Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 146 No. 3940 (2016)

The architecture of prions: how understanding would provide new therapeutic insights

  • Hasier Eraña
  • Joaquín Castilla
Cite this as:
Swiss Med Wkly. 2016;146:w14354


Compelling evidence from the last three decades clearly shows that transmissible spongiform encephalopathies (TSEs) develop as a result of a poorly understood misfolding event that converts the cellular prion protein (PrPC) to an isoform known as PrPSc which is aggregated, protease resistant and able to impose its aberrant conformation onto PrPC, leading to its accumulation in the central nervous system. Despite all the knowledge gathered in more than thirty years of research and the general understanding of the pathological processes, the molecular mechanisms remain elusive, making it difficult to develop rational therapeutic strategies for this group of incurable diseases. In this review article, we give an overview of what is known about prion architecture and how the limited structural information available has been used in the quest for remedies for these devastating disorders.


  1. Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science. 1982;216:136–44.
  2. Collinge J. Prion diseases of humans and animals: their causes and molecular basis. Annu Rev Neurosci. 2001;24:519–550.
  3. Jeffrey M, Gonzalez L. Classical sheep transmissible spongiform encephalopathies: pathogenesis, pathological phenotypes and clinical disease. Neuropathol Appl Neurobiol. 2007;33:373–94.
  4. Williams ES, Young S. Spongiform encephalopathies in Cervidae. Rev Sci Tech. 1992;11:551–67.
  5. Bradley R, Collee JG, Liberski PP. Variant CJD (vCJD) and bovine spongiform encephalopathy (BSE): 10 and 20 years on: part 1. Folia Neuropathol. 2006;44:93–101.
  6. Marsh RF, Hadlow WJ. Transmissible mink encephalopathy. Rev Sci Tech. 1992;11:539–50.
  7. Soto C, Satani N. The intricate mechanisms of neurodegeneration in prion diseases. Trends Mol Med. 2011;17:14–24.
  8. Bolton DC, Mckinley MP, Prusiner SB. Identification of a protein that purifies with the scrapie prion. Science. 1982;218:1309–11.
  9. Oesch B, Westaway D, Walchli M, Mckinley MP, Kent SB, Aebersold R, et al. A cellular gene encodes scrapie PrP 27–30 protein. Cell. 1985;40:735–46.
  10. Gajdusek C, Gibbs C, Alpers M. Experimental transmission of kuru-like syndrome to chimpanzees. Nature. 1966; 209: 794–6.
  11. Masters CL, Gajdusek DC, Gibbs CJ, Jr. The familial occurrence of Creutzfeldt-Jakob disease and Alzheimer's disease. Brain. 1981;104:535–58.
  12. Hsiao KK, Cass C, Schellenberg GD, Bird T, Devine-Gage E, Wisniewski H, et al. A prion protein variant in a family with the telencephalic form of Gerstmann-Straussler-Scheinker syndrome. Neurology. 1991;41:681–4.
  13. Bruce ME. TSE strain variation. Br Med Bull. 2003;66:99–108.
  14. Kascsak RJ, Rubenstein R, Merz PA, Carp RI, Robakis NK, Wisniewski HM, et al. Immunological comparison of scrapie-associated fibrils isolated from animals infected with four different scrapie strains. J Virol. 1986;59:676–83.
  15. Kascsak RJ, Rubenstein R, Carp RI. Evidence for biological and structural diversity among scrapie strains. Curr Top Microbiol Immunol. 1991;172:139–52.
  16. Bruce M, Chree A, Mconnell I, Foster J, Pearson G, Fraser H. Transmission of bovine spongiform encephalopathy and scrapie to mice: strain variation and the species barrier. Philos Trans R Soc Lond B Biol Sci. 1994;343:405–11.
  17. Kocisko DA, Priola SA, Raymond GJ, Chesebro B, Lansbury PT, Jr., Caughey B. Species specificity in the cell-free conversion of prion protein to protease-resistant forms: a model for the scrapie species barrier. Proc Natl Acad Sci U S A. 1995;92:3923–7.
  18. Prusiner SB, Scott MR, Dearmond SJ, Cohen FE. Prion protein biology. Cell. 1998;93:337–48.
  19. Saijo E, Hughson AG, Raymond GJ, Suzuki A, Horiuchi M, Caughey B. PrPSc-Specific Antibody Reveals C-terminal Conformational Differences between Prion Strains. J Virol. 2016;90:4905–13.
  20. Caughey B, Raymond GJ. Sulfated polyanion inhibition of scrapie-associated PrP accumulation in cultured cells. J Virol. 1993;67:643–50.
  21. Gabizon R, Meiner Z, Halimi M, Ben-Sasson SA. Heparin-like molecules bind differentially to prion-proteins and change their intracellular metabolic fate. J Cell Physiol. 1993;157:319–25.
  22. Doh-ura K, Kuge T, Uomoto M, Nishizawa K, Kawasaki Y, Iha M. Prophylactic effect of dietary seaweed Fucoidan against enteral prion infection. Antimicrob Agents Chemother. 2007;51:2274–7.
  23. Engelstein R, Ovadia H, Gabizon R. Copaxone interferes with the PrP Sc-GAG interaction. Eur J Neurol. 2007;14:877–84.
  24. Farquhar C, Dickinson A, Bruce M. Prophylactic potential of pentosan polysulphate in transmissible spongiform encephalopathies. Lancet. 1999;353:117.
  25. Caughey B, Race RE. Potent inhibition of scrapie-associated PrP accumulation by congo red. J Neurochem. 1992;59:768–71.
  26. Ladogana A, Casaccia P, Ingrosso L, Cibati M, Salvatore M, Xi YG, et al. Sulphate polyanions prolong the incubation period of scrapie-infected hamsters. J Gen Virol. 1992;73(3):661–5.
  27. Caughey B, Raymond LD, Raymond GJ, Maxson L, Silveira J, Baron GS. Inhibition of protease-resistant prion protein accumulation in vitro by curcumin. J Virol. 2003;77:5499–502.
  28. Caughey WS, Raymond LD, Horiuchi M, Caughey B. Inhibition of protease-resistant prion protein formation by porphyrins and phthalocyanines. Proc Natl Acad Sci U S A. 1998;95:12117–22.
  29. Priola SA, Raines A, Caughey W. Prophylactic and therapeutic effects of phthalocyanine tetrasulfonate in scrapie-infected mice. J Infect Dis. 2003;188:699–705.
  30. Gupta AN, Neupane K, Rezajooei N, Cortez LM, Sim VL, Woodside MT. Pharmacological chaperone reshapes the energy landscape for folding and aggregation of the prion protein. Nat Commun. 2016;7:12058.
  31. Forloni G, Iussich S, Awan T, Colombo L, Angeretti N, Girola L, et al. Tetracyclines affect prion infectivity. Proc Natl Acad Sci U S A. 2002;99:10849–54.
  32. Guo YJ, Han J, Yao HL, Zhang BY, Gao JM, Zhang J, et al. Treatment of scrapie pathogen 263K with tetracycline partially abolishes protease-resistant activity in vitro and reduces infectivity in vivo. Biomed Environ Sci. 2007;20:198–202.
  33. Doh-Ura K, Iwaki T, Caughey B. Lysosomotropic agents and cysteine protease inhibitors inhibit scrapie-associated prion protein accumulation. J Virol. 2000;74:4894–7.
  34. Korth C, May BC, Cohen FE, Prusiner SB. Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci U S A. 2001;98:9836–41.
  35. Ryou C, Legname G, Peretz D, Craig JC, Baldwin MA, Prusiner SB. Differential inhibition of prion propagation by enantiomers of quinacrine. Lab Invest. 2003;83:837–43.
  36. Taraboulos A, Scott M, Semenov A, Avrahami D, Laszlo L, Prusiner SB. Cholesterol depletion and modification of COOH-terminal targeting sequence of the prion protein inhibit formation of the scrapie isoform. J Cell Biol. 1995;129:121–32. Erratum in: J Cell Bio.l 1995 Jul;130(2):501.
  37. Mangé A, Nishida N, Milhavet O, Mcmahon HE, Casanova D, Lehmann S. Amphotericin B inhibits the generation of the scrapie isoform of the prion protein in infected cultures. J Virol. 2000;74:3135–40.
  38. Klingenstein R, Lober S, Kujala P, Godsave S, Leliveld SR, Gmeiner P, et al. Tricyclic antidepressants, quinacrine and a novel, synthetic chimera thereof clear prions by destabilizing detergent-resistant membrane compartments. J Neurochem. 2006;98:748–59.
  39. Gilch S, Kehler C, Schatzl HM. The prion protein requires cholesterol for cell surface localization. Mol Cell Neurosci. 2006;31:346–53.
  40. Kempster S, Bate C, Williams A. Simvastatin treatment prolongs the survival of scrapie-infected mice. Neuroreport. 2007;18:479–82.
  41. Tilly G, Chapuis J, Vilette D, Laude H, Vilotte JL. Efficient and specific down-regulation of prion protein expression by RNAi. Biochem Biophys Res Commun. 2003;305:548–51.
  42. Pfeifer A, Eigenbrod S, Al-Khadra S, Hofmann A, Mitteregger G, Moser M, et al. Lentivector-mediated RNAi efficiently suppresses prion protein and prolongs survival of scrapie-infected mice. J Clin Invest. 2006;116:3204–10.
  43. Leucht C, Simoneau S, Rey C, Vana K, Rieger R, Lasmezas CI et al. The 37 kDa/67 kDa laminin receptor is required for PrP(Sc) propagation in scrapie-infected neuronal cells. EMBO Rep. 2003;4:290–5.
  44. Bate C, Reid S, Williams A. Phospholipase A2 inhibitors or platelet-activating factor antagonists prevent prion replication. J Biol Chem. 2004;279:36405–11.
  45. Ertmer A, Gilch S, Yun SW, Flechsig E, Klebl B, Stein-Gerlach M, et al. The tyrosine kinase inhibitor STI571 induces cellular clearance of PrPSc in prion-infected cells. J Biol Chem. 2004;279:41918–27.
  46. Yun SW, Ertmer A, Flechsig E, Gilch S, Riederer P, Gerlach M, et al. The tyrosine kinase inhibitor imatinib mesylate delays prion neuroinvasion by inhibiting prion propagation in the periphery. J Neurovirol. 2007;13:328–37.
  47. Zuber C, Mitteregger G, Schuhmann N, Rey C, Knackmuss S, Rupprecht W, et al. Delivery of single-chain antibodies (scFvs) directed against the 37/67 kDa laminin receptor into mice via recombinant adeno-associated viral vectors for prion disease gene therapy. J Gen Virol. 2008;89:2055–61.
  48. Supattapone S, Nguyen HO, Cohen FE, Prusiner SB, Scott MR. Elimination of prions by branched polyamines and implications for therapeutics. Proc Natl Acad Sci U S A. 1999;96:14529–34.
  49. Winklhofer KF, Tatzelt J. Cationic lipopolyamines induce degradation of PrPSc in scrapie-infected mouse neuroblastoma cells. Biol Chem. 2000;381:463–9.
  50. Bera A, Nandi PK. Biological polyamines inhibit nucleic-acid-induced polymerisation of prion protein. Arch Virol. 2007;152:655–68.
  51. Otto M, Cepek L, Ratzka P, Doehlinger S, Boekhoff I, Wiltfang J, et al. Efficacy of flupirtine on cognitive function in patients with CJD: A double-blind study. Neurology. 2004;62:714–8.
  52. Dirikoc S, Priola SA, Marella M, Zsurger N, Chabry J. Nonpsychoactive cannabidiol prevents prion accumulation and protects neurons against prion toxicity. J Neurosci. 2007;27:9537–44.
  53. Kimata A, Nakagawa H, Ohyama R, Fukuuchi T, Ohta S, Suzuki T,, et al. New series of antiprion compounds: pyrazolone derivatives have the potent activity of inhibiting protease-resistant prion protein accumulation. J Med Chem. 2007;50:5053–6.
  54. Hay B, Barry RA, Lieberburg I, Prusiner SB, Lingappa VR. Biogenesis and transmembrane orientation of the cellular isoform of the scrapie prion protein Mol Cell Biol. 1987;7:914–20. Erratum in: Mol Cell Biol. 1987;7(5):2035.
  55. Stahl N, Borchelt DR, Hsiao K, Prusiner SB. Scrapie prion protein contains a phosphatidylinositol glycolipid. Cell. 1987;51:229–40.
  56. Haraguchi T, Fisher S, Olofsson S, Endo T, Groth D, Tarentino A, et al. Asparagine-linked glycosylation of the scrapie and cellular prion proteins. Arch Biochem Biophys. 1989;274:1–13.
  57. Harris DA, Huber MT, Van Dijken P, Shyng SL, Chait BT, Wang R. Processing of a cellular prion protein: identification of N- and C-terminal cleavage sites. Biochemistry. 1993;32:1009–16.
  58. Riek R, Hornemann S, Wider G, Glockshuber R, Wuthrich K. NMR characterization of the full-length recombinant murine prion protein, mPrP(23–231). FEBS Lett. 1997;413:282–8.
  59. Zahn R, Liu A, Luhrs T, Riek R, Von Schroetter C, Lopez Garcia F, et al. NMR solution structure of the human prion protein. Proc Natl Acad Sci U S A. 2000;97:145–50.
  60. Colling SB, Collinge J, Jefferys JG. Hippocampal slices from prion protein null mice: disrupted Ca(2+)-activated K+ currents. Neurosci Lett. 1996;209:49–52.
  61. Jackson GS, Murray I, Hosszu LL, Gibbs N, Waltho JP, Clarke AR, et al. Location and properties of metal-binding sites on the human prion protein. Proc Natl Acad Sci U S A. 2001;98:8531–5.
  62. Mouillet-Richard S, Ermonval M, Chebassier C, Laplanche JL, Lehmann S, Launay JM, et al. Signal transduction through prion protein. Science. 2000;289:1925–8.
  63. Chiarini LB, Freitas AR, Zanata SM, Brentani RR, Martins VR, Linden R. Cellular prion protein transduces neuroprotective signals. EMBO J. 2002;21:3317–26.
  64. Mattei V, Garofalo T, Misasi R, Circella A, Manganelli V, Lucania G, et al. Prion protein is a component of the multimolecular signaling complex involved in T cell activation. FEBS Lett. 2004;560:14–8.
  65. De Almeida CJ, Chiarini LB, Da Silva JP, Pm ES, Martins MA, Linden R. The cellular prion protein modulates phagocytosis and inflammatory response. J Leukoc Biol. 2005;77:238–46.
  66. Bainbridge J, Walker KB. The normal cellular form of prion protein modulates T cell responses. Immunol Lett. 2005;96:147–50.
  67. Kuwahara C, Takeuchi AM, Nishimura T, Haraguchi K, Kubosaki A, Matsumoto Y, et al. Prions prevent neuronal cell-line death. Nature. 1999;400:225–6.
  68. Bounhar Y, Zhang Y, Goodyer CG, Leblanc A. Prion protein protects human neurons against Bax-mediated apoptosis. J Biol Chem. 2001;276:39145–9.
  69. Bremer J, Baumann F, Tiberi C, Wessig C, Fischer H, Schwarz P, et al. Axonal prion protein is required for peripheral myelin maintenance. Nat Neurosci. 2010;13:310–8.
  70. Bueler H, Aguzzi A, Sailer A, Greiner RA, Autenried P, Aguet M, et al. Mice devoid of PrP are resistant to scrapie. Cell. 1993;73:1339–47.
  71. Singh J, Udgaonkar JB. Molecular Mechanism of the Misfolding and Oligomerization of the Prion Protein: Current Understanding and Its Implications. Biochemistry. 2015;54:4431–42.
  72. Van Der Kamp MW, Daggett V. The consequences of pathogenic mutations to the human prion protein. Protein Eng Des Sel. 2009;22:461–8.
  73. Beck JA, Mead S, Campbell TA, Dickinson A, Wientjens DP, Croes EA, et al. Two-octapeptide repeat deletion of prion protein associated with rapidly progressive dementia. Neurology. 2001;57:354–6.
  74. Goldfarb LG, Brown P, McCombie WR, Goldgaber D, Swergold GD, Wills PR, et al. Transmissible familial Creutzfeldt-Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene. Proc Natl Acad Sci U S A. 1991;88:10926–30.
  75. Liemann S, Glockshuber R. Influence of amino acid substitutions related to inherited human prion diseases on the thermodynamic stability of the cellular prion protein. Biochemistry. 1999;38:3258–67.
  76. Swietnicki W, Petersen RB, Gambetti P, Surewicz WK. Familial mutations and the thermodynamic stability of the recombinant human prion protein. J Biol Chem. 1998;273:31048–52.
  77. Cappai R, Stewart L, Jobling MF, Thyer JM, White AR, Beyreuther K, et al. Familial prion disease mutation alters the secondary structure of recombinant mouse prion protein: implications for the mechanism of prion formation. Biochemistry. 1999;38:3280–4.
  78. Apetri AC, Surewicz WK. Kinetic intermediate in the folding of human prion protein. J Biol Chem. 2002;277:44589–92.
  79. Heppner FL, Musahl C, Arrighi I, Klein MA, Rulicke T, Oesch B et al. Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies. Science. 2001;294:178–82.
  80. Peretz D, Williamson RA, Kaneko K, Vergara J, Leclerc E, Schmitt-Ulms G, et al. Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature. 2001;412:739–43.
  81. White AR, Enever P, Tayebi M, Mushens R, Linehan J, Brandner S, et al. Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature. 2003;422:80–3.
  82. Antonyuk SV, Trevitt CR, Strange RW, Jackson GS, Sangar D, Batchelor M, et al. Crystal structure of human prion protein bound to a therapeutic antibody. Proc Natl Acad Sci U S A. 2009;106:2554–8.
  83. Chakroun N, Fornili A, Prigent S, Kleinjung J, Dreiss CA, Rezaei H, et al. Decrypting Prion Protein Conversion into a β-Rich Conformer by Molecular Dynamics. J Chem Theory Comput. 2013;9:2455–65.
  84. Chen J, Thirumalai D. Helices 2 and 3 are the initiation sites in the PrP(C) –> PrP(SC) transition. Biochemistry. 2013;52:310–9.
  85. Morrissey MP, Shakhnovich EI. Evidence for the role of PrP(C) helix 1 in the hydrophilic seeding of prion aggregates. Proc Natl Acad Sci U S A. 1999;96:11293–8.
  86. Campos SR, Machuqueiro M, Baptista AM. Constant-pH molecular dynamics simulations reveal a beta-rich form of the human prion protein. J Phys Chem B. 2010;114:12692–700.
  87. Ziegler J, Sticht H, Marx UC, Müller W, Rösch P, Schwarzinger S. CD and NMR studies of prion protein (PrP) helix 1. Novel implications for its role in the PrPC–>PrPSc conversion process. J Biol Chem. 2003; 278: 50175-50181.
  88. Tatzelt J, Prusiner SB, Welch WJ. Chemical chaperones interfere with the formation of scrapie prion protein. EMBO J. 1996;15:6363–73.
  89. Caughey B, Brown K, Raymond GJ, Katzenstein GE, Thresher W. Binding of the protease-sensitive form of PrP (prion protein) to sulfated glycosaminoglycan and congo red [corrected]. J Virol. 1994;68:2135–41.
  90. Kocisko DA, Caughey B. Searching for anti-prion compounds: cell-based high-throughput in vitro assays and animal testing strategies. Methods Enzymol. 2006;412:223–34.
  91. Kocisko DA, Bertholet N, Moore RA, Caughey B, Vaillant A. Identification of prion inhibitors by a fluorescence-polarization-based competitive binding assay. Anal Biochem. 2007;363:154–6.
  92. Lee KS, Raymond LD, Schoen B, Raymond GJ, Kett L, Moore RA, et al. Hemin interactions and alterations of the subcellular localization of prion protein. J Biol Chem. 2007;282:36525–33.
  93. Nicoll AJ, Trevitt CR, Tattum MH, Risse E, Quarterman E, Ibarra AA, et al. Pharmacological chaperone for the structured domain of human prion protein. Proc Natl Acad Sci U S A. 2010;107:17610–5.
  94. Meli M, Gasset M, Colombo G. Dynamic diagnosis of familial prion diseases supports the beta2-alpha2 loop as a universal interference target. PLoS One. 2011;6:e19093.
  95. Hadzi S, Ondracka A, Jerala R, Hafner-Bratkovic I. Pathological mutations H187R and E196K facilitate subdomain separation and prion protein conversion by destabilization of the native structure. FASEB J. 2015;29:882–93.
  96. Biljan I, Giachin G, Ilc G, Zhukov I, Plavec J, Legname G. Structural basis for the protective effect of the human prion protein carrying the dominant-negative E219K polymorphism. Biochem J. 2012;446:243–51.
  97. Asante EA, Smidak M, Grimshaw A, Houghton R, Tomlinson A, Jeelani A, et al. A naturally occurring variant of the human prion protein completely prevents prion disease. Nature. 2015;522:478–81.
  98. Kong Q, Mills JL, Kundu B, Li X, Qing L, Surewicz K, et al. Thermodynamic stabilization of the folded domain of prion protein inhibits prion infection in vivo. Cell Rep. 2013;4:248–54.
  99. Ouidja MO, Petit E, Kerros ME, Ikeda Y, Morin C, Carpentier G, et al. Structure-activity studies of heparan mimetic polyanions for anti-prion therapies. Biochem Biophys Res Commun. 2007;363:95–100.
  100. Guo K, Mutter R, Heal W, Reddy TR, Cope H, Pratt S et al. Synthesis and evaluation of a focused library of pyridine dicarbonitriles against prion disease. Eur J Med Chem. 2008;43:93–106.
  101. Thompson MJ, Borsenberger V, Louth JC, Judd KE, Chen B. Design, synthesis, and structure-activity relationship of indole-3-glyoxylamide libraries possessing highly potent activity in a cell line model of prion disease. J Med Chem. 2009;52:7503–11.
  102. Venko K, Zuperl S, Novic M. Prediction of antiprion activity of therapeutic agents with structure-activity models. Mol Divers. 2014;18:133–48.
  103. Nguyen PH, Hammoud H, Halliez S, Pang Y, Evrard J, Schmitt M, et al. Structure-activity relationship study around guanabenz identifies two derivatives retaining antiprion activity but having lost α2-adrenergic receptor agonistic activity. ACS Chem Neurosci. 2014;5:1075–82.
  104. Hosokawa-Muto J, Kamatari YO, Nakamura HK, Kuwata K. Variety of antiprion compounds discovered through an in silico screen based on cellular-form prion protein structure: Correlation between antiprion activity and binding affinity. Antimicrob Agents Chemother. 2009;53:765–71.
  105. Ma B, Yamaguchi K, Fukuoka M, Kuwata K. Logical design of anti-prion agents using NAGARA. Biochem Biophys Res Commun. 2016;469:930–5.
  106. Horiuchi M, Caughey B. Specific binding of normal prion protein to the scrapie form via a localized domain initiates its conversion to the protease-resistant state. EMBO J. 1999;18:3193–203.
  107. Horiuchi M, Priola SA, Chabry J, Caughey B. Interactions between heterologous forms of prion protein: binding, inhibition of conversion, and species barriers. Proc Natl Acad Sci U S A. 2000;97:5836–41.
  108. Solforosi L, Bellon A, Schaller M, Cruite JT, Abalos GC, Williamson RA. Toward molecular dissection of PrPC-PrPSc interactions. J Biol Chem. 2007;282:7465–71.
  109. Turnbaugh JA, Unterberger U, Saa P, Massignan T, Fluharty BR, Bowman FP, et al. The N-terminal, polybasic region of PrP(C) dictates the efficiency of prion propagation by binding to PrP(Sc). J Neurosci. 2012;32:8817–30.
  110. Kurt TD, Bett C, Fernandez-Borges N, Joshi-Barr S, Hornemann S, Rulicke T, et al. Prion transmission prevented by modifying the beta2-alpha2 loop structure of host PrPC. J Neurosci. 2014;34:1022–7.
  111. Caughey B, Kocisko DA, Raymond GJ, Lansbury PT, Jr. Aggregates of scrapie-associated prion protein induce the cell-free conversion of protease-sensitive prion protein to the protease-resistant state. Chem Biol. 1995; 2: 807–17.
  112. Come JH, Fraser PE, Lansbury PT, Jr. A kinetic model for amyloid formation in the prion diseases: importance of seeding. Proc Natl Acad Sci U S A. 1993;90:5959–63.
  113. Priola SA, Caughey B, Race RE, Chesebro B. Heterologous PrP molecules interfere with accumulation of protease-resistant PrP in scrapie-infected murine neuroblastoma cells. J Virol. 1994;68:4873–8.
  114. Holscher C, Delius H, Burkle A. Overexpression of nonconvertible PrPc delta114–121 in scrapie-infected mouse neuroblastoma cells leads to trans-dominant inhibition of wild-type PrP(Sc) accumulation. J Virol. 1998;72:1153–9.
  115. Perrier V, Wallace AC, Kaneko K, Safar J, Prusiner SB, Cohen FE. Mimicking dominant negative inhibition of prion replication through structure-based drug design. Proc Natl Acad Sci U S A. 2000;97:6073–8.
  116. Silveira JR, Raymond GJ, Hughson AG, Race RE, Sim VL, Hayes SF, et al. The most infectious prion protein particles. Nature. 2005 437:257–61.
  117. Simoneau S, Rezaei H, Sales N, Kaiser-Schulz G, Lefebvre-Roque M, Vidal C, et al. In vitro and in vivo neurotoxicity of prion protein oligomers. PLoS Pathog. 2007;3:e125.
  118. Erlich P, Dumestre-Perard C, Ling WL, Lemaire-Vieille C, Schoehn G, Arlaud GJ, et al. Complement protein C1q forms a complex with cytotoxic prion protein oligomers. J Biol Chem. 285:19267–76.
  119. Bahadi R, Farrelly PV, Kenna BL, Kourie JI, Tagliavini F, Forloni G, et al. Channels formed with a mutant prion protein PrP(82-146) homologous to a 7-kDa fragment in diseased brain of GSS patients. Am J Physiol Cell Physiol. 2003;285:C862–72.
  120. Chich JF, Chapuis C, Henry C, Vidic J, Rezaei H, Noinville S. Vesicle permeabilization by purified soluble oligomers of prion protein: a comparative study of the interaction of oligomers and monomers with lipid membranes. J Mol Biol. 397:1017–30.
  121. Khosravani H, Zhang Y, Tsutsui S, Hameed S, Altier C, Hamid J, et al. Prion protein attenuates excitotoxicity by inhibiting NMDA receptors. J Gen Physiol. 2008;131:i5.
  122. Kristiansen M, Deriziotis P, Dimcheff DE, Jackson GS, Ovaa H, Naumann H, et al. Disease-associated prion protein oligomers inhibit the 26S proteasome. Mol Cell. 2007;26:175–88.
  123. Reimann RR, Sonati T, Hornemann S, Herrmann US, Arand M, Hawke S, et al. Differential Toxicity of Antibodies to the Prion Protein. PLoS Pathog. 2016;12:e1005401.
  124. Solforosi L, Criado JR, Mcgavern DB, Wirz S, Sanchez-Alavez M, Sugama S, et al. Cross-linking cellular prion protein triggers neuronal apoptosis in vivo. Science. 2004;303:1514–6.
  125. Halliday M, Radford H, Sekine Y, Moreno J, Verity N, Le Quesne J, et al. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death Dis. 2015;6:e1672.
  126. Mckinnon C, Goold R, Andre R, Devoy A, Ortega Z, Moonga J, et al. Prion-mediated neurodegeneration is associated with early impairment of the ubiquitin-proteasome system. Acta Neuropathol. 2016;131:411–25.
  127. Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, et al. Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature. 2012;485:507–11.
  128. Lefebvre-Roque M, Kremmer E, Gilch S, Zou WQ, Feraudet C, Gilles CM, et al. Toxic effects of intracerebral PrP antibody administration during the course of BSE infection in mice. Prion. 2007;1:198–206.
  129. Wang F, Wang X, Yuan CG, Ma J. Generating a prion with bacterially expressed recombinant prion protein. Science. 2010;327:1132–5.
  130. Cobb NJ, Sonnichsen FD, Mchaourab H, Surewicz WK. Molecular architecture of human prion protein amyloid: a parallel, in-register beta-structure. Proc Natl Acad Sci U S A. 2007;104:18946–51.
  131. Wille H, Bian W, Mcdonald M, Kendall A, Colby DW, Bloch L, et al. Natural and synthetic prion structure from X-ray fiber diffraction. Proc Natl Acad Sci U S A. 2009; 106: 16990–5.
  132. Huang Z, Prusiner SB, Cohen FE. Scrapie prions: a three-dimensional model of an infectious fragment. Fold Des. 1996;1:13–9.
  133. Downing DT, Lazo ND. Molecular modelling indicates that the pathological conformations of prion proteins might be beta-helical. Biochem J. 1999;343Pt 2:453–60.
  134. Wille H, Michelitsch MD, Guenebaut V, Supattapone S, Serban A, Cohen FE, et al. Structural studies of the scrapie prion protein by electron crystallography. Proc Natl Acad Sci U S A. 2002;99:3563–8.
  135. Mornon JP, Prat K, Dupuis F, Boisset N, Callebaut I. Structural features of prions explored by sequence analysis. II. A PrP(Sc) model. Cell Mol Life Sci. 2002;59:2144–54.
  136. Demarco ML, Daggett V. From conversion to aggregation: protofibril formation of the prion protein. Proc Natl Acad Sci U S A. 2004;101:2293–8.
  137. Govaerts C, Wille H, Prusiner SB, Cohen FE. Evidence for assembly of prions with left-handed beta-helices into trimers. Proc Natl Acad Sci U S A. 2004;101:8342–7.
  138. Stork M, Giese A, Kretzschmar HA, Tavan P. Molecular dynamics simulations indicate a possible role of parallel beta-helices in seeded aggregation of poly-Gln. Biophys J. 2005;88:2442–51.
  139. Langedijk JP, Fuentes G, Boshuizen R, Bonvin AM. Two-rung model of a left-handed beta-helix for prions explains species barrier and strain variation in transmissible spongiform encephalopathies. J Mol Biol. 2006;360:907–20.
  140. Requena JR, Wille H. The structure of the infectious prion protein: experimental data and molecular models. Prion. 2014;8:60–6.
  141. Noble GP, Wang DW, Walsh DJ, Barone JR, Miller MB, Nishina KA, et al. A Structural and Functional Comparison Between Infectious and Non-Infectious Autocatalytic Recombinant PrP Conformers. PLoS Pathog. 2015;11:e1005017.
  142. Marciniuk K, Maattanen P, Taschuk R, Airey TD, Potter A, Cashman NR et al. Development of a multivalent, PrP(Sc)-specific prion vaccine through rational optimization of three disease-specific epitopes. Vaccine. 2014; 32: 1988–97.
  143. Webb S, Lekishvili T, Loeschner C, Sellarajah S, Prelli F, Wisniewski T, et al. Mechanistic insights into the cure of prion disease by novel antiprion compounds. J Virol. 2007;81:10729–41.
  144. Margalith I, Suter C, Ballmer B, Schwarz P, Tiberi C, Sonati T, et al. Polythiophenes inhibit prion propagation by stabilizing prion protein (PrP) aggregates. J Biol Chem. 2012;287:18872–87.
  145. Mays CE, Joy S, Li L, Yu L, Genovesi S, West FG, et al. Prion inhibition with multivalent PrPSc binding compounds. Biomaterials. 2012;33:6808–22.
  146. Herrmann US, Schütz AK, Shirani H, Huang D, Saban D, Nuvolone M, et al. Structure-based drug design identifies polythiophenes as antiprion compounds. Sci Transl Med. 2015;7:299.
  147. Lundmark K, Westermark GT, Nystrom S, Murphy CL, Solomon A, Westermark P. Transmissibility of systemic amyloidosis by a prion-like mechanism. Proc Natl Acad Sci U S A. 2002;99:6979–84. Erratum in: Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3543.
  148. Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, et al. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science. 2006;313:1781–4.
  149. Eisele YS, Bolmont T, Heikenwalder M, Langer F, Jacobson LH, Yan ZX, et al. Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. Proc Natl Acad Sci U S A. 2009;106:12926–31.
  150. Luk KC, Song C, O'brien P, Stieber A, Branch JR, Brunden KR, et al. Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci U S A. 2009;106:20051–6.
  151. Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med. 2008;14:504–6.
  152. Cortez LM, Campeau J, Norman G, Kalayil M, Van Der Merwe J, Mckenzie D, et al. Bile Acids Reduce Prion Conversion, Reduce Neuronal Loss, and Prolong Male Survival in Models of Prion Disease. J Virol. 2015;89:7660–72.
  153. Kumar J, Namsechi R, Sim VL. Structure-Based Peptide Design to Modulate Amyloid Beta Aggregation and Reduce Cytotoxicity. PLoS One. 2015;10:e0129087.
  154. Lam HT, Graber MC, Gentry KA, Bieschke J. Stabilization of alpha-Synuclein Fibril Clusters Prevents Fragmentation and Reduces Seeding Activity and Toxicity. Biochemistry. 2016;55:675–85.
  155. Berry DB, Lu D, Geva M, Watts JC, Bhardwaj S, Oehler A, et al. Drug resistance confounding prion therapeutics. Proceedings of the National Academy of Sciences of the United States of America. 2013;110.
  156. Ghaemmaghami S, Ahn M, Lessard P, Giles K, Legname G, Dearmond SJ, et al. Continuous quinacrine treatment results in the formation of drug-resistant prions. PLoS Pathog. 2009;5:e1000673.
  157. Oelschlegel A, Weissmann C. Acquisition of Drug Resistance and Dependence by Prions. PLoS Pathog. 2013;9:e1003158.
  158. Kawasaki Y, Kawagoe K, Chen CJ, Teruya K, Sakasegawa Y, Doh-Ura K. Orally administered amyloidophilic compound is effective in prolonging the incubation periods of animals cerebrally infected with prion diseases in a prion strain-dependent manner. J Virol. 2007;81:12889–98.
  159. Jackrel ME, Shorter J. Engineering enhanced protein disaggregases for neurodegenerative disease. Prion. 2015;9:90–109.
  160. Chernoff YO, Lindquist SL, Ono B, Inge-Vechtomov SG, Liebman SW. Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]. Science. 1995;268:880–4.
  161. Wang H, Tian C, Fan XY, Chen LN, Lv Y, Sun J, et al. Polo-like kinase 3 (PLK3) mediates the clearance of the accumulated PrP mutants transiently expressed in cultured cells and pathogenic PrP(Sc) in prion infected cell line via protein interaction. Int J Biochem Cell Biol. 2015;62:24–35.
  162. Wang ZY, Shi Q, Wang SB, Tian C, Xu Y, Guo Y, et al. Co-expressions of casein kinase 2 (CK2) subunits restore the down-regulation of tubulin levels and disruption of microtubule structures caused by PrP mutants. J Mol Neurosci. 2013;50:14–22.
  163. Kovalchuk Ben-Zaken O, Nissan I, Tzaban S, Taraboulos A, Zcharia E, Matzger S, et al. Transgenic over-expression of mammalian heparanase delays prion disease onset and progression. Biochem Biophys Res Commun. 2015;464:698–704.