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Strains of Pathological Protein Aggregates in Neurodegenerative Diseases

DISCOVERIES (ISSN 2359-7232), 2017, July-September issue

CITATION: 

Wang X, Noroozian Z, Lynch M, Armstrong N, Schneider R, Liu M et al. Strains of Pathological Protein Aggregates in Neurodegenerative Diseases. Discoveries 2017, Jul-Sep; 5(3): e78. DOI: 10.15190/d.2017.8

Submitted: Sept. 3rd, 2017; Revised: Sept. 27th, 2017; Accepted: Sept. 29th, 2017; Published: Sept. 30, 2017;

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Strains of Pathological Protein Aggregates in Neurodegenerative Diseases

Xinzhu Wang (1,2), Zeinab Noroozian (1,3), Madelaine Lynch (1,3), Nicholas Armstrong (1), Raphael Schneider (1,2,4), Mingzhe Liu (1,3), Farinaz Ghodrati (1,2), Ashley B. Zhang (1,2), Yoo Jeong Yang (5), Amanda C. Hall (1), Michael Solarski (1,2), Samuel A. Killackey (1), Joel C. Watts (2,6,*) 

(1) Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

(2) Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada

(3) Sunnybrook Research Institute - Biological Sciences, Toronto, ON, Canada

(4) Department of Medicine, Division of Neurology, University of Toronto, Toronto, ON, Canada

(5) Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

(6) Department of Biochemistry, University of Toronto, Toronto, ON, Canada


*Corresponding author: Joel C. Watts, PhD, Tanz Centre for Research in Neurodegenerative Diseases and Department of Biochemistry, University of Toronto, Krembil Discovery Tower, Rm. 4KD481, 60 Leonard Ave., Toronto, ON, Canada, M5T 2S8;  

Abstract

The presence of protein aggregates in the brain is a hallmark of neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Considerable evidence has revealed that the pathological protein aggregates in many neurodegenerative diseases are able to self-propagate, which may enable pathology to spread from cell-to-cell within the brain. This property is reminiscent of what occurs in prion diseases such as Creutzfeldt-Jakob disease. A widely recognized feature of prion disorders is the existence of distinct strains of prions, which are thought to represent unique protein aggregate structures. A number of recent studies have pointed to the existence of strains of protein aggregates in other, more common neurodegenerative illnesses such as AD, PD, and related disorders. In this review, we outline the pathobiology of prion strains and discuss how the concept of protein aggregate strains may help to explain the heterogeneity inherent to many human neurodegenerative disorders.

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References

1. Watts JC, Balachandran A, Westaway D. The expanding universe of prion diseases. PLoS Pathog 2006, 2: e26.

2. Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science 1982, 216: 136-144.

3. Colby DW, Prusiner SB. Prions. Cold Spring Harb Perspect Biol 2011, 3: a006833.

4. Aguzzi A, Polymenidou M. Mammalian prion biology: one century of evolving concepts. Cell 2004, 116(2): 313-327.

5. Westergard L, Christensen HM, Harris DA. The cellular prion protein (PrP(C)): Its physiological function and role in disease. Biochim Biophys Acta 2007, 1772: 629-644.

6. 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: 310–318.

7. Kuffer A, Lakkaraju AK, Mogha A, Petersen SC, Airich K, Doucerain C, et al. The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6. Nature 2016, 536(7617): 464-468.

8. Büeler H, Aguzzi A, Sailer A, Greiner R-A, Autenried P, Aguet M, et al. Mice devoid of PrP are resistant to scrapie. Cell 1993, 73: 1339-1347.

9. Silveira JR, Raymond GJ, Hughson AG, Race RE, Sim VL, Hayes SF, et al. The most infectious prion protein particles. Nature 2005, 437: 257-261.

10. 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(8): e125.

11. Pattison IH, Millson GC. Scrapie produced experimentally in goats with special reference to the clinical syndrome. J Comp Pathol 1961, 71: 101–108.

12. Dickinson AG, Meikle VM, Fraser H. Genetical control of the concentration of ME7 scrapie agent in the brain of mice. J Comp Pathol 1969, 79: 15-22.

13. Dickinson AG, Meikle VMH. Host-genotype and agent effects in scrapie incubation: change in allelic interaction with different strains of agent. Mol Gen Genet 1971, 112: 73-79.

14. Westaway D, Goodman PA, Mirenda CA, McKinley MP, Carlson GA, Prusiner SB. Distinct prion proteins in short and long scrapie incubation period mice. Cell 1987, 51: 651-662.

15. Moore RC, Hope J, McBride PA, McConnell I, Selfridge J, Melton DW, et al. Mice with gene targetted prion protein alterations show that Prnp, Sinc and Prni are congruent. Nat Genet 1998, 18: 118-125.

16. Fraser H, Dickinson AG. Scrapie in mice.  Agent-strain differences in the distribution and intensity of grey matter vacuolation. J Comp Pathol 1973, 83: 29-40.

17. Bruce ME, Dickinson AG. Biological evidence that the scrapie agent has an independent genome. J Gen Virol 1987, 68: 79-89.

18. Aiken JM, Marsh RF. The search for scrapie agent nucleic acid. Microbiol Rev 1990, 54: 242-246.

19. Aguzzi A. Understanding the diversity of prions. Nat Cell Biol 2004, 6(4): 290-292.

20. Kascsak RJ, Rubenstein R, Merz PA, Carp RI, Wisniewski HM, Diringer H. Biochemical differences among scrapie-associated fibrils support the biological diversity of scrapie agents. J Gen Virol 1985, 66: 1715-1722.

21. Bessen RA, Marsh RF. Biochemical and physical properties of the prion protein from two strains of the transmissible mink encephalopathy agent. J Virol 1992, 66: 2096-2101.

22. Telling GC, Parchi P, DeArmond SJ, Cortelli P, Montagna P, Gabizon R, et al. Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 1996, 274: 2079-2082.

23. Safar J, Wille H, Itri V, Groth D, Serban H, Torchia M, et al. Eight prion strains have PrPSc molecules with different conformations. Nat Med 1998, 4: 1157-1165.

24. Bessen RA, Marsh RF. Identification of two biologically distinct strains of transmissible mink encephalopathy in hamsters. J Gen Virol 1992, 73: 329-334.

25. Hwang D, Lee IY, Yoo H, Gehlenborg N, Cho JH, Petritis B, et al. A systems approach to prion disease. Mol Syst Biol 2009, 5: 252.

26. Carlson GA, Ebeling C, Yang S-L, Telling G, Torchia M, Groth D, et al. Prion isolate specified allotypic interactions between the cellular and scrapie prion proteins in congenic and transgenic mice. Proc Natl Acad Sci USA 1994, 91: 5690-5694.

27. Bruce M, Chree A, McConnell 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: 405-411.

28. Fraser H. Diversity in the neuropathology of scrapie-like diseases in animals. British medical bulletin 1993, 49(4): 792-809.

29. Bruce ME, McBride PA, Farquhar CF. Precise targeting of the pathology of the sialoglycoprotein, PrP, and vacuolar degeneration in mouse scrapie. Neurosci Lett 1989, 102: 1-6.

30. Bett C, Joshi-Barr S, Lucero M, Trejo M, Liberski P, Kelly JW, et al. Biochemical properties of highly neuroinvasive prion strains. PLoS Pathog 2012, 8(2): e1002522.

31. Sigurdson CJ, Nilsson KP, Hornemann S, Manco G, Polymenidou M, Schwarz P, et al. Prion strain discrimination using luminescent conjugated polymers. Nat Methods 2007, 4: 1023–1030.

32. Gambetti P, Kong Q, Zou W, Parchi P, Chen SG. Sporadic and familial CJD: classification and characterisation. Br Med Bull 2003, 66: 213-239.

33. Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF. Molecular analysis of prion strain variation and the aetiology of "new variant" CJD. Nature 1996, 383: 685-690.

34. Khalili-Shirazi A, Summers L, Linehan J, Mallinson G, Anstee D, Hawke S, et al. PrP glycoforms are associated in a strain-specific ratio in native PrPSc. J Gen Virol 2005, 86(Pt 9): 2635-2644.

35. Wadsworth JDF, Hill AF, Joiner S, Jackson GS, Clarke AR, Collinge J. Strain-specific prion-protein conformation determined by metal ions. Nat Cell Biol 1999, 1: 55-59.

36. Hill AF, Desbruslais M, Joiner S, Sidle KCL, Gowland I, Collinge J, et al. The same prion strain causes vCJD and BSE. Nature 1997, 389: 448-450.

37. Morales R, Hu PP, Duran-Aniotz C, Moda F, Diaz-Espinoza R, Chen B, et al. Strain-dependent profile of misfolded prion protein aggregates. Sci Rep 2016, 6: 20526.

38. Tixador P, Herzog L, Reine F, Jaumain E, Chapuis J, Le Dur A, et al. The physical relationship between infectivity and prion protein aggregates is strain-dependent. PLoS Pathog 2010, 6: e1000859.

39. Peretz D, Scott M, Groth D, Williamson A, Burton D, Cohen FE, et al. Strain-specified relative conformational stability of the scrapie prion protein. Protein Sci 2001, 10: 854-863.

40. Legname G, Nguyen H-OB, Peretz D, Cohen FE, DeArmond SJ, Prusiner SB. Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes. Proc Natl Acad Sci USA 2006, 103: 19105-19110.

41. Ayers JI, Schutt CR, Shikiya RA, Aguzzi A, Kincaid AE, Bartz JC. The strain-encoded relationship between PrP replication, stability and processing in neurons is predictive of the incubation period of disease. PLoS Pathog 2011, 7: e1001317.

42. Somerville RA, Gentles N. Characterization of the effect of heat on agent strains of the transmissible spongiform encephalopathies. J Gen Virol 2011, 92(Pt 7): 1738-1748.

43. Wilham JM, Orru CD, Bessen RA, Atarashi R, Sano K, Race B, et al. Rapid end-point quantitation of prion seeding activity with sensitivity comparable to bioassays. PLoS Pathog 2010, 6: e1001217.

44. Orru CD, Favole A, Corona C, Mazza M, Manca M, Groveman BR, et al. Detection and discrimination of classical and atypical L-type bovine spongiform encephalopathy by real-time quaking-induced conversion. Journal of clinical microbiology 2015, 53(4): 1115-1120.

45. Orru CD, Groveman BR, Raymond LD, Hughson AG, Nonno R, Zou W, et al. Bank Vole Prion Protein As an Apparently Universal Substrate for RT-QuIC-Based Detection and Discrimination of Prion Strains. PLoS Pathog 2015, 11(6): e1004983.

46. Masujin K, Orru CD, Miyazawa K, Groveman BR, Raymond LD, Hughson AG, et al. Detection of Atypical H-Type Bovine Spongiform Encephalopathy and Discrimination of Bovine Prion Strains by Real-Time Quaking-Induced Conversion. Journal of clinical microbiology 2016, 54(3): 676-686.

47. Mahal SP, Baker CA, Demczyk CA, Smith EW, Julius C, Weissmann C. Prion strain discrimination in cell culture: the cell panel assay. Proc Natl Acad Sci USA 2007, 104: 20908–20913.

48. Zou WQ, Puoti G, Xiao X, Yuan J, Qing L, Cali I, et al. Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein. Ann Neurol 2010, 68: 162–172.

49. Brown P, Preece M, Brandel JP, Sato T, McShane L, Zerr I, et al. Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology 2000, 55: 1075-1081.

50. Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996, 347: 921-925.

51. Will RG. Acquired prion disease: iatrogenic CJD, variant CJD, kuru. Br Med Bull 2003, 66: 255-265.

52. Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, et al. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999, 46: 224-233.

53. Kropp S, Schulz-Schaeffer WJ, Finkenstaedt M, Riedemann C, Windl O, Steinhoff BJ, et al. The Heidenhain variant of Creutzfeldt-Jakob disease. Arch Neurol 1999, 56(1): 55-61.

54. Brownell B, Oppenheimer DR. An ataxic form of subacute presenile polioencephalopathy (Creutzfeldt-Jakob disease). J Neurol Neurosurg Psychiatry 1965, 28: 350-361.

55. Kong Q, Surewicz WK, Petersen RB, Zou W, Chen SG, Gambetti P, et al. Inherited prion diseases. In: Prusiner SB (ed). Prion Biology and Diseases, 2nd edn. Cold Spring Harbor Laboratory Press: Cold Spring Harbor, 2004, pp 673-775.

56. Mead S, Gandhi S, Beck J, Caine D, Gajulapalli D, Carswell C, et al. A novel prion disease associated with diarrhea and autonomic neuropathy. N Engl J Med 2013, 369(20): 1904-1914.

57. Owen F, Poulter M, Collinge J, Crow TJ. Codon 129 changes in the prion protein gene in Caucasians. Am J Hum Genet 1990, 46: 1215-1216.

58. Hill AF, Joiner S, Wadsworth JD, Sidle KC, Bell JE, Budka H, et al. Molecular classification of sporadic Creutzfeldt-Jakob disease. Brain 2003, 126: 1333-1346.

59. Cali I, Castellani R, Yuan J, Al-Shekhlee A, Cohen ML, Xiao X, et al. Classification of sporadic Creutzfeldt-Jakob disease revisited. Brain 2006, 129(Pt 9): 2266-2277.

60. Polymenidou M, Stoeck K, Glatzel M, Vey M, Bellon A, Aguzzi A. Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease. Lancet Neurol 2005, 4: 805-814.

61. Cali I, Castellani R, Alshekhlee A, Cohen Y, Blevins J, Yuan J, et al. Co-existence of scrapie prion protein types 1 and 2 in sporadic Creutzfeldt-Jakob disease: its effect on the phenotype and prion-type characteristics. Brain 2009, 132: 2643–2658.

62. Haldiman T, Kim C, Cohen Y, Chen W, Blevins J, Qing L, et al. Co-existence of distinct prion types enables conformational evolution of human PrPSc by competitive selection. J Biol Chem 2013, 288(41): 29846-29861.

63. Meissner B, Westner IM, Kallenberg K, Krasnianski A, Bartl M, Varges D, et al. Sporadic Creutzfeldt-Jakob disease: clinical and diagnostic characteristics of the rare VV1 type. Neurology 2005, 65(10): 1544-1550.

64. Moda F, Suardi S, Di Fede G, Indaco A, Limido L, Vimercati C, et al. MM2-thalamic Creutzfeldt-Jakob disease: neuropathological, biochemical and transmission studies identify a distinctive prion strain. Brain Pathol 2012, 22(5): 662-669.

65. Asante EA, Linehan JM, Desbruslais M, Joiner S, Gowland I, Wood AL, et al. BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein. EMBO J 2002, 21: 6358-6366.

66. Wadsworth JD, Asante EA, Desbruslais M, Linehan JM, Joiner S, Gowland I, et al. Human prion protein with valine 129 prevents expression of variant CJD phenotype. Science 2004, 306: 1793-1796.

67. Watts JC, Giles K, Serban A, Patel S, Oehler A, Bhardwaj S, et al. Modulation of Creutzfeldt-Jakob disease prion propagation by the A224V mutation. Ann Neurol 2015, 78(4): 540-553.

68. Nonno R, Di Bari MA, Cardone F, Vaccari G, Fazzi P, Dell'Omo G, et al. Efficient transmission and characterization of Creutzfeldt-Jakob disease strains in bank voles. PLoS Pathog 2006, 2: e12.

69. Bishop MT, Will RG, Manson JC. Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties. Proc Natl Acad Sci USA 2010, 107: 12005–12010.

70. Kobayashi A, Iwasaki Y, Otsuka H, Yamada M, Yoshida M, Matsuura Y, et al. Deciphering the pathogenesis of sporadic Creutzfeldt-Jakob disease with codon 129 M/V and type 2 abnormal prion protein. Acta neuropathologica communications 2013, 1: 74.

71. Govaerts C, Wille H, Prusiner SB, Cohen FE. Evidence for assembly of prions with left-handed β-helices into trimers. Proc Natl Acad Sci USA 2004, 101: 8342–8347.

72. DeMarco ML, Daggett V. From conversion to aggregation: protofibril formation of the prion protein. Proc Natl Acad Sci USA 2004, 101: 2293-2298.

73. 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 USA 2007, 104: 18946–18951.

74. Smirnovas V, Baron GS, Offerdahl DK, Raymond GJ, Caughey B, Surewicz WK. Structural organization of brain-derived mammalian prions examined by hydrogen-deuterium exchange. Nat Struct Mol Biol 2011, 18: 504–506.

75. Groveman BR, Dolan MA, Taubner LM, Kraus A, Wickner RB, Caughey B. Parallel in-register intermolecular beta-sheet architectures for prion-seeded prion protein (PrP) amyloids. J Biol Chem 2014, 289(35): 24129-24142.

76. Legname G, Baskakov IV, Nguyen H-OB, Riesner D, Cohen FE, DeArmond SJ, et al. Synthetic mammalian prions. Science 2004, 305: 673-676.

77. Colby DW, Giles K, Legname G, Wille H, Baskakov IV, DeArmond SJ, et al. Design and construction of diverse mammalian prion strains. Proc Natl Acad Sci USA 2009, 106: 20417–20422.

78. Colby DW, Wain R, Baskakov IV, Legname G, Palmer CG, Nguyen H-OB, et al. Protease-sensitive synthetic prions. PLoS Pathog 2010, 6: e1000736.

79. Makarava N, Kovacs GG, Bocharova O, Savtchenko R, Alexeeva I, Budka H, et al. Recombinant prion protein induces a new transmissible prion disease in wild-type animals. Acta Neuropathol 2010, 119: 177–187.

80. Kim JI, Cali I, Surewicz K, Kong Q, Raymond GJ, Atarashi R, et al. Mammalian prions generated from bacterially expressed prion protein in the absence of any mammalian cofactors. J Biol Chem 2010, 285: 14083–14087.

81. Wang F, Wang X, Yuan C-G, Ma J. Generating a prion with bacterially expressed recombinant prion protein. Science 2010, 327: 1132–1135.

82. Moda F, TN TL, Aulic S, Bistaffa E, Campagnani I, Virgilio T, et al. Synthetic prions with novel strain-specified properties. PLoS Pathog 2015, 11(12): e1005354.

83. Deleault NR, Harris BT, Rees JR, Supattapone S. Formation of native prions from minimal components in vitro. Proc Natl Acad Sci USA 2007, 104: 9741-9746.

84. Deleault NR, Piro JR, Walsh DJ, Wang F, Ma J, Geoghegan JC, et al. Isolation of phosphatidylethanolamine as a solitary cofactor for prion formation in the absence of nucleic acids. Proc Natl Acad Sci USA 2012, 109: 8546–8551.

85. Deleault NR, Walsh DJ, Piro JR, Wang F, Wang X, Ma J, et al. Cofactor molecules maintain infectious conformation and restrict strain properties in purified prions. Proc Natl Acad Sci U S A 2012, 109(28): E1938-1946.

86. Colby DW, Prusiner SB. De novo generation of prions. Nat Rev Microbiol 2011, 9: 771–777.

87. 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 USA 2009, 106: 16990–16995.

88. Baldwin MA, Pan K-M, Nguyen J, Huang Z, Groth D, Serban A, et al. Spectroscopic characterization of conformational differences between PrPC and PrPSc: an a-helix to b-sheet transition. Philos Trans R Soc Lond B Biol Sci 1994, 343: 435-441.

89. Caughey B, Raymond GJ, Bessen RA. Strain-dependent differences in b-sheet conformations of abnormal prion protein. J Biol Chem 1998, 273(48): 32230-32235.

90. Sim VL, Caughey B. Ultrastructures and strain comparison of under-glycosylated scrapie prion fibrils. Neurobiol Aging 2009, 30: 2031–2042.

91. Safar JG, Xiao X, Kabir ME, Chen S, Kim C, Haldiman T, et al. Structural determinants of phenotypic diversity and replication rate of human prions. PLoS Pathog 2015, 11(4): e1004832.

92. 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(6): e1005017.

93. Vazquez-Fernandez E, Vos MR, Afanasyev P, Cebey L, Sevillano AM, Vidal E, et al. The Structural Architecture of an Infectious Mammalian Prion Using Electron Cryomicroscopy. PLoS Pathog 2016, 12(9): e1005835.

94. Wickner RB. [URE3] as an altered URE2 protein: evidence for a prion analog in Saccharomyces cerevisiae. Science 1994, 264: 566–569.

95. Patino MM, Liu J-J, Glover JR, Lindquist S. Support for the prion hypothesis for inheritance of a phenotypic trait in yeast. Science 1996, 273: 622-626.

96. Schlumpberger M, Prusiner SB, Herskowitz I. Induction of distinct [URE3] yeast prion strains. Mol Cell Biol 2001, 21: 7035-7046.

97. Chien P, Weissman JS. Conformational diversity in a yeast prion dictates its seeding specificity. Nature 2001, 410: 223-227.

98. Stansfield I, Jones KM, Kushnirov VV, Dagkesamanskaya AR, Poznyakovski AI, Paushkin SV, et al. The products of the SUP45 (eRF1) and SUP35 genes interact to mediate translation termination in Saccharomyces cerevisiae. EMBO J 1995, 14: 4365-4373.

99. Glover JR, Kowal AS, Schirmer EC, Patino MM, Liu J-J, Lindquist S. Self-seeded fibers formed by Sup35, the protein determinant of [PSI+], a heritable prion-like factor of S. cerevisiae. Cell 1997, 89: 811-819.

100. King CY, Diaz-Avalos R. Protein-only transmission of three yeast prion strains. Nature 2004, 428: 319-323.

101. Nakayashiki T, Kurtzman CP, Edskes HK, Wickner RB. Yeast prions [URE3] and [PSI+] are diseases. Proc Natl Acad Sci USA 2005, 102: 10575-10580.

102. Halfmann R, Jarosz DF, Jones SK, Chang A, Lancaster AK, Lindquist S. Prions are a common mechanism for phenotypic inheritance in wild yeasts. Nature 2012, 482: 363–368.

103. True HL, Lindquist SL. A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 2000, 407: 477-483.

104. McGlinchey RP, Kryndushkin D, Wickner RB. Suicidal [PSI+] is a lethal yeast prion. Proc Natl Acad Sci U S A 2011, 108(13): 5337-5341.

105. Tanaka M, Chien P, Naber N, Cooke R, Weissman JS. Conformational variations in an infectious protein determine prion strain differences. Nature 2004, 428: 323-328.

106. Krishnan R, Lindquist SL. Structural insights into a yeast prion illuminate nucleation and strain diversity. Nature 2005, 435: 765-772.

107. Toyama BH, Kelly MJ, Gross JD, Weissman JS. The structural basis of yeast prion strain variants. Nature 2007, 449: 233-237.

108. Prusiner SB, Scott M, Foster D, Pan K-M, Groth D, Mirenda C, et al. Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell 1990, 63: 673-686.

109. Morales R, Abid K, Soto C. The prion strain phenomenon: molecular basis and unprecedented features. Biochim Biophys Acta 2007, 1772(6): 681-691.

110. Collinge J, Clarke AR. A general model of prion strains and their pathogenicity. Science 2007, 318: 930-936.

111. Agrimi U, Nonno R, Dell'Omo G, Di Bari MA, Conte M, Chiappini B, et al. Prion protein amino acid determinants of differential susceptibility and molecular feature of prion strains in mice and voles. PLoS Pathog 2008, 4: e1000113.

112. Di Bari MA, Nonno R, Castilla J, D'Agostino C, Pirisinu L, Riccardi G, et al. Chronic wasting disease in bank voles: characterisation of the shortest incubation time model for prion diseases. PLoS Pathog 2013, 9: e1003219.

113. Watts JC, Giles K, Patel S, Oehler A, Dearmond SJ, Prusiner SB. Evidence that bank vole PrP is a universal acceptor for prions. PLoS Pathog 2014, 10(4): e1003990.

114. Telling GC, Scott M, Hsiao KK, Foster D, Yang S-L, Torchia M, et al. Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric human-mouse prion protein. Proc Natl Acad Sci USA 1994, 91: 9936-9940.

115. Telling GC, Scott M, Mastrianni J, Gabizon R, Torchia M, Cohen FE, et al. Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell 1995, 83: 79-90.

116. Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, et al. Transmissions to mice indicate that 'new variant' CJD is caused by the BSE agent. Nature 1997, 389: 498-501.

117. Kimberlin RH, Cole S, Walker CA. Temporary and permanent modifications to a single strain of mouse scrapie on transmission to rats and hamsters. J Gen Virol 1987, 68: 1875-1881.

118. Giles K, Glidden DV, Beckwith R, Seoanes R, Peretz D, DeArmond SJ, et al. Resistance of bovine spongiform encephalopathy (BSE) prions to inactivation. PLoS Pathog 2008, 4: e1000206.

119. Peretz D, Williamson RA, Legname G, Matsunaga Y, Vergara J, Burton D, et al. A change in the conformation of prions accompanies the emergence of a new prion strain. Neuron 2002, 34: 921-932.

120. Bian J, Khaychuk V, Angers RC, Fernandez-Borges N, Vidal E, Meyerett-Reid C, et al. Prion replication without host adaptation during interspecies transmissions. Proc Natl Acad Sci U S A 2017, 114(5): 1141-1146.

121. Collinge J. Medicine. Prion strain mutation and selection. Science 2010, 328(5982): 1111-1112.

122. Weissmann C, Li J, Mahal SP, Browning S. Prions on the move. EMBO Rep 2011, 12(11): 1109-1117.

123. Li J, Browning S, Mahal SP, Oelschlegel AM, Weissmann C. Darwinian evolution of prions in cell culture. Science 2010, 327: 869–872.

124. Imberdis T, Harris DA. Synthetic Prions Provide Clues for Understanding Prion Diseases. Am J Pathol 2016, 186(4): 761-764.

125. Oelschlegel AM, Weissmann C. Acquisition of drug resistance and dependence by prions. PLoS Pathog 2013, 9: e1003158.

126. Ghaemmaghami S, Watts JC, Nguyen H-O, Hayashi S, DeArmond SJ, Prusiner SB. Conformational transformation and selection of synthetic prion strains. J Mol Biol 2011, 413: 527–542.

127. Giles K, Glidden DV, Patel S, Korth C, Groth D, Lemus A, et al. Human prion strain selection in transgenic mice. Ann Neurol 2010, 68: 151–161.

128. Makarava N, Kovacs GG, Savtchenko R, Alexeeva I, Budka H, Rohwer RG, et al. Genesis of mammalian prions: from non-infectious amyloid fibrils to a transmissible prion disease. PLoS Pathog 2011, 7: e1002419.

129. Makarava N, Kovacs GG, Savtchenko R, Alexeeva I, Ostapchenko VG, Budka H, et al. A new mechanism for transmissible prion diseases. J Neurosci 2012, 32(21): 7345-7355.

130. Makarava N, Baskakov IV. The evolution of transmissible prions: the role of deformed templating. PLoS Pathog 2013, 9(12): e1003759.

131. Makarava N, Savtchenko R, Alexeeva I, Rohwer RG, Baskakov IV. New Molecular Insight into Mechanism of Evolution of Mammalian Synthetic Prions. Am J Pathol 2016, 186(4): 1006-1014.

132. Shorter J. Emergence and natural selection of drug-resistant prions. Molecular bioSystems 2010, 6(7): 1115-1130.

133. Korth C, May BCH, Cohen FE, Prusiner SB. Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci USA 2001, 98: 9836-9841.

134. Bian J, Kang HE, Telling GC. Quinacrine promotes replication and conformational mutation of chronic wasting disease prions. Proc Natl Acad Sci U S A 2014, 111(16): 6028-6033.

135. 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.

136. Berry DB, Lu D, Geva M, Watts JC, Bhardwaj S, Oehler A, et al. Drug resistance confounding prion therapeutics. Proc Natl Acad Sci U S A 2013, 110(44): E4160-4169.

137. Giles K, Berry DB, Condello C, Dugger BN, Li Z, Oehler A, et al. Optimization of Aryl Amides that Extend Survival in Prion-Infected Mice. J Pharmacol Exp Ther 2016, 358(3): 537-547.

138. Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 2013, 501: 45–51.

139. Guo JL, Lee VM. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat Med 2014, 20(2): 130-138.

140. Goedert M. NEURODEGENERATION. Alzheimer's and Parkinson's diseases: The prion concept in relation to assembled Abeta, tau, and alpha-synuclein. Science 2015, 349(6248): 1255555.

141. Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol (Berl) 1991, 82: 239-259.

142. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003, 24: 197–211.

143. 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: 504-506.

144. Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, et al. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med 2008, 14: 501-503.

145. de Calignon A, Polydoro M, Suarez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, et al. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 2012, 73: 685–697.

146. Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C, et al. Trans-synaptic spread of tau pathology in vivo. PLoS ONE 2012, 7: e31302.

147. 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: 1781-1784.

148. Stöhr J, Watts JC, Mensinger ZL, Oehler A, Grillo SK, DeArmond SJ, et al. Purified and synthetic Alzheimer's amyloid beta (Aβ) prions. Proc Natl Acad Sci USA 2012, 109: 11025–11030.

149. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 2009, 11: 909–913.

150. Luk KC, Kehm VM, Zhang B, O'Brien P, Trojanowski JQ, Lee VMY. Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J Exp Med 2012, 209: 975–986.

151. Luk KC, Kehm V, Carroll J, Zhang B, O'Brien P, Trojanowski JQ, et al. Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 2012, 338: 949–953.

152. Ayers JI, Fromholt S, Koch M, DeBosier A, McMahon B, Xu G, et al. Experimental transmissibility of mutant SOD1 motor neuron disease. Acta Neuropathol 2014, 128(6): 791-803.

153. Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 2009, 284: 12845–12852.

154. Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A, et al. Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 2011, 72: 57–71.

155. Hansen C, Angot E, Bergstrom AL, Steiner JA, Pieri L, Paul G, et al. alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest 2011, 121: 715–725.

156. Woerman AL, Stohr J, Aoyagi A, Rampersaud R, Krejciova Z, Watts JC, et al. Propagation of prions causing synucleinopathies in cultured cells. Proc Natl Acad Sci U S A 2015, 112(35): E4949-4958.

157. Grad LI, Guest WC, Yanai A, Pokrishevsky E, O'Neill MA, Gibbs E, et al. Intermolecular transmission of superoxide dismutase 1 misfolding in living cells. Proc Natl Acad Sci USA 2011, 108: 16398–16403.

158. Münch C, O'Brien J, Bertolotti A. Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proc Natl Acad Sci USA 2011, 108: 3548–3553.

159. Ren PH, Lauckner JE, Kachirskaia I, Heuser JE, Melki R, Kopito RR. Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat Cell Biol 2009, 11: 219–225.

160. Walsh DM, Selkoe DJ. A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration. Nat Rev Neurosci 2016, 17(4): 251-260.

161. Prusiner SB. A unifying role for prions in neurodegenerative diseases. Science 2012, 336: 1511–1513.

162. Hardy J, Revesz T. The spread of neurodegenerative disease. N Engl J Med 2012, 366: 2126–2128.

163. Aguzzi A, Rajendran L. The transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron 2009, 64: 783–790.

164. Walker LC, Jucker M. Neurodegenerative diseases: expanding the prion concept. Annu Rev Neurosci 2015, 38: 87-103.

165. Watts JC, Prusiner SB. beta-Amyloid Prions and the Pathobiology of Alzheimer's Disease. Cold Spring Harbor perspectives in medicine 2017.

166. Riek R, Eisenberg DS. The activities of amyloids from a structural perspective. Nature 2016, 539(7628): 227-235.

167. Eisenberg D, Jucker M. The amyloid state of proteins in human diseases. Cell 2012, 148: 1188–1203.

168. Tycko R. Amyloid polymorphism: structural basis and neurobiological relevance. Neuron 2015, 86(3): 632-645.

169. Greenwald J, Riek R. Biology of amyloid: structure, function, and regulation. Structure 2010, 18: 1244–1260.

170. Colletier JP, Laganowsky A, Landau M, Zhao M, Soriaga AB, Goldschmidt L, et al. Molecular basis for amyloid-β polymorphism. Proc Natl Acad Sci USA 2011, 108: 16938–16943.

171. Petkova AT, Leapman RD, Guo Z, Yau WM, Mattson MP, Tycko R. Self-propagating, molecular-level polymorphism in Alzheimer's beta-amyloid fibrils. Science 2005, 307: 262–265.

172. Meinhardt J, Sachse C, Hortschansky P, Grigorieff N, Fandrich M. Abeta(1-40) fibril polymorphism implies diverse interaction patterns in amyloid fibrils. J Mol Biol 2009, 386(3): 869-877.

173. Paravastu AK, Leapman RD, Yau WM, Tycko R. Molecular structural basis for polymorphism in Alzheimer's beta-amyloid fibrils. Proc Natl Acad Sci USA 2008, 105: 18349–18354.

174. Kodali R, Williams AD, Chemuru S, Wetzel R. Aβ(1–40) forms five distinct amyloid structures whose β-sheet contents and fibril stabilities are correlated. J Mol Biol 2010, 401: 503–517.

175. Stöhr J, Condello C, Watts JC, Bloch L, Oehler A, Nick M, et al. Distinct synthetic Abeta prion strains producing different amyloid deposits in bigenic mice. Proc Natl Acad Sci U S A 2014, 111(28): 10329-10334.

176. Heilbronner G, Eisele YS, Langer F, Kaeser SA, Novotny R, Nagarathinam A, et al. Seeded strain-like transmission of beta-amyloid morphotypes in APP transgenic mice. EMBO Rep 2013, 14(11): 1017-1022.

177. Watts JC, Condello C, Stöhr J, Oehler A, Lee J, DeArmond SJ, et al. Serial propagation of distinct strains of Abeta prions from Alzheimer's disease patients. Proc Natl Acad Sci U S A 2014, 111(28): 10323-10328.

178. Paravastu AK, Qahwash I, Leapman RD, Meredith SC, Tycko R. Seeded growth of beta-amyloid fibrils from Alzheimer's brain-derived fibrils produces a distinct fibril structure. Proc Natl Acad Sci USA 2009, 106: 7443–7448.

179. Lu JX, Qiang W, Yau WM, Schwieters CD, Meredith SC, Tycko R. Molecular structure of beta-amyloid fibrils in Alzheimer's disease brain tissue. Cell 2013, 154(6): 1257-1268.

180. Qiang W, Yau WM, Lu JX, Collinge J, Tycko R. Structural variation in amyloid-beta fibrils from Alzheimer's disease clinical subtypes. Nature 2017, 541(7636): 217-221.

181. Cohen ML, Kim C, Haldiman T, ElHag M, Mehndiratta P, Pichet T, et al. Rapidly progressive Alzheimer's disease features distinct structures of amyloid-beta. Brain 2015, 138(Pt 4): 1009-1022.

182. Liu J, Costantino I, Venugopalan N, Fischetti RF, Hyman BT, Frosch MP, et al. Amyloid structure exhibits polymorphism on multiple length scales in human brain tissue. Sci Rep 2016, 6: 33079.

183. Levine H, 3rd, Walker LC. Molecular polymorphism of Abeta in Alzheimer's disease. Neurobiol Aging 2010, 31(4): 542-548.

184. Cleveland DW, Hwo SY, Kirschner MW. Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J Mol Biol 1977, 116(2): 207-225.

185. Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 1989, 3: 519-526.

186. Goedert M. The ordered assembly of tau is the gain-of-toxic function that causes human tauopathies. Alzheimers Dement 2016, 12(10): 1040-1050.

187. Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci 2001, 24: 1121–1159.

188. Siddiqua A, Margittai M. Three- and four-repeat Tau coassemble into heterogeneous filaments: an implication for Alzheimer disease. J Biol Chem 2010, 285(48): 37920-37926.

189. Dinkel PD, Siddiqua A, Huynh H, Shah M, Margittai M. Variations in filament conformation dictate seeding barrier between three- and four-repeat tau. Biochemistry 2011, 50(20): 4330-4336.

190. Siddiqua A, Luo Y, Meyer V, Swanson MA, Yu X, Wei G, et al. Conformational basis for asymmetric seeding barrier in filaments of three- and four-repeat tau. J Am Chem Soc 2012, 134(24): 10271-10278.

191. Frost B, Ollesch J, Wille H, Diamond MI. Conformational diversity of wild-type Tau fibrils specified by templated conformation change. J Biol Chem 2009, 284: 3546–3551.

192. Meyer V, Dinkel PD, Luo Y, Yu X, Wei G, Zheng J, et al. Single mutations in tau modulate the populations of fibril conformers through seed selection. Angew Chem Int Ed Engl 2014, 53(6): 1590-1593.

193. Meyer V, Holden MR, Weismiller HA, Eaton GR, Eaton SS, Margittai M. Fracture and Growth Are Competing Forces Determining the Fate of Conformers in Tau Fibril Populations. J Biol Chem 2016, 291(23): 12271-12281.

194. Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A, et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 2014, 82(6): 1271-1288.

195. Kaufman SK, Sanders DW, Thomas TL, Ruchinskas AJ, Vaquer-Alicea J, Sharma AM, et al. Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo. Neuron 2016, 92(4): 796-812.

196. Falcon B, Cavallini A, Angers R, Glover S, Murray TK, Barnham L, et al. Conformation determines the seeding potencies of native and recombinant Tau aggregates. J Biol Chem 2015, 290(2): 1049-1065.

197. Morozova OA, March ZM, Robinson AS, Colby DW. Conformational features of tau fibrils from Alzheimer's disease brain are faithfully propagated by unmodified recombinant protein. Biochemistry 2013, 52(40): 6960-6967.

198. Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J, et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci USA 2013, 110: 9535–9540.

199. Woerman AL, Aoyagi A, Patel S, Kazmi SA, Lobach I, Grinberg LT, et al. Tau prions from Alzheimer's disease and chronic traumatic encephalopathy patients propagate in cultured cells. Proc Natl Acad Sci U S A 2016, 113(50): E8187-E8196.

200. Guo JL, Narasimhan S, Changolkar L, He Z, Stieber A, Zhang B, et al. Unique pathological tau conformers from Alzheimer's brains transmit tau pathology in nontransgenic mice. J Exp Med 2016, 213(12): 2635-2654.

201. Goedert M. Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2001, 2: 492–501.

202. Vekrellis K, Xilouri M, Emmanouilidou E, Rideout HJ, Stefanis L. Pathological roles of alpha-synuclein in neurological disorders. Lancet Neurol 2011, 10(11): 1015-1025.

203. Lashuel HA, Overk CR, Oueslati A, Masliah E. The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci 2013, 14(1): 38-48.

204. Spillantini MG, Goedert M. The alpha-synucleinopathies: Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Ann N Y Acad Sci 2000, 920: 16-27.

205. Bousset L, Pieri L, Ruiz-Arlandis G, Gath J, Jensen PH, Habenstein B, et al. Structural and functional characterization of two alpha-synuclein strains. Nature communications 2013, 4: 2575.

206. Peelaerts W, Bousset L, Van der Perren A, Moskalyuk A, Pulizzi R, Giugliano M, et al. alpha-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 2015, 522(7556): 340-344.

207. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM. Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron 2002, 34: 521–533.

208. Watts JC, Giles K, Oehler A, Middleton L, Dexter DT, Gentleman SM, et al. Transmission of multiple system atrophy prions to transgenic mice. Proc Natl Acad Sci U S A 2013, 110(48): 19555-19560.

209. Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB, et al. Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc Natl Acad Sci U S A 2015, 112(38): E5308-5317.

210. Stefanova N, Bucke P, Duerr S, Wenning GK. Multiple system atrophy: an update. Lancet Neurol 2009, 8(12): 1172-1178.

211. Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A, Zhang B, et al. Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell 2013, 154: 103–117.

212. Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 2007, 53: 337–351.

213. Uversky VN. A protein-chameleon: conformational plasticity of alpha-synuclein, a disordered protein involved in neurodegenerative disorders. Journal of biomolecular structure & dynamics 2003, 21(2): 211-234.

214. Rosen DR, Siddique T, Patterson D, Figiewicz DA, Sapp P, Hentati A, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993, 362: 59-62.

215. Prudencio M, Hart PJ, Borchelt DR, Andersen PM. Variation in aggregation propensities among ALS-associated variants of SOD1: correlation to human disease. Hum Mol Genet 2009, 18(17): 3217-3226.

216. Bergh J, Zetterstrom P, Andersen PM, Brannstrom T, Graffmo KS, Jonsson PA, et al. Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping. Proc Natl Acad Sci U S A 2015, 112(14): 4489-4494.

217. Bidhendi EE, Bergh J, Zetterstrom P, Andersen PM, Marklund SL, Brannstrom T. Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis-like disease. J Clin Invest 2016, 126(6): 2249-2253.

218. Ayers JI, Diamond J, Sari A, Fromholt S, Galaleldeen A, Ostrow LW, et al. Distinct conformers of transmissible misfolded SOD1 distinguish human SOD1-FALS from other forms of familial and sporadic ALS. Acta Neuropathol 2016, 132(6): 827-840.

219. Kerman A, Liu HN, Croul S, Bilbao J, Rogaeva E, Zinman L, et al. Amyotrophic lateral sclerosis is a non-amyloid disease in which extensive misfolding of SOD1 is unique to the familial form. Acta Neuropathol 2010, 119(3): 335-344.

220. Da Cruz S, Bui A, Saberi S, Lee SK, Stauffer J, McAlonis-Downes M, et al. Misfolded SOD1 is not a primary component of sporadic ALS. Acta Neuropathol 2017.

221. Orru CD, Bongianni M, Tonoli G, Ferrari S, Hughson AG, Groveman BR, et al. A test for Creutzfeldt-Jakob disease using nasal brushings. N Engl J Med 2014, 371(6): 519-529.

222. Concha-Marambio L, Pritzkow S, Moda F, Tagliavini F, Ironside JW, Schulz PE, et al. Detection of prions in blood from patients with variant Creutzfeldt-Jakob disease. Sci Transl Med 2016, 8(370): 370ra183.

223. Tsuji H, Arai T, Kametani F, Nonaka T, Yamashita M, Suzukake M, et al. Molecular analysis and biochemical classification of TDP-43 proteinopathy. Brain 2012, 135(Pt 11): 3380-3391.

224. Shimonaka S, Nonaka T, Suzuki G, Hisanaga S, Hasegawa M. Templated Aggregation of TAR DNA-binding Protein of 43 kDa (TDP-43) by Seeding with TDP-43 Peptide Fibrils. J Biol Chem 2016, 291(17): 8896-8907.

225. Nekooki-Machida Y, Kurosawa M, Nukina N, Ito K, Oda T, Tanaka M. Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity. Proc Natl Acad Sci U S A 2009, 106(24): 9679-9684.

226. Westermark GT, Fandrich M, Westermark P. AA amyloidosis: pathogenesis and targeted therapy. Annu Rev Pathol 2015, 10: 321-344.

227. Murakami T, Inoshima Y, Kobayashi Y, Matsui T, Inokuma H, Ishiguro N. Atypical AA amyloid deposits in bovine AA amyloidosis. Amyloid 2012, 19(1): 15-20.

228. Sivalingam V, Prasanna NL, Sharma N, Prasad A, Patel BK. Wild-type hen egg white lysozyme aggregation in vitro can form self-seeding amyloid conformational variants. Biophysical chemistry 2016, 219: 28-37.

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