Three decades after the discovery of prions as the cause of Creutzfeldt-Jakob disease and other transmissible spongiform encephalopathies, we are still nowhere close to finding an effective therapy. Numerous pharmacological interventions have attempted to target various stages of disease progression, yet none has significantly ameliorated the course of disease. We still lack a mechanistic understanding of how the prions damage the brain, and this situation results in a dearth of validated pharmacological targets. In this review, we discuss the attempts to interfere with the replication of prions and to enhance their clearance. We also trace some of the possibilities to identify novel targets that may arise with increasing insights into prion biology.


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Literature Cited

  1. Aguzzi A. 1.  2009. Cell biology: beyond the prion principle. Nature 459:924–25 [Google Scholar]
  2. Aguzzi A, Rajendran L. 2.  2009. The transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron 64:783–90 [Google Scholar]
  3. Aguzzi A. 3.  2006. Prion diseases of humans and farm animals: epidemiology, genetics, and pathogenesis. J. Neurochem. 97:1726–39 [Google Scholar]
  4. Aguzzi A, Falsig J. 4.  2012. Prion propagation, toxicity and degradation. Nat. Neurosci. 15:936–39 [Google Scholar]
  5. Aguzzi A, Heikenwalder M. 5.  2006. Pathogenesis of prion diseases: current status and future outlook. Nat. Rev. Microbiol. 4:765–75 [Google Scholar]
  6. Aguzzi A, Heikenwalder M, Polymenidou M. 6.  2007. Insights into prion strains and neurotoxicity. Nat. Rev. Mol. Cell Biol. 8:552–61 [Google Scholar]
  7. Prusiner SB. 7.  1982. Novel proteinaceous infectious particles cause scrapie. Science 216:136–44 [Google Scholar]
  8. Aguzzi A, Sigurdson C, Heikenwaelder M. 8.  2008. Molecular mechanisms of prion pathogenesis. Annu. Rev. Pathol. Mech. Dis. 3:11–40 [Google Scholar]
  9. Brandner S, Raeber A, Sailer A, Blattler T, Fischer M. 9.  et al. 1996. Normal host prion protein (PrPC) is required for scrapie spread within the central nervous system. PNAS 93:13148–51 [Google Scholar]
  10. Stahl N, Borchelt DR, Prusiner SB. 10.  1990. Differential release of cellular and scrapie prion proteins from cellular membranes by phosphatidylinositol-specific phospholipase C. Biochemistry 29:5405–12 [Google Scholar]
  11. Mastrianni JA. 11.  2010. The genetics of prion diseases. Genet. Med. 12:187–95 [Google Scholar]
  12. Snow AD, Kisilevsky R, Willmer J, Prusiner SB, DeArmond SJ. 12.  1989. Sulfated glycosaminoglycans in amyloid plaques of prion diseases. Acta Neuropathol 77:337–42 [Google Scholar]
  13. Gabizon R, Meiner Z, Halimi M, Ben-Sasson SA. 13.  1993. Heparin-like molecules bind differentially to prion-proteins and change their intracellular metabolic fate. J. Cell Physiol. 157:319–25 [Google Scholar]
  14. Ingrosso L, Ladogana A, Pocchiari M. 14.  1995. Congo red prolongs the incubation period in scrapie-infected hamsters. J. Virol. 69:506–8 [Google Scholar]
  15. Poli G, Martino PA, Villa S, Carcassola G, Giannino ML. 15.  et al. 2004. Evaluation of anti-prion activity of Congo red and its derivatives in experimentally infected hamsters. Arzneim.-Forsch. 54:406–15 [Google Scholar]
  16. Supattapone S, Nguyen HO, Cohen FE, Prusiner SB, Scott MR. 16.  1999. Elimination of prions by branched polyamines and implications for therapeutics. PNAS 96:14529–34 [Google Scholar]
  17. Solassol J, Crozet C, Perrier V, Leclaire J, Béranger F. 17.  et al. 2004. Cationic phosphorus-containing dendrimers reduce prion replication both in cell culture and in mice infected with scrapie. J. Gen. Virol. 85:1791–99 [Google Scholar]
  18. Klajnert B, Cortijo-Arellano M, Cladera J, Majoral JP, Caminade AM, Bryszewska M. 18.  2007. Influence of phosphorus dendrimers on the aggregation of the prion peptide PrP 185–208. Biochem. Biophys. Res. Commun. 364:20–25 [Google Scholar]
  19. Doh-ura K, Ishikawa K, Murakami-Kubo I, Sasaki K, Mohri S. 19.  et al. 2004. Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion in animal models. J. Virol. 78:4999–5006 [Google Scholar]
  20. Honda H, Sasaki K, Minaki H, Masui K, Suzuki SO. 20.  et al. 2012. Protease-resistant PrP and PrP oligomers in the brain in human prion diseases after intraventricular pentosan polysulfate infusion. Neuropathology 32:124–32 [Google Scholar]
  21. Terzano MG, Montanari E, Calzetti S, Mancia D, Lechi A. 21.  1983. The effect of amantadine on arousal and EEG patterns in Creutzfeldt-Jakob disease. Arch. Neurol. 40:555–59 [Google Scholar]
  22. Ratcliffe J, Rittman A, Wolf S, Verity MA. 22.  1975. Creutzfeldt-Jakob disease with focal onset unsuccessfully treated with amantadine. Bull. Los Angel. Neurol. Soc. 40:18–20 [Google Scholar]
  23. Wolpow ER, Kleinman GM. 23.  1980. Case 45–1980—a 43-year-old man with progressive ataxia and deterioration of mental function. N. Engl. J. Med. 303:1162–71 [Google Scholar]
  24. David AS, Grant R, Ballantyne JP. 24.  1984. Unsuccessful treatment of Creutzfeldt-Jakob disease with acyclovir. Lancet 323:512–13 [Google Scholar]
  25. Newman PK. 25.  1984. Acyclovir in Creutzfeldt-Jakob disease. Lancet 323:793 [Google Scholar]
  26. Kovanen J, Haltia M, Cantell K. 26.  1980. Failure of interferon to modify Creutzfeldt-Jakob disease. Br. Med. J. 280:902 [Google Scholar]
  27. Otto M, Cepek L, Ratzka P, Doehlinger S, Boekhoff I. 27.  et al. 2004. Efficacy of flupirtine on cognitive function in patients with CJD: a double-blind study. Neurology 62:714–18 [Google Scholar]
  28. Love R. 28.  2001. Old drugs to treat new variant Creutzfeldt-Jakob disease. Lancet 358:563 [Google Scholar]
  29. Haïk S, Brandel JP, Salomon D, Sazdovitch V, Delasnerie-Lauprêtre N. 29.  et al. 2004. Compassionate use of quinacrine in Creutzfeldt–Jakob disease fails to show significant effects. Neurology 63:2413–15 [Google Scholar]
  30. Collinge J, Gorham M, Hudson F, Kennedy A, Keogh G. 30.  et al. 2009. Safety and efficacy of quinacrine in human prion disease (PRION-1 study): a patient-preference trial. Lancet Neurol 8:334–44 [Google Scholar]
  31. Geschwind MD, Kuo AL, Wong KS, Haman A, Devereux G. 31.  et al. 2013. Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease. Neurology 81:2015–23 [Google Scholar]
  32. Drisko JA. 32.  2002. The use of antioxidants in transmissible spongiform encephalopathies: a case report. J. Am. Coll. Nutr. 21:22–25 [Google Scholar]
  33. Tagliavini F. 33.  2008. Prion therapy: tetracyclic compounds in animal models and patients with Creutzfeldt-Jakob disease. Alzheimer's Dement 4:T149–50 [Google Scholar]
  34. Haïk S, Marcon G, Mallet A, Tettamanti M, Welaratne A. 34.  et al. 2014. Doxycycline in Creutzfeldt-Jakob disease: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol 13:150–58 [Google Scholar]
  35. Assar H, Topakian R, Weis S, Rahimi J, Trenkler J. 35.  et al. 2015. A case of variably protease-sensitive prionopathy treated with doxycyclin. J. Neurol. Neurosurg. Psychiatry 86:816–18 [Google Scholar]
  36. Li J, Browning S, Mahal SP, Oelschlegel AM, Weissmann C. 36.  2010. Darwinian evolution of prions in cell culture. Science 327:869–72 [Google Scholar]
  37. Falsig J, Sonati T, Herrmann US, Saban D, Li B. 37.  et al. 2012. Prion pathogenesis is faithfully reproduced in cerebellar organotypic slice cultures. PLOS Pathog 8:e1002985 [Google Scholar]
  38. Herrmann US, Sonati T, Falsig J, Reimann RR, Dametto P, O'Connor T. 38.  2015. Correction: Prion infections and anti-PrP antibodies trigger converging neurotoxic pathways. PLOS Pathog 11:e1004808 [Google Scholar]
  39. Herrmann US, Sonati T, Falsig J, Reimann RR, Dametto P. 39.  et al. 2015. Prion infections and anti-PrP antibodies trigger converging neurotoxic pathways. PLOS Pathog 11:e1004662 [Google Scholar]
  40. Knowles TP, Waudby CA, Devlin GL, Cohen SI, Aguzzi A. 40.  et al. 2009. An analytical solution to the kinetics of breakable filament assembly. Science 326:1533–37 [Google Scholar]
  41. Sonati T, Reimann RR, Falsig J, Baral PK, O'Connor T. 41.  et al. 2013. The toxicity of antiprion antibodies is mediated by the flexible tail of the prion protein. Nature 501:102–6 [Google Scholar]
  42. Zhu C, Herrmann US, Falsig J, Abakumova I, Nuvolone M. 42.  et al. 2016. A neuroprotective role for microglia in prion diseases. J. Exp. Med. 213:1047–59 [Google Scholar]
  43. Cox B, Ness F, Tuite M. 43.  2003. Analysis of the generation and segregation of propagons: entities that propagate the [PSI+] prion in yeast. Genetics 165:23–33 [Google Scholar]
  44. Nilsson KPR, Herland A, Hammarström P, Inganäs O. 44.  2005. Conjugated polyelectrolytes: conformation-sensitive optical probes for detection of amyloid fibril formation. Biochemistry 44:3718–24 [Google Scholar]
  45. Nilsson KPR, Ikenberg K, Åslund A, Fransson S, Konradsson P. 45.  et al. 2010. Structural typing of systemic amyloidoses by luminescent-conjugated polymer spectroscopy. Am. J. Pathol. 176:563–74 [Google Scholar]
  46. Sigurdson CJ, Aguzzi A. 46.  2007. Chronic wasting disease. Biochim. Biophys. Acta 1772:610–18 [Google Scholar]
  47. Margalith I, Suter C, Ballmer B, Schwarz P, Tiberi C. 47.  et al. 2012. Polythiophenes inhibit prion propagation by stabilizing prion protein (PrP) aggregates. J. Biol. Chem. 287:18872–87 [Google Scholar]
  48. Herrmann US, Schutz AK, Shirani H, Huang D, Saban D. 48.  et al. 2015. Structure-based drug design identifies polythiophenes as antiprion compounds. Sci. Transl. Med. 7:299ra123 [Google Scholar]
  49. Hipp MS, Park SH, Hartl FU. 49.  2014. Proteostasis impairment in protein-misfolding and -aggregation diseases. Trends Cell Biol 24:506–14 [Google Scholar]
  50. Kenward N, Hope J, Landon M, Mayer RJ. 50.  1994. Expression of polyubiquitin and heat-shock protein 70 genes increases in the later stages of disease progression in scrapie-infected mouse brain. J. Neurochem. 62:1870–77 [Google Scholar]
  51. Lowe J, Fergusson J, Kenward N, Laszlo L, Landon M. 51.  et al. 1992. Immunoreactivity to ubiquitin-protein conjugates is present early in the disease process in the brains of scrapie-infected mice. J. Pathol. 168:169–77 [Google Scholar]
  52. Kristiansen M, Deriziotis P, Dimcheff DE, Jackson GS, Ovaa H. 52.  et al. 2007. Disease-associated prion protein oligomers inhibit the 26S proteasome. Mol. Cell 26:175–88 [Google Scholar]
  53. Kristiansen M, Messenger MJ, Klöhn PC, Brandner S, Wadsworth JDF. 53.  et al. 2005. Disease-related prion protein forms aggresomes in neuronal cells leading to caspase activation and apoptosis. J. Biol. Chem. 280:38851–61 [Google Scholar]
  54. Deriziotis P, Andre R, Smith DM, Goold R, Kinghorn KJ. 54.  et al. 2011. Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition of substrate entry. EMBO J 30:3065–77 [Google Scholar]
  55. Groll M, Bajorek M, Kohler A, Moroder L, Rubin DM. 55.  et al. 2000. A gated channel into the proteasome core particle. Nat. Struct. Biol. 7:1062–67 [Google Scholar]
  56. Ma J, Lindquist S. 56.  2001. Wild-type PrP and a mutant associated with prion disease are subject to retrograde transport and proteasome degradation. PNAS 98:14955–60 [Google Scholar]
  57. Ma J, Lindquist S. 57.  2002. Conversion of PrP to a self-perpetuating PrPSc-like conformation in the cytosol. Science 298:1785–88 [Google Scholar]
  58. Lee AH, Iwakoshi NN, Anderson KC, Glimcher LH. 58.  2003. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. PNAS 100:9946–51 [Google Scholar]
  59. Deshaies RJ. 59.  2015. Protein degradation: prime time for PROTACs. Nat. Chem. Biol. 11:634–35 [Google Scholar]
  60. Sakamoto KM. 60.  2010. Protacs for treatment of cancer. Pediatr. Res. 67:505–8 [Google Scholar]
  61. Dantuma NP, Bott LC. 61.  2014. The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution. Front. Mol. Neurosci. 7:70 [Google Scholar]
  62. Kalmar B, Edet-Amana E, Greensmith L. 62.  2012. Treatment with a coinducer of the heat shock response delays muscle denervation in the SOD1-G93A mouse model of amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 13:378–92 [Google Scholar]
  63. Ron D, Walter P. 63.  2007. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8:519–29 [Google Scholar]
  64. Ellgaard L, McCaul N, Chatsisvili A, Braakman I. 64.  2016. Co- and post-translational protein folding in the ER. Traffic 17:615–38 [Google Scholar]
  65. Harding HP, Zhang Y, Ron D. 65.  1999. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397:271–74 [Google Scholar]
  66. Lee AS. 66.  2001. The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem. Sci. 26:504–10 [Google Scholar]
  67. Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH. 67.  et al. 2007. XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol. Cell 27:53–66 [Google Scholar]
  68. Dufey E, Sepulveda D, Rojas-Rivera D, Hetz C. 68.  2014. Cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. 1. An overview. Am. J. Physiol. Cell Physiol. 307:C582–94 [Google Scholar]
  69. Hetz C, Russelakis-Carneiro M, Maundrell K, Castilla J, Soto C. 69.  2003. Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein. EMBO J 22:5435–45 [Google Scholar]
  70. Torres M, Castillo K, Armisen R, Stutzin A, Soto C, Hetz C. 70.  2010. Prion protein misfolding affects calcium homeostasis and sensitizes cells to endoplasmic reticulum stress. PLOS ONE 5:e15658 [Google Scholar]
  71. Korolchuk VI, Menzies FM, Rubinsztein DC. 71.  2010. Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems. FEBS Lett 584:1393–98 [Google Scholar]
  72. Mallucci G, Dickinson A, Linehan J, Klöhn PC, Brandner S, Collinge J. 72.  2003. Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science 302:871–74 [Google Scholar]
  73. Moreno JA, Halliday M, Molloy C, Radford H, Verity N. 73.  et al. 2013. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci. Transl. Med. 5:206ra138 [Google Scholar]
  74. Halliday M, Radford H, Sekine Y, Moreno J, Verity N. 74.  et al. 2015. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death Dis 6:e1672 [Google Scholar]
  75. Das I, Krzyzosiak A, Schneider K, Wrabetz L, D'Antonio M. 75.  et al. 2015. Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science 348:239–42 [Google Scholar]
  76. Tribouillard-Tanvier D, Beringue V, Desban N, Gug F, Bach S. 76.  et al. 2008. Antihypertensive drug guanabenz is active in vivo against both yeast and mammalian prions. PLOS ONE 3:e1981 [Google Scholar]
  77. Rouvinski A, Karniely S, Kounin M, Moussa S, Goldberg MD. 77.  et al. 2014. Live imaging of prions reveals nascent PrPSc in cell-surface, raft-associated amyloid strings and webs. J. Cell Biol. 204:423–41 [Google Scholar]
  78. Goold R, Rabbanian S, Sutton L, Andre R, Arora P. 78.  et al. 2011. Rapid cell-surface prion protein conversion revealed using a novel cell system. Nat. Commun. 2:281 [Google Scholar]
  79. Kaneko K, Vey M, Scott M, Pilkuhn S, Cohen FE, Prusiner SB. 79.  1997. COOH-terminal sequence of the cellular prion protein directs subcellular trafficking and controls conversion into the scrapie isoform. PNAS 94:2333–38 [Google Scholar]
  80. Dearmond SJ, Bajsarowicz K. 80.  2010. PrPSc accumulation in neuronal plasma membranes links Notch-1 activation to dendritic degeneration in prion diseases. Mol. Neurodegener. 5:6 [Google Scholar]
  81. Shim SY, Karri S, Law S, Schatzl HM, Gilch S. 81.  2016. Prion infection impairs lysosomal degradation capacity by interfering with rab7 membrane attachment in neuronal cells. Sci. Rep. 6:21658 [Google Scholar]
  82. Yao H, Zhao D, Khan SH, Yang L. 82.  2013. Role of autophagy in prion protein-induced neurodegenerative diseases. Acta Biochim. Biophys. Sin. 45:494–502 [Google Scholar]
  83. Boellaard JW, Kao M, Schlote W, Diringer H. 83.  1991. Neuronal autophagy in experimental scrapie. Acta Neuropathol 82:225–28 [Google Scholar]
  84. Heiseke A, Aguib Y, Schatzl HM. 84.  2010. Autophagy, prion infection and their mutual interactions. Curr. Issues Mol. Biol. 12:87–97 [Google Scholar]
  85. Ertmer A, Gilch S, Yun SW, Flechsig E, Klebl B. 85.  et al. 2004. The tyrosine kinase inhibitor STI571 induces cellular clearance of PrPSc in prion-infected cells. J. Biol. Chem. 279:41918–27 [Google Scholar]
  86. Goold R, McKinnon C, Rabbanian S, Collinge J, Schiavo G, Tabrizi SJ. 86.  2013. Alternative fates of newly formed PrPSc upon prion conversion on the plasma membrane. J. Cell Sci. 126:3552–62 [Google Scholar]
  87. Heiseke A, Aguib Y, Riemer C, Baier M, Schätzl HM. 87.  2009. Lithium induces clearance of protease resistant prion protein in prion-infected cells by induction of autophagy. J. Neurochem. 109:25–34 [Google Scholar]
  88. Karapetyan YE, Sferrazza GF, Zhou M, Ottenberg G, Spicer T. 88.  et al. 2013. Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents. PNAS 110:7044–49 [Google Scholar]
  89. Cortes CJ, Qin K, Cook J, Solanki A, Mastrianni JA. 89.  2012. Rapamycin delays disease onset and prevents PrP plaque deposition in a mouse model of Gerstmann-Straussler-Scheinker disease. J. Neurosci. 32:12396–405 [Google Scholar]
  90. Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. 90.  2007. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and α-synuclein. J. Biol. Chem. 282:5641–52 [Google Scholar]
  91. Béranger F, Crozet C, Goldsborough A, Lehmann S. 91.  2008. Trehalose impairs aggregation of PrPSc molecules and protects prion-infected cells against oxidative damage. Biochem. Biophys. Res. Commun. 374:44–48 [Google Scholar]
  92. Yun SW, Ertmer A, Flechsig E, Gilch S, Riederer P. 92.  et al. 2007. The tyrosine kinase inhibitor imatinib mesylate delays prion neuroinvasion by inhibiting prion propagation in the periphery. J. Neurovirol. 13:328–37 [Google Scholar]
  93. Shorter J, Lindquist S. 93.  2004. Hsp104 catalyzes formation and elimination of self-replicating Sup35 prion conformers. Science 304:1793–97 [Google Scholar]
  94. Winkler J, Tyedmers J, Bukau B, Mogk A. 94.  2012. Hsp70 targets Hsp100 chaperones to substrates for protein disaggregation and prion fragmentation. J. Cell Biol. 198:387–404 [Google Scholar]
  95. Turturici G, Sconzo G, Geraci F. 95.  2011. Hsp70 and its molecular role in nervous system diseases. Biochem. Res. Int. 2011:618127 [Google Scholar]
  96. Tatzelt J, Prusiner SB, Welch WJ. 96.  1996. Chemical chaperones interfere with the formation of scrapie prion protein. EMBO J 15:6363–73 [Google Scholar]
  97. Cortez L, Sim V. 97.  2014. The therapeutic potential of chemical chaperones in protein folding diseases. Prion 8:197–202 [Google Scholar]
  98. Brody DL, Holtzman DM. 98.  2008. Active and passive immunotherapy for neurodegenerative disorders. Annu. Rev. Neurosci. 31:175–93 [Google Scholar]
  99. Souan L, Tal Y, Felling Y, Cohen IR, Taraboulos A, Mor F. 99.  2001. Modulation of proteinase-K resistant prion protein by prion peptide immunization. Eur. J. Immunol. 31:2338–46 [Google Scholar]
  100. Sigurdsson EM, Brown DR, Daniels M, Kascsak RJ, Kascsak R. 100.  et al. 2002. Immunization delays the onset of prion disease in mice. Am. J. Pathol. 161:13–17 [Google Scholar]
  101. Goñi F, Knudsen E, Schreiber F, Scholtzova H, Pankiewicz J. 101.  et al. 2005. Mucosal vaccination delays or prevents prion infection via an oral route. Neuroscience 133:413–21 [Google Scholar]
  102. Schwarz A, Krätke O, Burwinkel M, Riemer C, Schultz J. 102.  et al. 2003. Immunisation with a synthetic prion protein-derived peptide prolongs survival times of mice orally exposed to the scrapie agent. Neurosci. Lett. 350:187–89 [Google Scholar]
  103. Goñi F, Mathiason CK, Yim L, Wong K, Hayes-Klug J. 103.  et al. 2015. Mucosal immunization with an attenuated Salmonella vaccine partially protects white-tailed deer from chronic wasting disease. Vaccine 33:726–33 [Google Scholar]
  104. Pilon JL, Rhyan JC, Wolfe LL, Davis TR, McCollum MP. 104.  et al. 2013. Immunization with a synthetic peptide vaccine fails to protect mule deer (Odocoileus hemionus) from chronic wasting disease. J. Wildlife Dis. 49:694–98 [Google Scholar]
  105. Petsch B, Muller-Schiffmann A, Lehle A, Zirdum E, Prikulis I. 105.  et al. 2011. Biological effects and use of PrPSc- and PrP-specific antibodies generated by immunization with purified full-length native mouse prions. J. Virol. 85:4538–46 [Google Scholar]
  106. Xanthopoulos K, Lagoudaki R, Kontana A, Kyratsous C, Panagiotidis C. 106.  et al. 2013. Immunization with recombinant prion protein leads to partial protection in a murine model of TSEs through a novel mechanism. PLOS ONE 8:e59143 [Google Scholar]
  107. Fernandez-Borges N, Brun A, Whitton JL, Parra B, Diaz-San Segundo F. 107.  et al. 2006. DNA vaccination can break immunological tolerance to PrP in wild-type mice and attenuates prion disease after intracerebral challenge. J. Virol. 80:9970–76 [Google Scholar]
  108. Nitschke C, Flechsig E, van den Brandt J, Lindner N, Luhrs T. 108.  et al. 2007. Immunisation strategies against prion diseases: prime-boost immunisation with a PrP DNA vaccine containing foreign helper T-cell epitopes does not prevent mouse scrapie. Vet. Microbiol. 123:367–76 [Google Scholar]
  109. Polymenidou M, Heppner FL, Pellicioli EC, Urich E, Miele G. 109.  et al. 2004. Humoral immune response to native eukaryotic prion protein correlates with anti-prion protection. PNAS 101:Suppl. 214670–76 [Google Scholar]
  110. Tal Y, Souan L, Cohen IR, Meiner Z, Taraboulos A, Mor F. 110.  2003. Complete Freund's adjuvant immunization prolongs survival in experimental prion disease in mice. J. Neurosci. Res. 71:286–90 [Google Scholar]
  111. Sethi S, Lipford G, Wagner H, Kretzschmar H. 111.  2002. Postexposure prophylaxis against prion disease with a stimulator of innate immunity. Lancet 360:229–30 [Google Scholar]
  112. Heikenwalder M, Polymenidou M, Junt T, Sigurdson C, Wagner H. 112.  et al. 2004. Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nat. Med. 10:187–92 [Google Scholar]
  113. Bremer J, Heikenwalder M, Haybaeck J, Tiberi C, Krautler NJ. 113.  et al. 2009. Repetitive immunization enhances the susceptibility of mice to peripherally administered prions. PLOS ONE 4:e7160 [Google Scholar]
  114. Gabizon R, McKinley MP, Groth D, Prusiner SB. 114.  1988. Immunoaffinity purification and neutralization of scrapie prion infectivity. PNAS 85:6617–21 [Google Scholar]
  115. Peretz D, Williamson RA, Kaneko K, Vergara J, Leclerc E. 115.  et al. 2001. Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature 412:739–43 [Google Scholar]
  116. Enari M, Flechsig E, Weissmann C. 116.  2001. Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody. PNAS 98:9295–99 [Google Scholar]
  117. Perrier V, Solassol J, Crozet C, Frobert Y, Mourton-Gilles C. 117.  et al. 2004. Anti-PrP antibodies block PrPSc replication in prion-infected cell cultures by accelerating PrPC degradation. J. Neurochem. 89:454–63 [Google Scholar]
  118. Féraudet C, Morel N, Simon S, Volland H, Frobert Y. 118.  et al. 2005. Screening of 145 anti-PrP monoclonal antibodies for their capacity to inhibit PrPSc replication in infected cells. J. Biol. Chem. 280:11247–58 [Google Scholar]
  119. Solforosi L, Criado JR, McGavern DB, Wirz S, Sanchez-Alavez M. 119.  et al. 2004. Cross-linking cellular prion protein triggers neuronal apoptosis in vivo. Science 303:1514–16 [Google Scholar]
  120. Moda F, Vimercati C, Campagnani I, Ruggerone M, Giaccone G. 120.  et al. 2012. Brain delivery of AAV9 expressing an anti-PrP monovalent antibody delays prion disease in mice. Prion 6:383–90 [Google Scholar]
  121. Heppner FL, Musahl C, Arrighi I, Klein MA, Rulicke T. 121.  et al. 2001. Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies. Science 294:178–82 [Google Scholar]
  122. Sigurdsson EM, Sy MS, Li R, Scholtzova H, Kascsak RJ. 122.  et al. 2003. Anti-prion antibodies for prophylaxis following prion exposure in mice. Neurosci. Lett. 336:185–87 [Google Scholar]
  123. Ohsawa N, Song CH, Suzuki A, Furuoka H, Hasebe R, Horiuchi M. 123.  2013. Therapeutic effect of peripheral administration of an anti-prion protein antibody on mice infected with prions. Microbiol. Immunol. 57:288–97 [Google Scholar]
  124. Song CH, Furuoka H, Kim CL, Ogino M, Suzuki A. 124.  et al. 2008. Effect of intraventricular infusion of anti-prion protein monoclonal antibodies on disease progression in prion-infected mice. J. Gen. Virol. 89:1533–44 [Google Scholar]
  125. White AR, Enever P, Tayebi M, Mushens R, Linehan J. 125.  et al. 2003. Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature 422:80–83 [Google Scholar]
  126. Klöhn PC, Farmer M, Linehan JM, O'Malley C, Fernandez de Marco M. 126.  et al. 2012. PrP antibodies do not trigger mouse hippocampal neuron apoptosis. Science 335:52 [Google Scholar]
  127. Reimann RR, Sonati T, Hornemann S, Herrmann US, Arand M. 127.  et al. 2016. Differential toxicity of antibodies to the prion protein. PLOS Pathog 12:e1005401 [Google Scholar]
  128. Baral PK, Wieland B, Swayampakula M, Polymenidou M, Rahman MH. 128.  et al. 2012. Structural studies on the folded domain of the human prion protein bound to the Fab fragment of the antibody POM1. Acta Crystallogr. Sect. D Biol. Crystallogr. 68:1501–12 [Google Scholar]
  129. Frontzek K, Pfammatter M, Sorce S, Senatore A, Schwarz P. 129.  et al. 2016. Neurotoxic antibodies against the prion protein do not trigger prion replication. PLOS ONE 11:e0163601 [Google Scholar]
  130. Wei X, Roettger Y, Tan B, He Y, Dodel R. 130.  et al. 2012. Human anti-prion antibodies block prion peptide fibril formation and neurotoxicity. J. Biol. Chem. 287:12858–66 [Google Scholar]
  131. Roettger Y, Zerr I, Dodel R, Bach JP. 131.  2013. Prion peptide uptake in microglial cells—the effect of naturally occurring autoantibodies against prion protein. PLOS ONE 8:e67743 [Google Scholar]
  132. Lefebvre-Roque M, Kremmer E, Gilch S, Zou WQ, Féraudet C. 132.  et al. 2007. Toxic effects of intracerebral PrP antibody administration during the course of BSE infection in mice. Prion 1:198–206 [Google Scholar]
  133. Polymenidou M, Moos R, Scott M, Sigurdson C, Shi YZ. 133.  et al. 2008. The POM monoclonals: a comprehensive set of antibodies to non-overlapping prion protein epitopes. PLOS ONE 3:e3872 [Google Scholar]
  134. Klein MA, Frigg R, Flechsig E, Raeber AJ, Kalinke U. 134.  et al. 1997. A crucial role for B cells in neuroinvasive scrapie. Nature 390:687–90 [Google Scholar]
  135. Aguzzi A, Nuvolone M, Zhu C. 135.  2013. The immunobiology of prion diseases. Nat. Rev. Immunol. 13:888–902 [Google Scholar]
  136. Mohri S, Handa S, Tateishi J. 136.  1987. Lack of effect of thymus and spleen on the incubation period of Creutzfeldt-Jakob disease in mice. J. Gen. Virol. 68:Pt. 41187–89 [Google Scholar]
  137. Brown KL, Stewart K, Ritchie DL, Mabbott NA, Williams A. 137.  et al. 1999. Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells. Nat. Med. 5:1308–12 [Google Scholar]
  138. Aguzzi A, Kranich J, Krautler NJ. 138.  2014. Follicular dendritic cells: origin, phenotype, and function in health and disease. Trends Immunol 35:105–13 [Google Scholar]
  139. Montrasio F, Frigg R, Glatzel M, Klein MA, Mackay F. 139.  et al. 2000. Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science 288:1257–59 [Google Scholar]
  140. Mabbott NA, Mackay F, Minns F, Bruce ME. 140.  2000. Temporary inactivation of follicular dendritic cells delays neuroinvasion of scrapie. Nat. Med. 6:719–20 [Google Scholar]
  141. Mabbott NA, McGovern G, Jeffrey M, Bruce ME. 141.  2002. Temporary blockade of the tumor necrosis factor receptor signaling pathway impedes the spread of scrapie to the brain. J. Virol. 76:5131–39 [Google Scholar]
  142. Mabbott NA, Bruce ME, Botto M, Walport MJ, Pepys MB. 142.  2001. Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie. Nat. Med. 7:485–87 [Google Scholar]
  143. Klein MA, Kaeser PS, Schwarz P, Weyd H, Xenarios I. 143.  et al. 2001. Complement facilitates early prion pathogenesis. Nat. Med. 7:488–92 [Google Scholar]
  144. Cole S, Kimberlin RH. 144.  1985. Pathogenesis of mouse scrapie: dynamics of vacuolation in brain and spinal cord after intraperitoneal infection. Neuropathol. Appl. Neurobiol. 11:213–27 [Google Scholar]
  145. McBride PA, Beekes M. 145.  1999. Pathological PrP is abundant in sympathetic and sensory ganglia of hamsters fed with scrapie. Neurosci. Lett. 265:135–38 [Google Scholar]
  146. Glatzel M, Heppner FL, Albers KM, Aguzzi A. 146.  2001. Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron 31:25–34 [Google Scholar]
  147. Heppner FL, Christ AD, Klein MA, Prinz M, Fried M. 147.  et al. 2001. Transepithelial prion transport by M cells. Nat. Med. 7:976–77 [Google Scholar]
  148. Donaldson DS, Kobayashi A, Ohno H, Yagita H, Williams IR, Mabbott NA. 148.  2012. M cell-depletion blocks oral prion disease pathogenesis. Mucosal Immunol 5:216–25 [Google Scholar]
  149. Bodenheimer T. 149.  2000. Uneasy alliance—clinical investigators and the pharmaceutical industry. N. Engl. J. Med. 342:1539–44 [Google Scholar]
  150. Unkel S, Röver C, Stallard N, Benda N, Posch M. 150.  et al. 2016. Systematic reviews in paediatric multiple sclerosis and Creutzfeldt-Jakob disease exemplify shortcomings in methods used to evaluate therapies in rare conditions. Orphanet J. Rare Dis. 11:16 [Google Scholar]
  151. Stewart LA, Rydzewska LH, Keogh GF, Knight RS. 151.  2008. Systematic review of therapeutic interventions in human prion disease. Neurology 70:1272–81 [Google Scholar]
  152. Mead S, Ranopa M, Gopalakrishnan GS, Thompson AG, Rudge P. 152.  et al. 2011. PRION-1 scales analysis supports use of functional outcome measures in prion disease. Neurology 77:1674–83 [Google Scholar]
  153. Sheff B. 153.  2005. Mad cow disease and vCJD: understanding the risks. Nursing 35:74–75 [Google Scholar]
  154. Bailey B, Aranda S, Quinn K, Kean H. 154.  2000. Creutzfeldt-Jakob disease: extending palliative care nursing knowledge. Int. J. Palliat. Nurs. 6:131–39 [Google Scholar]
  155. Budka H, Will RG. 155.  2015. The end of the BSE saga: Do we still need surveillance for human prion diseases?. Swiss Med. Wkly. 145:w14212 [Google Scholar]
  156. 156. WHO (World Health Organ.). 2010. WHO Tables on Tissue Infectivity Distribution in Transmissible Spongiform Encephalopathies Geneva: WHO [Google Scholar]
  157. Luk C, Jones S, Thomas C, Fox NC, Mok TH. 157.  et al. 2016. Diagnosing sporadic Creutzfeldt-Jakob disease by the detection of abnormal prion protein in patient urine. JAMA Neurol 73:1454–60 [Google Scholar]
  158. Ritchie DL, Gibson SV, Abee CR, Kreil TR, Ironside JW, Brown P. 158.  2016. Blood transmission studies of prion infectivity in the squirrel monkey (Saimiri sciureus): the Baxter study. Transfusion 56:712–21 [Google Scholar]
  159. Fontenot AB. 159.  2003. The fundamentals of variant Creutzfeldt-Jakob disease. J. Neurosci. Nurs. 35:327–31 [Google Scholar]
  160. Lloyd-Williams M, Payne S. 160.  2002. Can multidisciplinary guidelines improve the palliation of symptoms in the terminal phase of dementia?. Int. J. Palliat. Nurs. 8:370–75 [Google Scholar]
  161. Tsuboi Y, Doh-ura K, Yamada T. 161.  2009. Continuous intraventricular infusion of pentosan polysulfate: clinical trial against prion diseases. Neuropathology 29:632–36 [Google Scholar]

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