular dendritic cell status dramatically impair scrapie agent neuroinvasion in aged mice. J Immunol 183 : 5199 5207.[PubMed]
146. 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 : 2068 2074.[PubMed]
147. Lee HS, Brown P, Cervenáková L, Garruto RM, Alpers MP, Gajdusek DC, Goldfarb LG . 2001. Increased susceptibility to Kuru of carriers of the PRNP 129 methionine/methionine genotype. J Infect Dis 183 : 192 196.[PubMed]
148. Mathiason CK, Hays SA, Powers J, Hayes-Klug J, Langenberg J, Dahmes SJ, Osborn