1932

Abstract

Prion diseases are rapidly progressive, incurable neurodegenerative disorders caused by misfolded, aggregated proteins known as prions, which are uniquely infectious. Remarkably, these infectious proteins have been responsible for widespread disease epidemics, including kuru in humans, bovine spongiform encephalopathy in cattle, and chronic wasting disease in cervids, the latter of which has spread across North America and recently appeared in Norway and Finland. The hallmark histopathological features include widespread spongiform encephalopathy, neuronal loss, gliosis, and deposits of variably sized aggregated prion protein, ranging from small, soluble oligomers to long, thin, unbranched fibrils, depending on the disease. Here, we explore recent advances in prion disease research, from the function of the cellular prion protein to the dysfunction triggering neurotoxicity, as well as mechanisms underlying prion spread between cells. We also highlight key findings that have revealed new therapeutic targets and consider unanswered questions for future research.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pathmechdis-012418-013109
2019-01-24
2024-05-23
Loading full text...

Full text loading...

/deliver/fulltext/pathmechdis/14/1/annurev-pathmechdis-012418-013109.html?itemId=/content/journals/10.1146/annurev-pathmechdis-012418-013109&mimeType=html&fmt=ahah

Literature Cited

  1. 1.  Bolton DC, McKinley MP, Prusiner SB 1982. Identification of a protein that purifies with the scrapie prion. Science 218:1309–11
    [Google Scholar]
  2. 2.  Prusiner SB 1982. Novel proteinaceous infectious particles cause scrapie. Science 216:136–44
    [Google Scholar]
  3. 3.  Prusiner SB, Scott MR, DeArmond SJ, Cohen FE 1998. Prion protein biology. Cell 93:337–48
    [Google Scholar]
  4. 4.  Basler K, Oesch B, Scott M, Westaway D, Walchli M, Groth DF et al. 1986. Scrapie and cellular PrP isoforms are encoded by the same chromosomal gene. Cell 46:417–28
    [Google Scholar]
  5. 5.  DeArmond SJ, Prusiner SB 1995. Etiology and pathogenesis of prion diseases. Am. J. Pathol. 146:785–811
    [Google Scholar]
  6. 6.  Takada LT, Geschwind MD 2013. Prion diseases. Semin. Neurol. 33:348–56
    [Google Scholar]
  7. 7.  Prusiner SB 1989. Creutzfeldt–Jakob disease and scrapie prions. Alzheimer Dis. Assoc. Disord. 3:52–78
    [Google Scholar]
  8. 8.  Scott MR, Will R, Ironside J, Nguyen HO, Tremblay P et al. 1999. Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans. PNAS 96:15137–42
    [Google Scholar]
  9. 9.  Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D et al. 1997. Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature 389:498–501
    [Google Scholar]
  10. 10.  Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW 2004. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 364:527–29
    [Google Scholar]
  11. 11.  Llewelyn CA, Hewitt PE, Knight RS, Amar K, Cousens S et al. 2004. Possible transmission of variant Creutzfeldt–Jakob disease by blood transfusion. Lancet 363:417–21
    [Google Scholar]
  12. 12.  Wroe SJ, Pal S, Siddique D, Hyare H, Macfarlane R et al. 2006. Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt–Jakob disease associated with blood transfusion: a case report. Lancet 368:2061–67
    [Google Scholar]
  13. 13.  Peden A, McCardle L, Head MW, Love S, Ward HJ et al. 2010. Variant CJD infection in the spleen of a neurologically asymptomatic UK adult patient with haemophilia. Haemophilia 16:296–304
    [Google Scholar]
  14. 14.  Gibbs CJ Jr, Joy A, Heffner R, Franko M, Miyazaki M et al. 1985. Clinical and pathological features and laboratory confirmation of Creutzfeldt–Jakob disease in a recipient of pituitary-derived human growth hormone. N. Engl. J. Med. 313:734–38
    [Google Scholar]
  15. 15.  Brown P 1998. Transmission of spongiform encephalopathy through biological products. Dev. Biol. Stand. 93:73–78
    [Google Scholar]
  16. 16.  Brown P, Preece M, Brandel JP, Sato T, McShane L et al. 2000. Iatrogenic Creutzfeldt–Jakob disease at the millennium. Neurology 55:1075–81
    [Google Scholar]
  17. 17.  Wells GA, Scott AC, Johnson CT, Gunning RF, Hancock RD et al. 1987. A novel progressive spongiform encephalopathy in cattle. Vet. Rec. 121:419–20
    [Google Scholar]
  18. 18.  Anderson RM, Donnelly CA, Ferguson NM, Woolhouse ME, Watt CJ et al. 1996. Transmission dynamics and epidemiology of BSE in British cattle. Nature 382:779–88
    [Google Scholar]
  19. 19.  Hill AF, Desbruslais M, Joiner S, Sidle KC, Gowland I et al. 1997. The same prion strain causes vCJD and BSE. Nature 389:448–50
    [Google Scholar]
  20. 20.  Diack AB, Head MW, McCutcheon S, Boyle A, Knight R et al. 2014. Variant CJD: 18 years of research and surveillance. Prion 8:286–95
    [Google Scholar]
  21. 21.  Baron T, Biacabe AG, Arsac JN, Benestad S, Groschup MH 2007. Atypical transmissible spongiform encephalopathies (TSEs) in ruminants. Vaccine 25:5625–30
    [Google Scholar]
  22. 22.  Benestad SL, Arsac JN, Goldmann W, Noremark M 2008. Atypical/Nor98 scrapie: properties of the agent, genetics, and epidemiology. Vet. Res. 39:19
    [Google Scholar]
  23. 23.  Biacabe AG, Morignat E, Vulin J, Calavas D, Baron TG 2008. Atypical bovine spongiform encephalopathies, France, 2001–2007. Emerg. Infect. Dis. 14:298–300
    [Google Scholar]
  24. 24.  Detwiler LA 1992. Scrapie. Rev. Sci. Tech. 11:491–537
    [Google Scholar]
  25. 25.  Williams ES, Young S 1980. Chronic wasting disease of captive mule deer: a spongiform encephalopathy. J. Wildl. Dis. 16:89–98
    [Google Scholar]
  26. 26.  Lee YH, Sohn HJ, Kim MJ, Kim HJ, Lee WY et al. 2013. Strain characterization of the Korean CWD cases in 2001 and 2004. J. Vet. Med. Sci. 75:95–98
    [Google Scholar]
  27. 27.  Benestad SL, Mitchell G, Simmons M, Ytrehus B, Vikoren T 2016. First case of chronic wasting disease in Europe in a Norwegian free-ranging reindeer. Vet. Res. 47:88
    [Google Scholar]
  28. 28. Dly. Finland. 2018. Moose dies of CWD for 1st time in Finland. Daily Finland March 9. http://dailyfinland.fi/national/4548/moose-dies-of-cwd-for-1st-time-in-finland
  29. 29.  Marsh RF, Hadlow WJ 1992. Transmissible mink encephalopathy. Rev. Sci. Tech. 11:539–50
    [Google Scholar]
  30. 30.  Mayor S, Riezman H 2004. Sorting GPI-anchored proteins. Nat. Rev. Mol. Cell Biol. 5:110–20
    [Google Scholar]
  31. 31.  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 382:180–82
    [Google Scholar]
  32. 32.  Shyng SL, Heuser JE, Harris DA 1994. A glycolipid-anchored prion protein is endocytosed via clathrin-coated pits. J. Cell Biol. 125:1239–50
    [Google Scholar]
  33. 33.  Sunyach C, Jen A, Deng J, Fitzgerald KT, Frobert Y et al. 2003. The mechanism of internalization of glycosylphosphatidylinositol-anchored prion protein. EMBO J 22:3591–601
    [Google Scholar]
  34. 34.  Yim YI, Park BC, Yadavalli R, Zhao X, Eisenberg E, Greene LE 2015. The multivesicular body is the major internal site of prion conversion. J. Cell Sci. 128:1434–43
    [Google Scholar]
  35. 35.  Guo BB, Bellingham SA, Hill AF 2015. The neutral sphingomyelinase pathway regulates packaging of the prion protein into exosomes. J. Biol. Chem. 290:3455–67
    [Google Scholar]
  36. 36.  Linsenmeier L, Altmeppen HC, Wetzel S, Mohammadi B, Saftig P, Glatzel M 2017. Diverse functions of the prion protein—Does proteolytic processing hold the key?. Biochim. Biophys. Acta 1864:2128–37
    [Google Scholar]
  37. 37.  Mange A, Beranger F, Peoc'h K, Onodera T, Frobert Y, Lehmann S 2004. Alpha- and beta- cleavages of the amino-terminus of the cellular prion protein. Biol. Cell 96:125–32
    [Google Scholar]
  38. 38.  Walmsley AR, Watt NT, Taylor DR, Perera WS, Hooper NM 2009. α-Cleavage of the prion protein occurs in a late compartment of the secretory pathway and is independent of lipid rafts. Mol. Cell. Neurosci. 40:242–48
    [Google Scholar]
  39. 39.  Praus M, Kettelgerdes G, Baier M, Holzhutter HG, Jungblut PR et al. 2003. Stimulation of plasminogen activation by recombinant cellular prion protein is conserved in the NH2-terminal fragment PrP23-110. Thromb. Haemost. 89:812–19
    [Google Scholar]
  40. 40.  Kornblatt JA, Marchal S, Rezaei H, Kornblatt MJ, Balny C et al. 2003. The fate of the prion protein in the prion/plasminogen complex. Biochem. Biophys. Res. Commun. 305:518–22
    [Google Scholar]
  41. 41.  Vincent B, Paitel E, Saftig P, Frobert Y, Hartmann D et al. 2001. The disintegrins ADAM10 and TACE contribute to the constitutive and phorbol ester–regulated normal cleavage of the cellular prion protein. J. Biol. Chem. 276:37743–46
    [Google Scholar]
  42. 42.  Barnewitz K, Maringer M, Mitteregger G, Giese A, Bertsch U, Kretzschmar HA 2006. Unaltered prion protein cleavage in plasminogen-deficient mice. NeuroReport 17:527–30
    [Google Scholar]
  43. 43.  Wik L, Klingeborn M, Willander H, Linne T 2012. Separate mechanisms act concurrently to shed and release the prion protein from the cell. Prion 6:498–509
    [Google Scholar]
  44. 44.  Mays CE, Coomaraswamy J, Watts JC, Yang J, Ko KW et al. 2014. Endoproteolytic processing of the mammalian prion glycoprotein family. FEBS J 281:862–76
    [Google Scholar]
  45. 45.  Borchelt DR, Rogers M, Stahl N, Telling G, Prusiner SB 1993. Release of the cellular prion protein from cultured cells after loss of its glycoinositol phospholipid anchor. Glycobiology 3:319–29
    [Google Scholar]
  46. 46.  Harris DA, Huber MT, van Dijken P, Shyng SL, Chait BT, Wang R 1993. Processing of a cellular prion protein: identification of N- and C-terminal cleavage sites. Biochemistry 32:1009–16
    [Google Scholar]
  47. 47.  Taylor DR, Parkin ET, Cocklin SL, Ault JR, Ashcroft AE et al. 2009. Role of ADAMs in the ectodomain shedding and conformational conversion of the prion protein. J. Biol. Chem. 284:22590–600
    [Google Scholar]
  48. 48.  Altmeppen HC, Prox J, Puig B, Kluth MA, Bernreuther C et al. 2011. Lack of a-disintegrin-and-metalloproteinase ADAM10 leads to intracellular accumulation and loss of shedding of the cellular prion protein in vivo. Mol. Neurodegener. 6:36
    [Google Scholar]
  49. 49.  Linsenmeier L, Mohammadi B, Wetzel S, Puig B, Jackson WS et al. 2018. Structural and mechanistic aspects influencing the ADAM10-mediated shedding of the prion protein. Mol. Neurodegener. 13:18
    [Google Scholar]
  50. 50.  Steele AD, Emsley JG, Ozdinler PH, Lindquist S, Macklis JD 2006. Prion protein (PrPc) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis. PNAS 103:3416–21
    [Google Scholar]
  51. 51.  Schmitt-Ulms G, Legname G, Baldwin MA, Ball HL, Bradon N et al. 2001. Binding of neural cell adhesion molecules (N-CAMs) to the cellular prion protein. J. Mol. Biol. 314:1209–25
    [Google Scholar]
  52. 52.  Santuccione A, Sytnyk V, Leshchyns'ka I, Schachner M 2005. Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth. J. Cell Biol. 169:341–54
    [Google Scholar]
  53. 53.  Roucou X, Gains M, LeBlanc AC 2004. Neuroprotective functions of prion protein. J. Neurosci. Res. 75:153–61
    [Google Scholar]
  54. 54.  Guillot-Sestier MV, Sunyach C, Druon C, Scarzello S, Checler F 2009. The α-secretase-derived N-terminal product of cellular prion, N1, displays neuroprotective function in vitro and in vivo. J. Biol. Chem. 284:35973–86
    [Google Scholar]
  55. 55.  Tobler I, Gaus SE, Deboer T, Achermann P, Fischer M et al. 1996. Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature 380:639–42
    [Google Scholar]
  56. 56.  Bremer J, Baumann F, Tiberi C, Wessig C, Fischer H et al. 2010. Axonal prion protein is required for peripheral myelin maintenance. Nat. Neurosci. 13:310–18
    [Google Scholar]
  57. 57.  Kuffer A, Lakkaraju AK, Mogha A, Petersen SC, Airich K et al. 2016. The prion protein is an agonistic ligand of the G protein–coupled receptor Adgrg6. Nature 536:464–68
    [Google Scholar]
  58. 58.  Brown DR, Qin K, Herms JW, Madlung A, Manson J et al. 1997. The cellular prion protein binds copper in vivo. Nature 390:684–87
    [Google Scholar]
  59. 59.  Watt NT, Taylor DR, Kerrigan TL, Griffiths HH, Rushworth JV et al. 2012. Prion protein facilitates uptake of zinc into neuronal cells. Nat. Commun. 3:1134
    [Google Scholar]
  60. 60.  Mouillet-Richard S, Ermonval M, Chebassier C, Laplanche JL, Lehmann S et al. 2000. Signal transduction through prion protein. Science 289:1925–28
    [Google Scholar]
  61. 61.  Lewis V, Hooper NM 2011. The role of lipid rafts in prion protein biology. Front. Biosci. 16:151–68
    [Google Scholar]
  62. 62.  Amin L, Nguyen XT, Rolle IG, D'Este E, Giachin G et al. 2016. Characterization of prion protein function by focal neurite stimulation. J. Cell Sci. 129:3878–91
    [Google Scholar]
  63. 63.  Willem M, Tahirovic S, Busche MA, Ovsepian SV, Chafai M et al. 2015. η-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature 526:443–47
    [Google Scholar]
  64. 64.  Andrew RJ, Kellett KA, Thinakaran G, Hooper NM 2016. A Greek tragedy: the growing complexity of Alzheimer amyloid precursor protein proteolysis. J. Biol. Chem. 291:19235–44
    [Google Scholar]
  65. 65.  Prusiner SB 2013. Biology and genetics of prions causing neurodegeneration. Annu. Rev. Genet. 47:601–23
    [Google Scholar]
  66. 66.  Collinge J 2016. Mammalian prions and their wider relevance in neurodegenerative diseases. Nature 539:217–26
    [Google Scholar]
  67. 67.  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 30:7672–80
    [Google Scholar]
  68. 68.  Apostol MI, Wiltzius JJ, Sawaya MR, Cascio D, Eisenberg D 2011. Atomic structures suggest determinants of transmission barriers in mammalian prion disease. Biochemistry 50:2456–63
    [Google Scholar]
  69. 69.  Sawaya MR, Sambashivan S, Nelson R, Ivanova MI, Sievers SA et al. 2007. Atomic structures of amyloid cross-β spines reveal varied steric zippers. Nature 447:453–57
    [Google Scholar]
  70. 70.  Kurt TD, Bett C, Fernandez-Borges N, Joshi-Barr S, Hornemann S et al. 2014. Prion transmission prevented by modifying the β2–α2 loop structure of host PrPC. J. Neurosci. 34:1022–27
    [Google Scholar]
  71. 71.  Kurt TD, Jiang L, Fernandez-Borges N, Bett C, Liu J et al. 2015. Human prion protein sequence elements impede cross-species chronic wasting disease transmission. J. Clin. Investig. 125:1485–96
    [Google Scholar]
  72. 72.  Hill AF, Joiner S, Linehan J, Desbruslais M, Lantos PL, Collinge J 2000. Species-barrier-independent prion replication in apparently resistant species. PNAS 29:10248–53
    [Google Scholar]
  73. 73.  Mallucci GR, Ratte S, Asante EA, Linehan J, Gowland I et al. 2002. Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration. EMBO J 21:202–10
    [Google Scholar]
  74. 74.  Linden R 2017. The biological function of the prion protein: a cell surface scaffold of signaling modules. Front. Mol. Neurosci. 10:77
    [Google Scholar]
  75. 75.  Rubinsztein DC 2006. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443:780–86
    [Google Scholar]
  76. 76.  McKinnon C, Goold R, Andre R, Devoy A, Ortega Z et al. 2016. Prion-mediated neurodegeneration is associated with early impairment of the ubiquitin–proteasome system. Acta Neuropathol 131:411–25
    [Google Scholar]
  77. 77.  Xu Y, Tian C, Wang SB, Xie WL, Guo Y et al. 2012. Activation of the macroautophagic system in scrapie-infected experimental animals and human genetic prion diseases. Autophagy 8:1604–20
    [Google Scholar]
  78. 78.  Soto C, Satani N 2011. The intricate mechanisms of neurodegeneration in prion diseases. Trends Mol. Med. 17:14–24
    [Google Scholar]
  79. 79.  Hetz C, Mollereau B 2014. Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat. Rev. Neurosci. 15:233–49
    [Google Scholar]
  80. 80.  Torres M, Matamala JM, Duran-Aniotz C, Cornejo VH, Foley A, Hetz C 2015. ER stress signaling and neurodegeneration: at the intersection between Alzheimer's disease and prion-related disorders. Virus Res 207:69–75
    [Google Scholar]
  81. 81.  Moreno JA, Radford H, Peretti D, Steinert JR, Verity N et al. 2012. Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature 485:507–11
    [Google Scholar]
  82. 82.  Caughey B, Baron GS, Chesebro B, Jeffrey M 2009. Getting a grip on prions: oligomers, amyloids, and pathological membrane interactions. Annu. Rev. Biochem. 78:177–204
    [Google Scholar]
  83. 83.  Wegmann S, Miesbauer M, Winklhofer KF, Tatzelt J, Muller DJ 2008. Observing fibrillar assemblies on scrapie-infected cells. Pflugers Arch 456:83–93
    [Google Scholar]
  84. 84.  Chiesa R 2015. The elusive role of the prion protein and the mechanism of toxicity in prion disease. PLOS Pathog 11:e1004745
    [Google Scholar]
  85. 85.  Altmeppen HC, Prox J, Krasemann S, Puig B, Kruszewski K et al. 2015. The sheddase ADAM10 is a potent modulator of prion disease. eLife 4:e04260
    [Google Scholar]
  86. 86.  Chesebro B, Trifilo M, Race R, Meade-White K, Teng C et al. 2005. Anchorless prion protein results in infectious amyloid disease without clinical scrapie. Science 308:1435–39
    [Google Scholar]
  87. 87.  Resenberger UK, Harmeier A, Woerner AC, Goodman JL, Muller V et al. 2011. The cellular prion protein mediates neurotoxic signalling of β-sheet-rich conformers independent of prion replication. EMBO J 30:2057–70
    [Google Scholar]
  88. 88.  Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM 2009. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers. Nature 457:1128–32
    [Google Scholar]
  89. 89.  Solforosi L, Bellon A, Schaller M, Cruite JT, Abalos GC, Williamson RA 2007. Toward molecular dissection of PrPC–PrPSc interactions. J. Biol. Chem. 282:7465–71
    [Google Scholar]
  90. 90.  Um JW, Nygaard HB, Heiss JK, Kostylev MA, Stagi M et al. 2012. Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat. Neurosci. 15:1227–35
    [Google Scholar]
  91. 91.  Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M et al. 2013. Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer Aβ oligomer bound to cellular prion protein. Neuron 79:887–902
    [Google Scholar]
  92. 92.  Sonati T, Reimann RR, Falsig J, Baral PK, O'Connor T et al. 2013. The toxicity of antiprion antibodies is mediated by the flexible tail of the prion protein. Nature 501:102–6
    [Google Scholar]
  93. 93.  Herrmann US, Sonati T, Falsig J, Reimann RR, Dametto P et al. 2015. Prion infections and anti-PrP antibodies trigger converging neurotoxic pathways. PLOS Pathog 11:e1004662
    [Google Scholar]
  94. 94.  Biasini E, Unterberger U, Solomon IH, Massignan T, Senatore A et al. 2013. A mutant prion protein sensitizes neurons to glutamate-induced excitotoxicity. J. Neurosci. 33:2408–18
    [Google Scholar]
  95. 95.  McBride PA, Schulz-Schaeffer WJ, Donaldson M, Bruce M, Diringer H et al. 2001. Early spread of scrapie from the gastrointestinal tract to the central nervous system involves autonomic fibers of the splanchnic and vagus nerves. J. Virol. 75:9320–27
    [Google Scholar]
  96. 96.  Fox KA, Jewell JE, Williams ES, Miller MW 2006. Patterns of PrPCWD accumulation during the course of chronic wasting disease infection in orally inoculated mule deer (Odocoileus hemionus). J. Gen. Virol. 87:3451–61
    [Google Scholar]
  97. 97.  Kaatz M, Fast C, Ziegler U, Balkema-Buschmann A, Hammerschmidt B et al. 2012. Spread of classic BSE prions from the gut via the peripheral nervous system to the brain. Am. J. Pathol. 181:515–24
    [Google Scholar]
  98. 98.  Fraser H 1982. Neuronal spread of scrapie agent and targeting of lesions within the retino–tectal pathway. Nature 295:149–50
    [Google Scholar]
  99. 99.  Glatzel M, Heppner FL, Albers KM, Aguzzi A 2001. Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron 31:25–34
    [Google Scholar]
  100. 100.  Prinz M, Heikenwalder M, Junt T, Schwarz P, Glatzel M et al. 2003. Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. Nature 425:957–62
    [Google Scholar]
  101. 101.  Bett C, Joshi-Barr S, Lucero M, Trejo M, Liberski P et al. 2012. Biochemical properties of highly neuroinvasive prion strains. PLOS Pathog 8:e1002522
    [Google Scholar]
  102. 102.  Bett C, Kurt TD, Lucero M, Trejo M, Rozemuller AJ et al. 2013. Defining the conformational features of anchorless, poorly neuroinvasive prions. PLOS Pathog 9:e1003280
    [Google Scholar]
  103. 103.  Bett C, Lawrence J, Kurt TD, Orru C, Aguilar-Calvo P et al. 2017. Enhanced neuroinvasion by smaller, soluble prions. Acta Neuropathol. Commun. 5:32
    [Google Scholar]
  104. 104.  Aguilar-Calvo P, Bett C, Sevillano AM, Kurt TD, Lawrence J et al. 2018. Generation of novel neuroinvasive prions following intravenous challenge. Brain Pathol In press. https://doi.org/10.1111/bpa.12598
    [Crossref]
  105. 105.  Elder AM, Henderson DM, Nalls AV, Hoover EA, Kincaid AE et al. 2015. Immediate and ongoing detection of prions in the blood of hamsters and deer following oral, nasal, or blood inoculations. J. Virol. 89:7421–24
    [Google Scholar]
  106. 106.  Donaldson DS, Kobayashi A, Ohno H, Yagita H, Williams IR, Mabbott NA 2012. M cell–depletion blocks oral prion disease pathogenesis. Mucosal Immunol 5:216–25
    [Google Scholar]
  107. 107.  Heppner FL, Christ AD, Klein MA, Prinz M, Fried M et al. 2001. Transepithelial prion transport by M cells. Nat. Med. 7:976–77
    [Google Scholar]
  108. 108.  Donaldson DS, Sehgal A, Rios D, Williams IR, Mabbott NA 2016. Increased abundance of M cells in the gut epithelium dramatically enhances oral prion disease susceptibility. PLOS Pathog 12:e1006075
    [Google Scholar]
  109. 109.  Miyazawa K, Kanaya T, Takakura I, Tanaka S, Hondo T et al. 2010. Transcytosis of murine-adapted bovine spongiform encephalopathy agents in an in vitro bovine M cell model. J. Virol. 84:12285–91
    [Google Scholar]
  110. 110.  Takakura I, Miyazawa K, Kanaya T, Itani W, Watanabe K et al. 2011. Orally administered prion protein is incorporated by M cells and spreads into lymphoid tissues with macrophages in prion protein knockout mice. Am. J. Pathol. 179:1301–9
    [Google Scholar]
  111. 111.  Sigurdson CJ, Heikenwalder M, Manco G, Barthel M, Schwarz P et al. 2009. Bacterial colitis increases susceptibility to oral prion disease. J. Infect. Dis 199:243–52
    [Google Scholar]
  112. 112.  Hoffmann C, Ziegler U, Buschmann A, Weber A, Kupfer L et al. 2007. Prions spread via the autonomic nervous system from the gut to the central nervous system in cattle incubating bovine spongiform encephalopathy. J. Gen. Virol. 88:1048–55
    [Google Scholar]
  113. 113.  Masujin K, Matthews D, Wells GA, Mohri S, Yokoyama T 2007. Prions in the peripheral nerves of bovine spongiform encephalopathy–affected cattle. J. Gen. Virol. 88:1850–58
    [Google Scholar]
  114. 114.  Sigurdson CJ, Williams ES, Miller MW, Spraker TR, O'Rourke KI, Hoover EA 1999. Oral transmission and early lymphoid tropism of chronic wasting disease PrPres in mule deer fawns (Odocoileus hemionus). J. Gen. Virol. 80:2757–64
    [Google Scholar]
  115. 115.  Heggebo R, Press CM, Gunnes G, Lie KI, Tranulis MA et al. 2000. Distribution of prion protein in the ileal Peyer's patch of scrapie-free lambs and lambs naturally and experimentally exposed to the scrapie agent. J. Gen. Virol. 81:2327–37
    [Google Scholar]
  116. 116.  Raymond CR, Aucouturier P, Mabbott NA 2007. In vivo depletion of CD11c+ cells impairs scrapie agent neuroinvasion from the intestine. J. Immunol. 179:7758–66
    [Google Scholar]
  117. 117.  Cordier-Dirikoc S, Chabry J 2008. Temporary depletion of CD11c+ dendritic cells delays lymphoinvasion after intraperitonal scrapie infection. J. Virol. 82:8933–36
    [Google Scholar]
  118. 118.  Heikenwalder M, Zeller N, Seeger H, Prinz M, Klohn PC et al. 2005. Chronic lymphocytic inflammation specifies the organ tropism of prions. Science 307:1107–10
    [Google Scholar]
  119. 119.  Seeger H, Heikenwalder M, Zeller N, Kranich J, Schwarz P et al. 2005. Coincident scrapie infection and nephritis lead to urinary prion excretion. Science 310:324–26
    [Google Scholar]
  120. 120.  Ligios C, Cancedda MG, Carta A, Santucciu C, Maestrale C et al. 2011. Sheep with scrapie and mastitis transmit infectious prions through the milk. J. Virol. 85:1136–39
    [Google Scholar]
  121. 121.  Ligios C, Sigurdson CJ, Santucciu C, Carcassola G, Manco G et al. 2005. PrPSc in mammary glands of sheep affected by scrapie and mastitis. Nat. Med. 11:1137–38
    [Google Scholar]
  122. 122.  Sigurdson CJ, Barillas-Mury C, Miller MW, Oesch B, van Keulen LJ et al. 2002. PrPCWD lymphoid cell targets in early and advanced chronic wasting disease of mule deer. J. Gen. Virol. 83:2617–28
    [Google Scholar]
  123. 123.  Endres R, Alimzhanov MB, Plitz T, Futterer A, Kosco-Vilbois MH et al. 1999. Mature follicular dendritic cell networks depend on expression of lymphotoxin β receptor by radioresistant stromal cells and of lymphotoxin β and tumor necrosis factor by B cells. J. Exp. Med. 189:159–68
    [Google Scholar]
  124. 124.  Aydar Y, Sukumar S, Szakal AK, Tew JG 2005. The influence of immune complex–bearing follicular dendritic cells on the IgM response, Ig class switching, and production of high affinity IgG. J. Immunol. 174:5358–66
    [Google Scholar]
  125. 125.  McCulloch L, Brown KL, Bradford BM, Hopkins J, Bailey M et al. 2011. Follicular dendritic cell–specific prion protein (PrP) expression alone is sufficient to sustain prion infection in the spleen. PLOS Pathog 7:e1002402
    [Google Scholar]
  126. 126.  Klein MA, Kaeser PS, Schwarz P, Weyd H, Xenarios I et al. 2001. Complement facilitates early prion pathogenesis. Nat. Med. 7:488–92
    [Google Scholar]
  127. 127.  Mabbott NA, Bruce ME, Botto M, Walport MJ, Pepys MB 2001. Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie. Nat. Med. 7:485–87
    [Google Scholar]
  128. 128.  Michel B, Ferguson A, Johnson T, Bender H, Meyerett-Reid C et al. 2012. Genetic depletion of complement receptors CD21/35 prevents terminal prion disease in a mouse model of chronic wasting disease. J. Immunol. 189:4520–27
    [Google Scholar]
  129. 129.  Zabel MD, Heikenwalder M, Prinz M, Arrighi I, Schwarz P et al. 2007. Stromal complement receptor CD21/35 facilitates lymphoid prion colonization and pathogenesis. J. Immunol. 179:6144–52
    [Google Scholar]
  130. 130.  Montrasio F, Frigg R, Glatzel M, Klein MA, Mackay F et al. 2000. Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science 288:1257–59
    [Google Scholar]
  131. 131.  Mabbott NA, Young J, McConnell I, Bruce ME 2003. Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphotoxin pathway dramatically reduces scrapie susceptibility. J. Virol. 77:6845–54
    [Google Scholar]
  132. 132.  Beringue V, Herzog L, Jaumain E, Reine F, Sibille P et al. 2012. Facilitated cross-species transmission of prions in extraneural tissue. Science 335:472–75
    [Google Scholar]
  133. 133.  Srivastava S, Makarava N, Katorcha E, Savtchenko R, Brossmer R, Baskakov IV 2015. Post-conversion sialylation of prions in lymphoid tissues. PNAS 112:E6654–62
    [Google Scholar]
  134. 134.  Katorcha E, Makarava N, Savtchenko R, Baskakov IV 2015. Sialylation of the prion protein glycans controls prion replication rate and glycoform ratio. Sci. Rep. 5:16912
    [Google Scholar]
  135. 135.  Cronier S, Laude H, Peyrin JM 2004. Prions can infect primary cultured neurons and astrocytes and promote neuronal cell death. PNAS 101:12271–76
    [Google Scholar]
  136. 136.  Cronier S, Carimalo J, Schaeffer B, Jaumain E, Beringue V et al. 2012. Endogenous prion protein conversion is required for prion-induced neuritic alterations and neuronal death. FASEB J 26:3854–61
    [Google Scholar]
  137. 137.  Zhu C, Herrmann US, Falsig J, Abakumova I, Nuvolone M et al. 2016. A neuroprotective role for microglia in prion diseases. J. Exp. Med. 213:1047–59
    [Google Scholar]
  138. 138.  Kanu N, Imokawa Y, Drechsel DN, Williamson RA, Birkett CR et al. 2002. Transfer of scrapie prion infectivity by cell contact in culture. Curr. Biol. 12:523–30
    [Google Scholar]
  139. 139.  Gousset K, Schiff E, Langevin C, Marijanovic Z, Caputo A et al. 2009. Prions hijack tunnelling nanotubes for intercellular spread. Nat. Cell Biol. 11:328–36
    [Google Scholar]
  140. 140.  Zhu S, Victoria GS, Marzo L, Ghosh R, Zurzolo C 2015. Prion aggregates transfer through tunneling nanotubes in endocytic vesicles. Prion 9:125–35
    [Google Scholar]
  141. 141.  Victoria GS, Arkhipenko A, Zhu S, Syan S, Zurzolo C 2016. Astrocyte-to-neuron intercellular prion transfer is mediated by cell–cell contact. Sci. Rep. 6:20762
    [Google Scholar]
  142. 142.  Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K 2006. Staging of Alzheimer disease–associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404
    [Google Scholar]
  143. 143.  Braak H, Braak E 2000. Pathoanatomy of Parkinson's disease. J. Neurol. 247:Suppl. 2II3–10
    [Google Scholar]
  144. 144.  Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E 2003. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24:197–211
    [Google Scholar]
  145. 145.  Brettschneider J, Del Tredici K, Lee VM, Trojanowski JQ 2015. Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat. Rev. Neurosci. 16:109–20
    [Google Scholar]
  146. 146.  Arellano-Anaya ZE, Huor A, Leblanc P, Lehmann S, Provansal M et al. 2015. Prion strains are differentially released through the exosomal pathway. Cell. Mol. Life Sci. 72:1185–96
    [Google Scholar]
  147. 147.  Vella LJ, Sharples RA, Lawson VA, Masters CL, Cappai R, Hill AF 2007. Packaging of prions into exosomes is associated with a novel pathway of PrP processing. J. Pathol. 211:582–90
    [Google Scholar]
  148. 148.  Fevrier B, Vilette D, Archer F, Loew D, Faigle W et al. 2004. Cells release prions in association with exosomes. PNAS 101:9683–88
    [Google Scholar]
  149. 149.  Coleman BM, Hanssen E, Lawson VA, Hill AF 2012. Prion-infected cells regulate the release of exosomes with distinct ultrastructural features. FASEB J 26:4160–73
    [Google Scholar]
  150. 150.  Guo BB, Bellingham SA, Hill AF 2016. Stimulating the release of exosomes increases the intercellular transfer of prions. J. Biol. Chem. 291:5128–37
    [Google Scholar]
  151. 151.  Saa P, Castilla J, Soto C 2005. Cyclic amplification of protein misfolding and aggregation. Methods Mol. Biol. 299:53–65
    [Google Scholar]
  152. 152.  Papadopoulos VE, Nikolopoulou G, Antoniadou I, Karachaliou A, Arianoglou G et al. 2018. Modulation of β-glucocerebrosidase increases α-synuclein secretion and exosome release in mouse models of Parkinson's disease. Hum. Mol. Genet. 27:1696–1710
    [Google Scholar]
  153. 153.  Wang X, Gerdes HH 2015. Transfer of mitochondria via tunneling nanotubes rescues apoptotic PC12 cells. Cell Death Differ 22:1181–91
    [Google Scholar]
  154. 154.  Abounit S, Bousset L, Loria F, Zhu S, de Chaumont F et al. 2016. Tunneling nanotubes spread fibrillar α-synuclein by intercellular trafficking of lysosomes. EMBO J 35:2120–38
    [Google Scholar]
  155. 155.  Annunziata I, Patterson A, Helton D, Hu H, Moshiach S et al. 2013. Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-β secretion via deregulated lysosomal exocytosis. Nat. Commun. 4:2734
    [Google Scholar]
  156. 156.  Dickinson AG 1976. Scrapie in sheep and goats. Front. Biol. 44:209–41
    [Google Scholar]
  157. 157.  Tanaka M, Chien P, Naber N, Cooke R, Weissman JS 2004. Conformational variations in an infectious protein determine prion strain differences. Nature 428:323–28
    [Google Scholar]
  158. 158.  Colby DW, Prusiner SB 2011. Prions. Cold Spring Harb. Perspect. Biol. 3:a006833
    [Google Scholar]
  159. 159.  Wille H, Bian W, McDonald M, Kendall A, Colby DW et al. 2009. Natural and synthetic prion structure from X-ray fiber diffraction. PNAS 106:16990–95
    [Google Scholar]
  160. 160.  Ghaemmaghami S, Watts JC, Nguyen HO, Hayashi S, DeArmond SJ, Prusiner SB 2011. Conformational transformation and selection of synthetic prion strains. J. Mol. Biol. 413:527–42
    [Google Scholar]
  161. 161.  Peretz D, Scott MR, Groth D, Williamson RA, Burton DR et al. 2001. Strain-specified relative conformational stability of the scrapie prion protein. Protein Sci 10:854–63
    [Google Scholar]
  162. 162.  Ayers JI, Schutt CR, Shikiya RA, Aguzzi A, Kincaid AE, Bartz JC 2011. The strain-encoded relationship between PrP replication, stability and processing in neurons is predictive of the incubation period of disease. PLOS Pathog 7:e1001317
    [Google Scholar]
  163. 163.  Safar JG, Xiao X, Kabir ME, Chen S, Kim C et al. 2015. Structural determinants of phenotypic diversity and replication rate of human prions. PLOS Pathog 11:e1004832
    [Google Scholar]
  164. 164.  Cescatti M, Saverioni D, Capellari S, Tagliavini F, Kitamoto T et al. 2016. Analysis of conformational stability of abnormal prion protein aggregates across the spectrum of Creutzfeldt–Jakob disease prions. J. Virol. 90:6244–54
    [Google Scholar]
  165. 165.  Nazor KE, Kuhn F, Seward T, Green M, Zwald D et al. 2005. Immunodetection of disease-associated mutant PrP, which accelerates disease in GSS transgenic mice. EMBO J 24:2472–80
    [Google Scholar]
  166. 166.  Safar J, Wille H, Itri V, Groth D, Serban H et al. 1998. Eight prion strains have PrPSc molecules with different conformations. Nat. Med. 4:1157–65
    [Google Scholar]
  167. 167.  Kim EJ, Cho SS, Jeong BH, Kim YS, Seo SW et al. 2012. Glucose metabolism in sporadic Creutzfeldt–Jakob disease: a statistical parametric mapping analysis of 18F-FDG PET. Eur. J. Neurol. 19:488–93
    [Google Scholar]
  168. 168.  Saverioni D, Notari S, Capellari S, Poggiolini I, Giese A et al. 2013. Analyses of protease resistance and aggregation state of abnormal prion protein across the spectrum of human prions. J. Biol. Chem. 288:27972–85
    [Google Scholar]
  169. 169.  Shikiya RA, Eckland TE, Young AJ, Bartz JC 2014. Prion formation, but not clearance, is supported by protein misfolding cyclic amplification. Prion 8:415–20
    [Google Scholar]
  170. 170.  Büeler HR, Aguzzi A, Sailer A, Greiner RA, Autenried P et al. 1993. Mice devoid of PrP are resistant to scrapie. Cell 73:1339–47
    [Google Scholar]
  171. 171.  Büeler HR, Fischer M, Lang Y, Bluethmann H, Lipp HP et al. 1992. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356:577–82
    [Google Scholar]
  172. 172.  Prusiner SB, Groth D, Serban A, Koehler R, Foster D et al. 1993. Ablation of the prion protein (PrP) gene in mice prevents scrapie and facilitates production of anti-PrP antibodies. PNAS 90:10608–12
    [Google Scholar]
  173. 173.  Manson JC, Clarke AR, Hooper ML, Aitchison L, McConnell I, Hope J 1994. 129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal. Mol. Neurobiol. 8:121–27
    [Google Scholar]
  174. 174.  Prusiner SB, Scott M, Foster D, Pan KM, Groth D et al. 1990. Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell 63:673–86
    [Google Scholar]
  175. 175.  Manson JC, Clarke AR, McBride PA, McConnell I, Hope J 1994. PrP gene dosage determines the timing but not the final intensity or distribution of lesions in scrapie pathology. Neurodegeneration 3:331–40
    [Google Scholar]
  176. 176.  Mays CE, Titlow W, Seward T, Telling GC, Ryou C 2009. Enhancement of protein misfolding cyclic amplification by using concentrated cellular prion protein source. Biochem. Biophys. Res. Commun. 388:306–10
    [Google Scholar]
  177. 177.  Mays CE, van der Merwe J, Kim C, Haldiman T, McKenzie D et al. 2015. Prion infectivity plateaus and conversion to symptomatic disease originate from falling precursor levels and increased levels of oligomeric PrPSc species. J. Virol. 89:12418–26
    [Google Scholar]
  178. 178.  Katorcha E, Makarava N, Savtchenko R, D'Azzo A, Baskakov IV 2014. Sialylation of prion protein controls the rate of prion amplification, the cross-species barrier, the ratio of PrPSc glycoform and prion infectivity. PLOS Pathog 10:e1004366
    [Google Scholar]
  179. 179.  Srivastava S, Katorcha E, Daus ML, Lasch P, Beekes M, Baskakov IV 2017. Sialylation controls prion fate in vivo. J. Biol. Chem. 292:2359–68
    [Google Scholar]
  180. 180.  Deleault NR, Lucassen RW, Supattapone S 2003. RNA molecules stimulate prion protein conversion. Nature 425:717–20
    [Google Scholar]
  181. 181.  Saa P, Sferrazza GF, Ottenberg G, Oelschlegel AM, Dorsey K, Lasmezas CI 2012. Strain-specific role of RNAs in prion replication. J. Virol. 86:10494–504
    [Google Scholar]
  182. 182.  Deleault NR, Piro JR, Walsh DJ, Wang F, Ma J et al. 2012. Isolation of phosphatidylethanolamine as a solitary cofactor for prion formation in the absence of nucleic acids. PNAS 109:8546–51
    [Google Scholar]
  183. 183.  Shikiya RA, Langenfeld KA, Eckland TE, Trinh J, Holec SA et al. 2017. PrPSc formation and clearance as determinants of prion tropism. PLOS Pathog 13:e1006298
    [Google Scholar]
  184. 184.  Puoti G, Giaccone G, Rossi G, Canciani B, Bugiani O, Tagliavini F 1999. Sporadic Creutzfeldt–Jakob disease: co-occurrence of different types of PrPSc in the same brain. Neurology. 532173–76
  185. 185.  Haldiman T, Kim C, Cohen Y, Chen W, Blevins J et al. 2013. Co-existence of distinct prion types enables conformational evolution of human PrPSc by competitive selection. J. Biol. Chem. 288:29846–61
    [Google Scholar]
  186. 186.  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 4:805–14
    [Google Scholar]
  187. 187.  Schoch G, Seeger H, Bogousslavsky J, Tolnay M, Janzer RC et al. 2006. Analysis of prion strains by PrPSc profiling in sporadic Creutzfeldt–Jakob disease. PLOS Med 3:e14
    [Google Scholar]
  188. 188.  Notari S, Capellari S, Langeveld J, Giese A, Strammiello R et al. 2007. A refined method for molecular typing reveals that co-occurrence of PrPSc types in Creutzfeldt–Jakob disease is not the rule. Lab. Investig 87:1103–12
    [Google Scholar]
  189. 189.  Notari S, Capellari S, Giese A, Westner I, Baruzzi A et al. 2004. Effects of different experimental conditions on the PrPSc core generated by protease digestion: implications for strain typing and molecular classification of CJD. J. Biol. Chem. 279:16797–804
    [Google Scholar]
  190. 190.  Bartz JC, Kramer ML, Sheehan MH, Hutter JA, Ayers JI et al. 2007. Prion interference is due to a reduction in strain-specific PrPSc levels. J. Virol. 81:689–97
    [Google Scholar]
  191. 191.  Kimberlin RH, Walker CA 1985. Competition between strains of scrapie depends on the blocking agent being infectious. Intervirology 23:74–81
    [Google Scholar]
  192. 192.  Taylor DM, Dickinson AG, Fraser H, Marsh RF 1986. Evidence that transmissible mink encephalopathy agent is biologically inactive in mice. Neuropathol. Appl. Neurobiol. 12:207–15
    [Google Scholar]
  193. 193.  Langenfeld KA, Shikiya RA, Kincaid AE, Bartz JC 2016. Incongruity between prion conversion and incubation period following coinfection. J. Virol. 90:5715–23
    [Google Scholar]
  194. 194.  Collinge J, Clarke AR 2007. A general model of prion strains and their pathogenicity. Science 318:930–36
    [Google Scholar]
  195. 195.  Li J, Browning S, Mahal SP, Oelschlegel AM, Weissmann C 2010. Darwinian evolution of prions in cell culture. Science 327:869–72
    [Google Scholar]
  196. 196.  Mahal SP, Browning S, Li J, Suponitsky-Kroyter I, Weissmann C 2010. Transfer of a prion strain to different hosts leads to emergence of strain variants. PNAS 107:22653–58
    [Google Scholar]
  197. 197.  Gonzalez-Montalban N, Lee YJ, Makarava N, Savtchenko R, Baskakov IV 2013. Changes in prion replication environment cause prion strain mutation. FASEB J 27:3702–10
    [Google Scholar]
  198. 198.  Makarava N, Baskakov IV 2013. The evolution of transmissible prions: the role of deformed templating. PLOS Pathog 9:e1003759
    [Google Scholar]
  199. 199.  Mallucci G, Dickinson A, Linehan J, Klohn PC, Brandner S, Collinge J 2003. Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science 302:871–74
    [Google Scholar]
  200. 200.  Moreno JA, Halliday M, Molloy C, Radford H, Verity N 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]
/content/journals/10.1146/annurev-pathmechdis-012418-013109
Loading
/content/journals/10.1146/annurev-pathmechdis-012418-013109
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error