The prion paradigm has emerged as a unifying molecular principle for the pathogenesis of many age-related neurodegenerative diseases. This paradigm holds that a fundamental cause of specific disorders is the misfolding and seeded aggregation of certain proteins. The concept arose from the discovery that devastating brain diseases called spongiform encephalopathies are transmissible to new hosts by agents consisting solely of a misfolded protein, now known as the prion protein. Accordingly, “prion” was defined as a “proteinaceous infectious particle.” As the concept has expanded to include other diseases, many of which are not infectious by any conventional definition, the designation of prions as infectious agents has become problematic. We propose to define prions as “proteinaceous nucleating particles” to highlight the molecular action of the agents, lessen unwarranted apprehension about the transmissibility of noninfectious proteopathies, and promote the wider acceptance of this revolutionary paradigm by the biomedical community.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Aguzzi A. 2003. Prions and the immune system: a journey through gut, spleen, and nerves. Adv. Immunol. 81:123–71 [Google Scholar]
  2. Aguzzi A, Heikenwalder M, Polymenidou M. 2007. Insights into prion strains and neurotoxicity. Nat. Rev. Mol. Cell Biol. 8:552–61 [Google Scholar]
  3. Ahmed Z, Cooper J, Murray TK, Garn K, McNaughton E. et al. 2014. A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: The pattern of spread is determined by connectivity, not proximity. Acta Neuropathol. 127:667–83 [Google Scholar]
  4. Al-Chalabi A, Jones A, Troakes C, King A, Al-Sarraj S, van den Berg LH. 2012. The genetics and neuropathology of amyotrophic lateral sclerosis. Acta Neuropathol. 124:339–52 [Google Scholar]
  5. Ano Bom APD, Rangel LP, Costa DCF, de Oliveira GAP, Sanches D. et al. 2012. Mutant p53 aggregates into prion-like amyloid oligomers and fibrils: implications for cancer. J. Biol. Chem. 287:28152–62 [Google Scholar]
  6. Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW. 1991. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cereb. Cortex 1:103–16 [Google Scholar]
  7. Aulić S, Le TTN, Moda F, Abounit S, Corvaglia S. et al. 2014. Defined α-synuclein prion-like molecular assemblies spreading in cell culture. BMC Neurosci. 15:69 [Google Scholar]
  8. Avila J, Lucas JJ, Perez M, Hernandez F. 2004. Role of tau protein in both physiological and pathological conditions. Physiol. Rev. 84:361–84 [Google Scholar]
  9. Baker HF, Ridley RM, Duchen LW, Crow TJ, Bruton CJ. 1993. Evidence for the experimental transmission of cerebral β-amyloidosis to primates. Int. J. Exp. Pathol. 74:441–54 [Google Scholar]
  10. Balch WE, Morimoto RI, Dillin A, Kelly JW. 2008. Adapting proteostasis for disease intervention. Science 319:916–19 [Google Scholar]
  11. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A. et al. 2012. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N. Engl. J. Med. 367:795–804 [Google Scholar]
  12. Bennion Callister J, Pickering-Brown SM. 2014. Pathogenesis/genetics of frontotemporal dementia and how it relates to ALS. Exp. Neurol. 262:Part B84–90 [Google Scholar]
  13. Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR. et al. 2011. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat. Neurosci. 14:750–56 [Google Scholar]
  14. Boluda S, Iba M, Zhang B, Raible KM, Lee VMY, Trojanowski JQ. 2015. Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer's disease or corticobasal degeneration brains. Acta Neuropathol. 129:221–37 [Google Scholar]
  15. Braak H, Braak E. 1995. Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol. Aging 16:271–78 [Google Scholar]
  16. Braak H, Brettschneider J, Ludolph AC, Lee VM, Trojanowski JQ, Del Tredici K. 2013. Amyotrophic lateral sclerosis—a model of corticofugal axonal spread. Nat. Rev. Neurol. 9:708–14 [Google Scholar]
  17. Brettschneider J, Del Tredici K, Irwin DJ, Grossman M, Robinson JL. et al. 2014. Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD). Acta Neuropathol. 127:423–39 [Google Scholar]
  18. Brown P, Brandel JP, Sato T, Nakamura Y, MacKenzie J. et al. 2012. Iatrogenic Creutzfeldt-Jakob disease, final assessment. Emerg. Infect. Dis. 18:901–7 [Google Scholar]
  19. Buyukmihci N, Goehring-Harmon F, Marsh RF. 1983. Neural pathogenesis of experimental scrapie after intraocular inoculation of hamsters. Exp. Neurol. 81:396–406 [Google Scholar]
  20. Cai X, Chen J, Xu H, Liu S, Jiang QX. et al. 2014. Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156:1207–22 [Google Scholar]
  21. 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]
  22. Chesebro B, Race R, Wehrly K, Nishio J, Bloom M. et al. 1985. Identification of scrapie prion protein-specific mRNA in scrapie-infected and uninfected brain. Nature 315:331–33 [Google Scholar]
  23. Chiti F, Dobson CM. 2006. Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem. 75:333–66 [Google Scholar]
  24. Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S. et al. 2013. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. PNAS 110:9535–40 [Google Scholar]
  25. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S. et al. 2009. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11:909–13 [Google Scholar]
  26. Clavaguera F, Hench J, Lavenir I, Schweighauser G, Frank S. et al. 2014. Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice. Acta Neuropathol. 127:299–301 [Google Scholar]
  27. Colby DW, Wain R, Baskakov IV, Legname G, Palmer CG. et al. 2010. Protease-sensitive synthetic prions. PLOS Pathog. 6:e1000736 [Google Scholar]
  28. Collinge J, Clarke AR. 2007. A general model of prion strains and their pathogenicity. Science 318:930–36 [Google Scholar]
  29. Collins SJ, Lawson VA, Masters CL. 2004. Transmissible spongiform encephalopathies. Lancet 363:51–61 [Google Scholar]
  30. Cruts M, Gijselinck I, Van Langenhove T, van der Zee J, Van Broeckhoven C. 2013. Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum. Trends Neurosci. 36:450–59 [Google Scholar]
  31. Cushman M, Johnson BS, King OD, Gitler AD, Shorter J. 2010. Prion-like disorders: blurring the divide between transmissibility and infectivity. J. Cell Sci. 123:1191–201 [Google Scholar]
  32. DeArmond SJ, Prusiner SB. 1995. Etiology and pathogenesis of prion diseases. Am. J. Pathol. 146:785–811 [Google Scholar]
  33. de Calignon A, Polydoro M, Suarez-Calvet M, William C, Adamowicz DH. et al. 2012. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73:685–97 [Google Scholar]
  34. Deleault NR, Walsh DJ, Piro JR, Wang F, Wang X. et al. 2012. Cofactor molecules maintain infectious conformation and restrict strain properties in purified prions. PNAS 109:E1938–46 [Google Scholar]
  35. Domert J, Rao SB, Agholme L, Brorsson AC, Marcusson J. et al. 2014. Spreading of amyloid-β peptides via neuritic cell-to-cell transfer is dependent on insufficient cellular clearance. Neurobiol. Dis. 65:82–92 [Google Scholar]
  36. Duran-Aniotz C, Morales R, Moreno-Gonzalez I, Hu PP, Fedynyshyn J, Soto C. 2014. Aggregate-depleted brain fails to induce Aβ deposition in a mouse model of Alzheimer's disease. PLOS ONE 9:e89014 [Google Scholar]
  37. Duran-Aniotz C, Morales R, Moreno-Gonzalez I, Hu PP, Soto C. 2013. Brains from non-Alzheimer's individuals containing amyloid deposits accelerate Aβ deposition in vivo. Acta Neuropathol. Commun. 1:76 [Google Scholar]
  38. Eisele YS, Bolmont T, Heikenwalder M, Langer F, Jacobson LH. et al. 2009. Induction of cerebral β-amyloidosis: intracerebral versus systemic Aβ inoculation. PNAS 106:12926–31 [Google Scholar]
  39. Eisele YS, Fritschi SK, Hamaguchi T, Obermüller U, Füger P. et al. 2014. Multiple factors contribute to the peripheral induction of cerebral β-amyloidosis. J. Neurosci. 34:10264–73 [Google Scholar]
  40. Eisele YS, Obermüller U, Heilbronner G, Baumann F, Kaeser SA. et al. 2010. Peripherally applied Aβ-containing inoculates induce cerebral β-amyloidosis. Science 330:980–82 [Google Scholar]
  41. Eisenberg D, Jucker M. 2012. The amyloid state of proteins in human diseases. Cell 148:1188–203 [Google Scholar]
  42. Fast C, Groschup MH. 2013. Classical and atypical scrapie in sheep and goats. Prions and Diseases, Vol. 2 Animals, Humans and the Environment WQ Zou, P Gambetti 15–44 New York: Springer [Google Scholar]
  43. Forget KJ, Tremblay G, Roucou X. 2013. p53 Aggregates penetrate cells and induce the co-aggregation of intracellular p53. PLOS ONE 8:e69242 [Google Scholar]
  44. Frank SA. 2014. Somatic mosaicism and disease. Curr. Biol. 24:R577–81 [Google Scholar]
  45. Franklin BS, Bossaller L, De Nardo D, Ratter JM, Stutz A. et al. 2014. The adaptor ASC has extracellular and ‘prionoid’ activities that propagate inflammation. Nat. Immunol. 15:727–37 [Google Scholar]
  46. Fraser H. 1982. Neuronal spread of scrapie agent and targeting of lesions within the retino-tectal pathway. Nature 295:149–50 [Google Scholar]
  47. Fritschi SK, Cintron A, Ye L, Mahler J, Bühler A. et al. 2014a. Aβ seeds resist inactivation by formaldehyde. Acta Neuropathol. 128:477–84 [Google Scholar]
  48. Fritschi SK, Langer F, Kaeser SA, Maia LF, Portelius E. et al. 2014b. Highly potent soluble amyloid-β seeds in human Alzheimer brain but not cerebrospinal fluid. Brain 137:2909–15 [Google Scholar]
  49. Frost B, Jacks RL, Diamond MI. 2009. Propagation of tau misfolding from the outside to the inside of a cell. J. Biol. Chem. 284:12845–52 [Google Scholar]
  50. Furukawa Y, Kaneko K, Watanabe S, Yamanaka K, Nukina N. 2011. A seeding reaction recapitulates intracellular formation of Sarkosyl-insoluble transactivation response element (TAR) DNA-binding protein-43 inclusions. J. Biol. Chem. 286:18664–72 [Google Scholar]
  51. Gajdusek DC. 1977. Unconventional viruses and the origin and disappearance of kuru. Science 197:943–60 [Google Scholar]
  52. Gambetti P, Cali I, Notari S, Kong Q, Zou WQ, Surewicz WK. 2011. Molecular biology and pathology of prion strains in sporadic human prion diseases. Acta Neuropathol. 121:79–90 [Google Scholar]
  53. Goedert M, Spillantini MG, Del Tredici K, Braak H. 2013. 100 years of Lewy pathology. Nat. Rev. Neurol. 9:13–24 [Google Scholar]
  54. Goudsmit J, Morrow CH, Asher DM, Yanagihara RT, Masters CL. et al. 1980. Evidence for and against the transmissibility of Alzheimer disease. Neurology 30:945–50 [Google Scholar]
  55. Grad LI, Cashman NR. 2014. Prion-like activity of Cu/Zn superoxide dismutase: implications for amyotrophic lateral sclerosis. Prion 8:33–41 [Google Scholar]
  56. Grad LI, Yerbury JJ, Turner BJ, Guest WC, Pokrishevsky E. et al. 2014. Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms. PNAS 111:3620–25 [Google Scholar]
  57. Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A. et al. 2013. Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell 154:103–17 [Google Scholar]
  58. Guo JL, Lee VMY. 2014. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat. Med. 20:130–38 [Google Scholar]
  59. Hamaguchi T, Eisele YS, Varvel NH, Lamb BT, Walker LC, Jucker M. 2012. The presence of Aβ seeds, and not age per se, is critical to the initiation of Aβ deposition in the brain. Acta Neuropathol. 123:31–37 [Google Scholar]
  60. Han TW, Kato M, Xie S, Wu LC, Mirzaei H. et al. 2012. Cell-free formation of RNA granules: Bound RNAs identify features and components of cellular assemblies. Cell 149:768–79 [Google Scholar]
  61. Hardy J, Revesz T. 2012. The spread of neurodegenerative disease. N. Engl. J. Med. 366:2126–28 [Google Scholar]
  62. Hardy J, Selkoe DJ. 2002. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297:353–56 [Google Scholar]
  63. Heilbronner G, Eisele YS, Langer F, Kaeser SA, Novotny R. et al. 2013. Seeded strain-like transmission of β-amyloid morphotypes in APP transgenic mice. EMBO Rep. 14:1017–22 [Google Scholar]
  64. Heuer E, Rosen RF, Cintron A, Walker LC. 2012. Nonhuman primate models of Alzheimer-like cerebral proteopathy. Curr. Pharm. Des. 18:1159–69 [Google Scholar]
  65. Holtzman DM, Morris JC, Goate AM. 2011. Alzheimer's disease: the challenge of the second century. Sci. Transl. Med. 3:77sr1 [Google Scholar]
  66. Horvath S. 2013. DNA methylation age of human tissues and cell types. Genome Biol. 14:R115 [Google Scholar]
  67. Hou F, Sun L, Zheng H, Skaug B, Jiang QX, Chen ZJ. 2011. MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146:448–61 [Google Scholar]
  68. Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VMY. 2013. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy. J. Neurosci. 33:1024–37 [Google Scholar]
  69. Irwin DJ, Abrams JY, Schonberger LB, Leschek EW, Mills JL. et al. 2013. Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol. 70:462–68 [Google Scholar]
  70. Iturria-Medina Y, Sotero RC, Toussaint PJ, Evans AC, Alzheimer's Dis. Neuroimaging Initiat. 2014. Epidemic spreading model to characterize misfolded proteins propagation in aging and associated neurodegenerative disorders. PLOS Comput. Biol. 10:e1003956 [Google Scholar]
  71. Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS. et al. 2010. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 9:119–28 [Google Scholar]
  72. Johnson RT. 2005. Prion diseases. Lancet Neurol. 4:635–42 [Google Scholar]
  73. Jucker M. 2010. The benefits and limitations of animal models for translational research in neurodegenerative diseases. Nat. Med. 16:1210–14 [Google Scholar]
  74. Jucker M, Walker LC. 2011. Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann. Neurol. 70:532–40 [Google Scholar]
  75. Jucker M, Walker LC. 2013. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501:45–51 [Google Scholar]
  76. Kane MD, Lipinski WJ, Callahan MJ, Bian F, Durham RA. et al. 2000. Evidence for seeding of β-amyloid by intracerebral infusion of Alzheimer brain extracts in β-amyloid precursor protein-transgenic mice. J. Neurosci. 20:3606–11 [Google Scholar]
  77. Kato M, Han TW, Xie S, Shi K, Du X. et al. 2012. Cell-free formation of RNA granules: Low complexity sequence domains form dynamic fibers within hydrogels. Cell 149:753–67 [Google Scholar]
  78. Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J. et al. 2013. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495:467–73 [Google Scholar]
  79. Kimberlin RH, Walker CA. 1986. Pathogenesis of scrapie (strain 263K) in hamsters infected intracerebrally, intraperitoneally or intraocularly. J. Gen. Virol. 67:Part 2255–63 [Google Scholar]
  80. King OD, Gitler AD, Shorter J. 2012. The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res. 1462:61–80 [Google Scholar]
  81. Knowles TP, Vendruscolo M, Dobson CM. 2014. The amyloid state and its association with protein misfolding diseases. Nat. Rev. Mol. Cell Biol. 15:384–96 [Google Scholar]
  82. Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. 2008. Lewy body–like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat. Med. 14:504–6 [Google Scholar]
  83. Krauss S, Vorberg I. 2013. Prions ex vivo: what cell culture models tell us about infectious proteins. Int. J. Cell Biol. 2013:704546 [Google Scholar]
  84. Langer F, Eisele YS, Fritschi SK, Staufenbiel M, Walker LC, Jucker M. 2011. Soluble Aβ seeds are potent inducers of cerebral β-amyloid deposition. J. Neurosci. 31:14488–95 [Google Scholar]
  85. Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Guerrero-Munoz MJ, Kiritoshi T. et al. 2012. Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau. Sci. Rep. 2:700 [Google Scholar]
  86. Lee VMY, Goedert M, Trojanowski JQ. 2001. Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24:1121–59 [Google Scholar]
  87. Li JY, Englund E, Holton JL, Soulet D, Hagell P. et al. 2008. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat. Med. 14:501–3 [Google Scholar]
  88. Li YR, King OD, Shorter J, Gitler AD. 2013. Stress granules as crucibles of ALS pathogenesis. J. Cell Biol. 201:361–72 [Google Scholar]
  89. Liberski PP, Hainfellner JA, Sikorska B, Budka H. 2012. Prion protein (PrP) deposits in the tectum of experimental Gerstmann-Straüssler-Scheinker disease following intraocular inoculation. Folia Neuropathol. 50:85–88 [Google Scholar]
  90. Liebman SW, Chernoff YO. 2012. Prions in yeast. Genetics 191:1041–72 [Google Scholar]
  91. Ling SC, Polymenidou M, Cleveland DW. 2013. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79:416–38 [Google Scholar]
  92. Liu L, Drouet V, Wu JW, Witter MP, Small SA. et al. 2012. Trans-synaptic spread of tau pathology in vivo. PLOS ONE 7:e31302 [Google Scholar]
  93. Lladó L, Baliellas C, Casasnovas C, Ferrer I, Fabregat J. et al. 2010. Risk of transmission of systemic transthyretin amyloidosis after domino liver transplantation. Liver Transplant. 16:1386–92 [Google Scholar]
  94. Lu JX, Qiang W, Yau WM, Schwieters CD, Meredith SC, Tycko R. 2013. Molecular structure of β-amyloid fibrils in Alzheimer's disease brain tissue. Cell 154:1257–68 [Google Scholar]
  95. Luk KC, Kehm V, Carroll J, Zhang B, O'Brien P. et al. 2012a. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338:949–53 [Google Scholar]
  96. Luk KC, Kehm VM, Zhang B, O'Brien P, Trojanowski JQ, Lee VMY. 2012b. Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J. Exp. Med. 209:975–86 [Google Scholar]
  97. Luk KC, Song C, O'Brien P, Stieber A, Branch JR. et al. 2009. Exogenous α-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. PNAS 106:20051–56 [Google Scholar]
  98. Maji SK, Perrin MH, Sawaya MR, Jessberger S, Vadodaria K. et al. 2009. Functional amyloids as natural storage of peptide hormones in pituitary secretory granules. Science 325:328–32 [Google Scholar]
  99. Masuda-Suzukake M, Nonaka T, Hosokawa M, Kubo M, Shimozawa A. et al. 2014. Pathological alpha-synuclein propagates through neural networks. Acta Neuropathol. Commun. 2:88 [Google Scholar]
  100. Masuda-Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T. et al. 2013. Prion-like spreading of pathological α-synuclein in brain. Brain 136:1128–38 [Google Scholar]
  101. McConnell MJ, Lindberg MR, Brennand KJ, Piper JC, Voet T. et al. 2013. Mosaic copy number variation in human neurons. Science 342:632–37 [Google Scholar]
  102. Mehta AK, Rosen RF, Childers WS, Gehman JD, Walker LC, Lynn DG. 2013. Context dependence of protein misfolding and structural strains in neurodegenerative diseases. Biopolymers 100:722–30 [Google Scholar]
  103. Meinhardt J, Sachse C, Hortschansky P, Grigorieff N, Fändrich M. 2009. Aβ(1-40) fibril polymorphism implies diverse interaction patterns in amyloid fibrils. J. Mol. Biol. 386:869–77 [Google Scholar]
  104. Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C. et al. 2006. Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host. Science 313:1781–84 [Google Scholar]
  105. Mizielinska S, Grönke S, Niccoli T, Ridler CE, Clayton EL. et al. 2014. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 345:1192–94 [Google Scholar]
  106. Morales R, Duran-Aniotz C, Castilla J, Estrada LD, Soto C. 2012. De novo induction of amyloid-β deposition in vivo. Mol. Psychiatry 17:1347–53 [Google Scholar]
  107. Mougenot AL, Nicot S, Bencsik A, Morignat E, Verchere J. et al. 2012. Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol. Aging 33:2225–28 [Google Scholar]
  108. Munch C, O'Brien J, Bertolotti A. 2011. Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. PNAS 108:3548–53 [Google Scholar]
  109. Murakami T, Ishiguro N, Higuchi K. 2014. Transmission of systemic AA amyloidosis in animals. Vet. Pathol. 51:363–71 [Google Scholar]
  110. Nath S, Agholme L, Kurudenkandy FR, Granseth B, Marcusson J, Hallbeck M. 2012. Spreading of neurodegenerative pathology via neuron-to-neuron transmission of β-amyloid. J. Neurosci. 32:8767–77 [Google Scholar]
  111. Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H. et al. 2012. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J. Neuropathol. Exp. Neurol. 71:362–81 [Google Scholar]
  112. Newby GA, Lindquist S. 2013. Blessings in disguise: biological benefits of prion-like mechanisms. Trends Cell Biol. 23:251–59 [Google Scholar]
  113. Nilsson KPR, Åslund A, Berg I, Nyström S, Konradsson P. et al. 2007. Imaging distinct conformational states of amyloid-β fibrils in Alzheimer's disease using novel luminescent probes. ACS Chem. Biol. 2:553–60 [Google Scholar]
  114. Nonaka T, Masuda-Suzukake M, Arai T, Hasegawa Y, Akatsu H. et al. 2013. Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep. 4:124–34 [Google Scholar]
  115. Oesch B, Westaway D, Wälchli M, McKinley MP, Kent SBH. et al. 1985. A cellular gene encodes scrapie PrP 27-30 protein. Cell 40:735–46 [Google Scholar]
  116. Paravastu AK, Leapman RD, Yau WM, Tycko R. 2008. Molecular structural basis for polymorphism in Alzheimer's β-amyloid fibrils. PNAS 105:18349–54 [Google Scholar]
  117. Paravastu AK, Qahwash I, Leapman RD, Meredith SC, Tycko R. 2009. Seeded growth of β-amyloid fibrils from Alzheimer's brain-derived fibrils produces a distinct fibril structure. PNAS 106:7443–48 [Google Scholar]
  118. Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W. et al. 1999. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann. Neurol. 46:224–33 [Google Scholar]
  119. Pecho-Vrieseling E, Rieker C, Fuchs S, Bleckmann D, Esposito MS. et al. 2014. Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons. Nat. Neurosci. 17:1064–72 [Google Scholar]
  120. Peeraer E, Bottelbergs A, Van Kolen K, Stancu IC, Vasconcelos B. et al. 2015. Intracerebral injection of preformed synthetic tau fibrils initiates widespread tauopathy and neuronal loss in the brains of tau transgenic mice. Neurobiol. Dis. 73:83–95 [Google Scholar]
  121. Petkova AT, Leapman RD, Guo Z, Yau WM, Mattson MP, Tycko R. 2005. Self-propagating, molecular-level polymorphism in Alzheimer's β-amyloid fibrils. Science 307:262–65 [Google Scholar]
  122. Prusiner SB. 1982. Novel proteinaceous infectious particles cause scrapie. Science 216:136–44 [Google Scholar]
  123. Prusiner SB. 1984. Some speculations about prions, amyloid, and Alzheimer's disease. N. Engl. J. Med. 310:661–63 [Google Scholar]
  124. Prusiner SB. 1998. Prions. PNAS 95:13363–83 [Google Scholar]
  125. Prusiner SB. 2012. A unifying role for prions in neurodegenerative diseases. Science 336:1511–13 [Google Scholar]
  126. Prusiner SB. 2013. Biology and genetics of prions causing neurodegeneration. Annu. Rev. Genet. 47:601–23 [Google Scholar]
  127. Rademakers R, Neumann M, Mackenzie IR. 2012. Advances in understanding the molecular basis of frontotemporal dementia. Nat. Rev. Neurol. 8:423–34 [Google Scholar]
  128. Raj A, LoCastro E, Kuceyeski A, Tosun D, Relkin N. et al. 2015. Network diffusion model of progression predicts longitudinal patterns of atrophy and metabolism in Alzheimer's disease. Cell Rep. 10:359–69 [Google Scholar]
  129. Rangel LP, Costa DCF, Vieira TCRG, Silva JL. 2014. The aggregation of mutant p53 produces prion-like properties in cancer. Prion 8:75–84 [Google Scholar]
  130. Raveendra BL, Siemer AB, Puthanveettil SV, Hendrickson WA, Kandel ER, McDermott AE. 2013. Characterization of prion-like conformational changes of the neuronal isoform of Aplysia CPEB. Nat. Struct. Mol. Biol. 20:495–501 [Google Scholar]
  131. Ravits JM, La Spada AR. 2009. ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology 73:805–11 [Google Scholar]
  132. Recasens A, Dehay B, Bové J, Carballo-Carbajal I, Dovero S. et al. 2014. Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys. Ann. Neurol. 75:351–62 [Google Scholar]
  133. Ren PH, Lauckner JE, Kachirskaia I, Heuser JE, Melki R, Kopito RR. 2009. Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat. Cell Biol. 11:219–25 [Google Scholar]
  134. Rosen RF, Ciliax BJ, Wingo TS, Gearing M, Dooyema J. et al. 2010. Deficient high-affinity binding of Pittsburgh compound B in a case of Alzheimer's disease. Acta Neuropathol. 119:221–33 [Google Scholar]
  135. Rosen RF, Fritz JJ, Dooyema J, Cintron AF, Hamaguchi T. et al. 2012. Exogenous seeding of cerebral β-amyloid deposition in βAPP-transgenic rats. J. Neurochem. 120:660–66 [Google Scholar]
  136. Rosen RF, Walker LC, LeVine H III. 2011. PIB binding in aged primate brain: enrichment of high-affinity sites in humans with Alzheimer's disease. Neurobiol. Aging 32:223–34 [Google Scholar]
  137. 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]
  138. Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H. et al. 2014. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82:1271–88 [Google Scholar]
  139. Saper CB, Wainer BH, German DC. 1987. Axonal and transneuronal transport in the transmission of neurological disease: potential role in system degenerations, including Alzheimer's disease. Neuroscience 23:389–98 [Google Scholar]
  140. Saunders SE, Bartelt-Hunt SL, Bartz JC. 2012. Occurrence, transmission, and zoonotic potential of chronic wasting disease. Emerg. Infect. Dis. 18:369–76 [Google Scholar]
  141. Selkoe DJ. 2012. Preventing Alzheimer's disease. Science 337:1488–92 [Google Scholar]
  142. Si K, Lindquist S, Kandel ER. 2003. A neuronal isoform of the Aplysia CPEB has prion-like properties. Cell 115:879–91 [Google Scholar]
  143. Silveira JR, Raymond GJ, Hughson AG, Race RE, Sim VL. et al. 2005. The most infectious prion protein particles. Nature 437:257–61 [Google Scholar]
  144. Sipe JD, Benson MD, Buxbaum JN, Ikeda S, Merlini G. et al. 2014. Nomenclature 2014: amyloid fibril proteins and clinical classification of the amyloidosis. Amyloid 21:221–24 [Google Scholar]
  145. Song HL, Shim S, Kim DH, Won SH, Joo S. et al. 2014. β-Amyloid is transmitted via neuronal connections along axonal membranes. Ann. Neurol. 75:88–97 [Google Scholar]
  146. Spillantini MG, Goedert M. 2013. Tau pathology and neurodegeneration. Lancet Neurol. 12:609–22 [Google Scholar]
  147. Stedman TL. 2012. Stedman's Medical Dictionary for the Health Professions and Nursing Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins [Google Scholar]
  148. Stöhr J, Condello C, Watts JC, Bloch L, Oehler A. et al. 2014. Distinct synthetic Aβ prion strains producing different amyloid deposits in bigenic mice. PNAS 111:10329–34 [Google Scholar]
  149. Stöhr J, Watts JC, Mensinger ZL, Oehler A, Grillo SK. et al. 2012. Purified and synthetic Alzheimer's amyloid beta (Aβ) prions. PNAS 109:11025–30 [Google Scholar]
  150. Sugiyama S, Tanaka M. 2014. Self-propagating amyloid as a critical regulator for diverse cellular functions. J. Biochem. 155:345–51 [Google Scholar]
  151. Tanaka M, Collins SR, Toyama BH, Weissman JS. 2006. The physical basis of how prion conformations determine strain phenotypes. Nature 442:585–89 [Google Scholar]
  152. Tuite MF. 2013. The natural history of yeast prions. Adv. Appl. Microbiol. 84:85–137 [Google Scholar]
  153. Udan M, Baloh RH. 2011. Implications of the prion-related Q/N domains in TDP-43 and FUS. Prion 5:1–5 [Google Scholar]
  154. Van Langenhove T, van der Zee J, Van Broeckhoven C. 2012. The molecular basis of the frontotemporal lobar degeneration–amyotrophic lateral sclerosis spectrum. Ann. Med. 44:817–28 [Google Scholar]
  155. Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM. et al. 2011. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72:57–71 [Google Scholar]
  156. Walker LC, Callahan MJ, Bian F, Durham RA, Roher AE, Lipinski WJ. 2002. Exogenous induction of cerebral β-amyloidosis in βAPP-transgenic mice. Peptides 23:1241–47 [Google Scholar]
  157. Walker LC, LeVine H III. 2012. Corruption and spread of pathogenic proteins in neurodegenerative diseases. J. Biol. Chem. 287:33109–15 [Google Scholar]
  158. Wang F, Wang X, Yuan CG, Ma J. 2010. Generating a prion with bacterially expressed recombinant prion protein. Science 327:1132–35 [Google Scholar]
  159. Watts JC, Condello C, Stöhr J, Oehler A, Lee J. et al. 2014. Serial propagation of distinct strains of Aβ prions from Alzheimer's disease patients. PNAS 111:10323–28 [Google Scholar]
  160. Watts JC, Giles K, Grillo SK, Lemus A, DeArmond SJ, Prusiner SB. 2011. Bioluminescence imaging of Aβ deposition in bigenic mouse models of Alzheimer's disease. PNAS 108:2528–33 [Google Scholar]
  161. Watts JC, Giles K, Oehler A, Middleton L, Dexter DT. et al. 2013. Transmission of multiple system atrophy prions to transgenic mice. PNAS 110:19555–60 [Google Scholar]
  162. Westermark GT, Westermark P. 2010. Prion-like aggregates: infectious agents in human disease. Trends Mol. Med. 16:501–7 [Google Scholar]
  163. Wickner RB, Edskes HK, Bateman DA, Kelly AC, Gorkovskiy A. et al. 2013. Amyloids and yeast prion biology. Biochemistry 52:1514–27 [Google Scholar]
  164. Williams ES. 2005. Chronic wasting disease. Vet. Pathol. 42:530–49 [Google Scholar]
  165. Wu JW, Herman M, Liu L, Simoes S, Acker CM. et al. 2013. Small misfolded Tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J. Biol. Chem. 288:1856–70 [Google Scholar]
  166. Xing Y, Nakamura A, Chiba T, Kogishi K, Matsushita T. et al. 2001. Transmission of mouse senile amyloidosis. Lab. Investig. 81:493–99 [Google Scholar]
  167. Xu J, Reumers J, Couceiro JR, De Smet F, Gallardo R. et al. 2011. Gain of function of mutant p53 by coaggregation with multiple tumor suppressors. Nat. Chem. Biol. 7:285–95 [Google Scholar]
  168. Ye L, Hamaguchi T, Fritschi SK, Eisele YS, Obermüller U. et al. 2015. Progression of seed-induced Aβ deposition within the limbic connectome. Brain Pathol. In press. doi: 10.1111/bpa.12252 [Google Scholar]
  169. Zhang Y, Wang F, Wang X, Zhang Z, Xu Y. et al. 2014. Comparison of 2 synthetically generated recombinant prions. Prion 8:215–20 [Google Scholar]
  170. Zhou J, Gennatas ED, Kramer JH, Miller BL, Seeley WW. 2012. Predicting regional neurodegeneration from the healthy brain functional connectome. Neuron 73:1216–27 [Google Scholar]

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