Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative disorders affecting humans and other mammalian species. The central event in TSE pathogenesis is the conformational conversion of the cellular prion protein, , into the aggregate, β-sheet rich, amyloidogenic form, . Increasing evidence indicates that distinct conformers, forming distinct ordered aggregates, can encipher the phenotypic TSE variants related to prion strains. Prion strains are TSE isolates that, after inoculation into syngenic hosts, cause disease with distinct characteristics, such as incubation period, pattern of distribution, and regional severity of histopathological changes in the brain. In analogy with other amyloid forming proteins, toxicity is thought to derive from the existence of various intermediate structures prior to the amyloid fiber formation and/or their specific interaction with membranes. The latter appears particularly relevant for the pathogenesis of TSEs associated with GPI-anchored , which involves major cellular membrane distortions in neurons. In this review, we update the current knowledge on the molecular mechanisms underlying three fundamental aspects of the basic biology of prions such as the putative mechanism of prion protein conversion to the pathogenic form and its propagation, the molecular basis of prion strains, and the mechanism of induced neurotoxicity by aggregates. 1. Introduction Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are rapidly progressive neurodegenerative disorders that affect many species of mammals. In humans, they comprise Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), kuru, Gerstmann-Str？ussler-Scheinker disease (GSS), and the recently described variably protease-sensitive prionopathy (VPSPr), whereas natural TSEs in animals include scrapie of sheep and goats, bovine spongiform encephalopathy (BSE), and chronic wasting disease (CWD) in deer and elk. Prion diseases belong to the growing group of disorders that are attributed to misfolding and ordered aggregation of proteins, which include Alzheimer’s disease, Parkinson’s disease, systemic amyloidosis, and many others. In prion disease, in particular, the cellular prion protein, , after partial misfolding, converts into a partially protease-resistant disease-associated isoform, , which aggregates in the brain and forms deposits that are associated with the neurodegenerative changes. Distinguishing features of prion diseases among these disorders, however, are their wide
References
[1]
B. Caughey, G. J. Raymond, and R. A. Bessen, “Strain-dependent differences in β-sheet conformations of abnormal prion protein,” Journal of Biological Chemistry, vol. 273, no. 48, pp. 32230–32235, 1999.
[2]
B. W. Caughey, “Secondary structure analysis of the scrapie-associated protein PrP 27–30 in water by infrared spectroscopy,” Biochemistry, vol. 30, no. 31, pp. 7672–7680, 1991.
[3]
C. Govaerts, H. Wille, S. B. Prusiner, and F. E. Cohen, “Evidence for assembly of prions with left-handed β-helices into trimers,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 22, pp. 8342–8347, 2004.
[4]
M. P. McKinley, R. Meyer k., L. Kenaga et al., “Scrapie prion rod formation in vitro requires both detergent extraction and limited proteolysis,” Journal of Virology, vol. 65, no. 3, pp. 1340–1351, 1991.
[5]
J. T. Nguyen, H. Inouye, M. A. Baldwin et al., “X-ray diffraction of scrapie prion rods and PrP peptides,” Journal of Molecular Biology, vol. 252, no. 4, pp. 412–422, 1995.
[6]
D. Peretz, R. A. Williamson, Y. Matsunaga et al., “A conformational transition at the N terminus of the prion protein features in formation of the scrapie isoform,” Journal of Molecular Biology, vol. 273, no. 3, pp. 614–622, 1997.
[7]
H. Wille, W. Bian, M. McDonald et al., “Natural and synthetic prion structure from X-ray fiber diffraction,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 40, pp. 16990–16995, 2009.
[8]
R. A. Williamson, D. Peretz, C. Pinilla et al., “Mapping the prion protein using recombinant antibodies,” Journal of Virology, vol. 72, no. 11, pp. 9413–9418, 1998.
[9]
W. Zou, M. Colucci, P. Gambetti, and S. G. Chen, “Characterization of prion proteins,” Methods in Molecular Biology, vol. 217, pp. 305–314, 2003.
[10]
R. Riek, G. Wider, M. Billeter, S. Hornemann, R. Glockshuber, and K. Wüthrich, “Prion protein NMR structure and familial human spongiform encephalopathies,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 20, pp. 11667–11672, 1998.
[11]
K.-M. Pan, M. Baldwin, J. Nguyen et al., “Conversion of α-helices into β-sheets features in the formation of the scrapie prion proteins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 23, pp. 10962–10966, 1993.
[12]
M. L. DeMarco, J. Silveira, B. Caughey, and V. Daggett, “Structural properties of prion protein protofibrils and fibrils: an experimental assessment of atomic models,” Biochemistry, vol. 45, no. 51, pp. 15573–15582, 2006.
[13]
V. Smirnovas, G. S. Baron, D. K. Offerdahl, G. J. Raymond, B. Caughey, and W. K. Surewicz, “Structural organization of brain-derived mammalian prions examined by hydrogen-deuterium exchange,” Nature Structural and Molecular Biology, vol. 18, no. 4, pp. 504–506, 2011.
[14]
Z. Xie, K. I. O'Rourke, Z. Dong et al., “Chronic wasting disease of elk and deer and Creutzfeldt-Jakob disease: comparative analysis of the scrapie prion protein,” Journal of Biological Chemistry, vol. 281, no. 7, pp. 4199–4206, 2006.
[15]
S. Capellari, R. Strammiello, D. Saverioni, H. Kretzschmar, and P. Parchi, “Genetic Creutzfeldt-Jakob disease and fatal familial insomnia: insights into phenotypic variability and disease pathogenesis,” Acta Neuropathologica, vol. 121, no. 1, pp. 21–37, 2011.
[16]
M. W. van der Kamp and V. Daggett, “The consequences of pathogenic mutations to the human prion protein,” Protein Engineering, Design and Selection, vol. 22, no. 8, pp. 461–468, 2009.
[17]
Y. Zhang, W. Swietnicki, M. G. Zagorski, W. K. Surewicz, and F. D. S？nnichsen, “Solution structure of the E200K variant of human prion protein. Implications for the mechanism of pathogenesis in familial prion diseases,” Journal of Biological Chemistry, vol. 275, no. 43, pp. 33650–33654, 2000.
[18]
W. Swietnicki, R. B. Petersen, P. Gambetti, and W. K. Surewicz, “Familial mutations and the thermodynamic stability of the recombinant human prion protein,” Journal of Biological Chemistry, vol. 273, no. 47, pp. 31048–31052, 1998.
[19]
S. Liemann and R. Glockshuber, “Influence of amino acid substitutions related to inherited human prion diseases on the thermodynamic stability of the cellular prion protein,” Biochemistry, vol. 38, no. 11, pp. 3258–3267, 1999.
[20]
A. C. Apetri, K. Surewicz, and W. K. Surewicz, “The effect of disease-associated mutations on the folding pathway of human prion protein,” Journal of Biological Chemistry, vol. 279, no. 17, pp. 18008–18014, 2004.
[21]
I. Biljan, G. Ilc, G. Giachin et al., “Toward the molecular basis of inherited prion diseases: NMR structure of the human prion protein with v210i mutation,” Journal of Molecular Biology, vol. 412, no. 4, pp. 660–673, 2011.
[22]
G. Ilc, G. Giachin, M. Jaremko et al., “NMR structure of the human prion protein with the pathological Q212P mutation reveals unique structural features,” PLoS ONE, vol. 5, no. 7, Article ID e11715, 2010.
[23]
S. Lee, L. Antony, R. Hartmann et al., “Conformational diversity in prion protein variants influences intermolecular beta-sheet formation,” EMBO Journal, vol. 29, no. 1, pp. 251–262, 2010.
[24]
G. Rossetti, G. Giachin, G. Legname, and P. Carloni, “Structural facets of disease-linked human prion protein mutants: a molecular dynamic study,” Proteins, vol. 78, no. 16, pp. 3270–3280, 2010.
[25]
G. Rossetti, X. Cong, R. Caliandro, G. Legname, and P. Carloni, “Common structural traits across pathogenic mutants of the human prion protein and their implications for familial prion diseases,” Journal of Molecular Biology, vol. 411, no. 3, pp. 700–712, 2011.
[26]
K. K. Hsiao, M. Scott, D. Foster, D. F. Groth, S. J. DeArmond, and S. B. Prusiner, “Spontaneous neurodegeneration in transgenic mice with mutant prion protein,” Science, vol. 250, no. 4987, pp. 1587–1590, 1990.
[27]
K. E. Nazor, F. Kuhn, T. Seward et al., “Immunodetection of disease-associated mutant PrP, which accelerates disease in GSS transgenic mice,” EMBO Journal, vol. 24, no. 13, pp. 2472–2480, 2005.
[28]
J. C. Manson, E. Jamieson, H. Baybutt et al., “A single amino acid alteration (101L) introduced into murine PrP dramatically alters incubation time of transmissible spongiform encephalopathy,” EMBO Journal, vol. 18, no. 23, pp. 6855–6864, 1999.
[29]
E. A. Asante, I. Gowland, A. Grimshaw et al., “Absence of spontaneous disease and comparative prion susceptibility of transgenic mice expressing mutant human prion proteins,” Journal of General Virology, vol. 90, no. 3, pp. 546–558, 2009.
[30]
R. M. Barron, V. Thomson, E. Jamieson et al., “Changing a single amino acid in the N-terminus of murine PrP alters TSE incubation time across three species barriers,” EMBO Journal, vol. 20, no. 18, pp. 5070–5078, 2001.
[31]
R. Chiesa, P. Piccardo, B. Ghetti, and D. A. Harris, “Neurological illness in transgenic mice expressing a prion protein with an insertional mutation,” Neuron, vol. 21, no. 6, pp. 1339–1351, 1998.
[32]
S. Dossena, L. Imeri, M. Mangieri et al., “Mutant prion protein expression causes motor and memory deficits and abnormal sleep patterns in a transgenic mouse model,” Neuron, vol. 60, no. 4, pp. 598–609, 2008.
[33]
R. S. Hegde, J. A. Mastrianni, M. R. Scott et al., “A transmembrane form of the prion protein in neurodegenerative disease,” Science, vol. 279, no. 5352, pp. 827–834, 1998.
[34]
G. C. Telling, T. Haga, M. Torchia, P. Tremblay, S. J. DeArmond, and S. B. Prusiner, “Interactions between wild-type and mutant prion proteins modulate neurodegeneration in transgenic mice,” Genes and Development, vol. 10, no. 14, pp. 1736–1750, 1996.
[35]
C. J. Sigurdson, K. P. R. Nilsson, S. Hornemann et al., “De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 1, pp. 304–309, 2009.
[36]
W. S. Jackson, A. W. Borkowski, H. Faas et al., “Spontaneous generation of prion infectivity in fatal familial insomnia knockin mice,” Neuron, vol. 63, no. 4, pp. 438–450, 2009.
[37]
W. S. Jackson, A. W. Borkows, N. E. Watson, et al., “Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 36, pp. 14759–14764, 2013.
[38]
Y. Friedman-Levi, Z. Meiner, T. Canello et al., “Fatal prion disease in a mouse model of genetic E200K Creutzfeldt-Jakob disease,” PLoS Pathogens, vol. 7, no. 11, Article ID e1002350, 2011.
[39]
A. Senatore, S. Colleoni, C. Verderio et al., “Mutant PrP suppresses glutamatergic neurotransmission in cerebellar granule neurons by impairing membrane delivery of VGCC α2δ-1 subunit,” Neuron, vol. 74, no. 2, pp. 300–313, 2012.
[40]
J. L. Silva, T. C. R. G. Vieira, M. P. B. Gomes, L. P. Rangel, S. M. N. Scapin, and Y. Cordeiro, “Experimental approaches to the interaction of the prion protein with nucleic acids and glycosaminoglycans: modulators of the pathogenic conversion,” Methods, vol. 53, no. 3, pp. 306–317, 2011.
[41]
J. Ma, “The role of cofactors in prion propagation and infectivity,” PLoS Pathogens, vol. 8, no. 4, Article ID e1002589, 2012.
[42]
S. L. Kil and B. Caughey, “A simplified recipe for prions,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 23, pp. 9551–9552, 2007.
[43]
G. M. Shaked, Z. Meiner, I. Avraham, A. Taraboulos, and R. Gabizon, “Reconstitution of prion infectivity from solubilized protease-resistant PrP and nonprotein components of prion rods,” Journal of Biological Chemistry, vol. 276, no. 17, pp. 14324–14328, 2001.
[44]
C. Wong, L.-W. Xiong, M. Horiuchi et al., “Sulfated glycans and elevated temperature stimulate -dependent cell-free formation of protease-resistant prion protein,” EMBO Journal, vol. 20, no. 3, pp. 377–386, 2001.
[45]
T. Yokoyama, A. Takeuchi, M. Yamamoto, T. Kitamoto, J. W. Ironside, and M. Morita, “Heparin enhances the cell-protein misfolding cyclic amplification efficiency of variant Creutzfeldt-Jakob disease,” Neuroscience Letters, vol. 498, no. 2, pp. 119–123, 2011.
[46]
N. R. Deleault, J. C. Geoghegan, K. Nishina, R. Kascsak, R. A. Williamson, and S. Supattapone, “Protease-resistant prion protein amplification reconstituted with partially purified substrates and synthetic polyanions,” Journal of Biological Chemistry, vol. 280, no. 29, pp. 26873–26879, 2005.
[47]
N. R. Deleault, R. W. Lucassen, and S. Supattapone, “RNA molecules stimulate prion protein conversion,” Nature, vol. 425, no. 6959, pp. 717–720, 2003.
[48]
J. C. Geoghegan, P. A. Valdes, N. R. Orem et al., “Selective incorporation of polyanionic molecules into hamster prions,” Journal of Biological Chemistry, vol. 282, no. 50, pp. 36341–36353, 2007.
[49]
G. P. Saborio, B. Permanne, and C. Soto, “Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding,” Nature, vol. 411, no. 6839, pp. 810–813, 2001.
[50]
F. Wang, X. Wang, C.-G. Yuan, and J. Ma, “Generating a prion with bacterially expressed recombinant prion protein,” Science, vol. 327, no. 5969, pp. 1132–1135, 2010.
[51]
N. R. Deleault, R. Kascsak, J. C. Geoghegan, and S. Supattapone, “Species-dependent differences in cofactor utilization for formation of the protease-resistant prion protein in vitro,” Biochemistry, vol. 49, no. 18, pp. 3928–3934, 2010.
[52]
N. Gonzalez-Montalban, N. Makarava, R. Savtchenko, and I. V. Baskakov, “Relationship between conformational stability and amplification efficiency of prions,” Biochemistry, vol. 50, no. 37, pp. 7933–7940, 2011.
[53]
P. K. Nandi and E. Leclerc, “Polymerization of murine recombinant prion protein in nucleic acid solution,” Archives of Virology, vol. 144, no. 9, pp. 1751–1763, 1999.
[54]
Y. Cordeiro, F. Machado, L. Juliano et al., “DNA converts cellular prion protein into the β-sheet conformation and inhibits prion peptide aggregation,” Journal of Biological Chemistry, vol. 276, no. 52, pp. 49400–49409, 2001.
[55]
N. R. Deleault, J. R. Piro, D. J. Walsh, et al., “Isolation of phosphatidylethanolamine as a solitary cofactor for prion formation in the absence of nucleic acids,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 22, pp. 8546–8551, 2012.
[56]
N. R. Deleault, D. J. Walsh, J. R. Piro, et al., “Cofactor molecules maintain infectious conformation and restrict strain properties in purified prions,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 28, pp. E1938–E1946, 2012.
[57]
P. Saá, G. F. Sferrazza, G. Ottenberg, A. M. Oelschlegel, K. Dorsey, and C. I. Lasmézas, “Strain-specific role of RNAs in prion replication,” Journal of Virology, vol. 86, no. 19, pp. 10494–10504, 2012.
[58]
D. R. Taylor and N. M. Hooper, “The prion protein and lipid rafts (review),” Molecular Membrane Biology, vol. 23, no. 1, pp. 89–99, 2006.
[59]
A. Santuccione, V. Sytnyk, I. Leshchyns'ka, and M. Schachner, “Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth,” Journal of Cell Biology, vol. 169, no. 2, pp. 341–354, 2005.
[60]
M. Roffé, F. H. Beraldo, R. Bester et al., “Prion protein interaction with stress-inducible protein 1 enhances neuronal protein synthesis via mTOR,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 29, pp. 13147–13152, 2010.
[61]
T. G. Santos, F. H. Beraldo, G. N. M. Hajj, et al., “Laminin-gamma1 chain and stress inducible protein 1 synergistically mediate -dependent axonal growth via Ca2+ mobilization in dorsal root ganglia neurons,” Journal of Neurochemistry, vol. 124, no. 2, pp. 210–223, 2013.
[62]
T. G. Santos, I. R. Silva, B. Costa-Silva, A. P. Lepique, V. R. Martins, and M. H. Lopes, “Enhanced neural progenitor/stem cells self-renewal via the interaction of stress-inducible protein 1 with the prion protein,” Stem Cells, vol. 29, no. 7, pp. 1126–1136, 2011.
[63]
A. Jen, C. J. Parkyn, R. C. Mootoosamy et al., “Neuronal low-density lipoprotein receptor-related protein 1 binds and endocytoses prion fibrils via receptor cluster 4,” Journal of Cell Science, vol. 123, no. 2, pp. 246–255, 2010.
[64]
J. V. Rushworth, H. H. Griffiths, N. T. Watt, and N. M. Hooper, “Prion protein-mediated toxicity of amyloid-beta oligomers requires lipid rafts and the transmembrane LRP1,” Journal of Biological Chemistry, vol. 288, no. 13, pp. 8935–8951, 2013.
[65]
V. Devanathan, I. Jakovcevski, A. Santuccione et al., “Cellular form of prion protein inhibits reelin-mediated shedding of Caspr from the neuronal cell surface to potentiate Caspr-mediated inhibition of neurite outgrowth,” Journal of Neuroscience, vol. 30, no. 27, pp. 9292–9305, 2010.
[66]
N. Naslavsky, R. Stein, A. Yanai, G. Friedlander, and A. Taraboulos, “Characterization of detergent-insoluble complexes containing the cellular prion protein and its scrapie isoform,” Journal of Biological Chemistry, vol. 272, no. 10, pp. 6324–6331, 1997.
[67]
N. Naslavsky, H. Shmeeda, G. Friedlander et al., “Sphingolipid depletion increases formation of the scrapie prion protein in neuroblastoma cells infected with prions,” Journal of Biological Chemistry, vol. 274, no. 30, pp. 20763–20771, 1999.
[68]
T. R. Klein, D. Kirsch, R. Kaufmann, and D. Riesner, “Prion rods contain small amounts of two host sphingolipids as revealed by thin-layer chromatography and mass spectrometry,” Biological Chemistry, vol. 379, no. 6, pp. 655–666, 1998.
[69]
V. Campana, D. Sarnataro, and C. Zurzolo, “The highways and byways of prion protein trafficking,” Trends in Cell Biology, vol. 15, no. 2, pp. 102–111, 2005.
[70]
T. J. T. Pinheiro, “The role of rafts in the fibrillization and aggregation of prions,” Chemistry and Physics of Lipids, vol. 141, no. 1-2, pp. 66–71, 2006.
[71]
B. Caughey and G. J. Raymond, “The scrapie-associated form of PrP is made from a cell surface precursor that is both protease- and phospholipase-sensitive,” Journal of Biological Chemistry, vol. 266, no. 27, pp. 18217–18223, 1991.
[72]
D. R. Borchelt, A. Taraboulos, and S. B. Prusiner, “Evidence for synthesis of scrapie prion proteins in the endocytic pathway,” Journal of Biological Chemistry, vol. 267, no. 23, pp. 16188–16199, 1992.
[73]
B. Caughey, G. J. Raymond, D. Ernst, and R. E. Race, “N-terminal truncation of the scrapie-associated form of PrP by lysosomal protease(s): implications regarding the site of conversion of PrP to the protease-resistant state,” Journal of Virology, vol. 65, no. 12, pp. 6597–6603, 1991.
[74]
A. Taraboulos, A. J. Raeber, D. R. Borchelt, D. Serban, and S. B. Prusiner, “Synthesis and trafficking of prion proteins in cultured cells,” Molecular Biology of the Cell, vol. 3, no. 8, pp. 851–863, 1992.
[75]
A. Taraboulos, D. Serban, and S. B. Prusiner, “Scrapie prion proteins accumulate in the cytoplasm of persistently infected cultured cells,” Journal of Cell Biology, vol. 110, no. 6, pp. 2117–2132, 1990.
[76]
F. Béranger, A. Mangé, B. Goud, and S. Lehmann, “Stimulation of retrograde transport toward the endoplasmic reticulum increases accumulation of in prion-infected cells,” Journal of Biological Chemistry, vol. 277, no. 41, pp. 38972–38977, 2002.
[77]
S. F. Godsave, H. Wille, P. Kujala et al., “Cryo-immunogold electron microscopy for prions: toward identification of a conversion site,” Journal of Neuroscience, vol. 28, no. 47, pp. 12489–12499, 2008.
[78]
L. Ivanova, S. Barmada, T. Kummer, and D. A. Harris, “Mutant prion proteins are partially retained in the endoplasmic reticulum,” Journal of Biological Chemistry, vol. 276, no. 45, pp. 42409–42421, 2001.
[79]
Z. Marijanovic, A. Caputo, V. Campana, and C. Zurzolo, “Identification of an intracellular site of prion conversion,” PLoS Pathogens, vol. 5, no. 5, Article ID e1000426, 2009.
[80]
V. Lewis and N. M. Hooper, “The role of lipid rafts in prion protein biology,” Frontiers in Bioscience, vol. 16, pp. 151–168, 2011.
[81]
F. Pimpinelli, S. Lehmann, and I. Maridonneau-Parini, “The scrapie prion protein is present in flotillin-1-positive vesicles in central- but not peripheral-derived neuronal cell lines,” European Journal of Neuroscience, vol. 21, no. 8, pp. 2063–2072, 2005.
[82]
I. H. Pattison and G. C. Millson, “Scrapie produced experimentally in goats with special reference to the clinical syndrome,” Journal of Comparative Pathology and Therapeutics, vol. 71, pp. 101–109, 1961.
[83]
M. E. Bruce, I. McConnell, H. Fraser, and A. G. Dickinson, “The disease characteristics of different strains of scrapie in Sinc congenic mouse lines: implications for the nature of the agent and host control of pathogenesis,” Journal of General Virology, vol. 72, no. 3, pp. 595–603, 1991.
[84]
H. Fraser, “The pathology of a natural and experimental scrapie,” Frontiers of Biology, vol. 44, pp. 267–305, 1976.
[85]
R. Hecker, A. Taraboulos, M. Scott et al., “Replication of distinct scrapie prion isolates is region specific in brains of transgenic mice and hamsters,” Genes and Development, vol. 6, no. 7, pp. 1213–1228, 1992.
[86]
B. Chesebro, “BSE and prions: uncertainties about the agent,” Science, vol. 279, no. 5347, pp. 42–43, 1998.
[87]
C. F. Farquhar, R. A. Somerville, and M. E. Bruce, “Straining the prion hypothesis,” Nature, vol. 391, no. 6665, pp. 345–346, 1998.
[88]
R. J. Kascsak, R. Rubenstein, and P. A. Merz, “Immunological comparison of scrapie-associated fibrils isolated from animals infected with four different scrapie strains,” Journal of Virology, vol. 59, no. 3, pp. 676–683, 1986.
[89]
R. J. Kascsak, R. Rubenstein, and P. A. Merz, “Biochemical differences among scrapie-associated fibrils support the biological diversity of scrapie agents,” Journal of General Virology, vol. 66, no. 8, pp. 1715–1722, 1985.
[90]
R. A. Bessen and R. F. Marsh, “Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy,” Journal of Virology, vol. 68, no. 12, pp. 7859–7868, 1994.
[91]
R. A. Bessen, D. A. Kocisko, G. J. Raymond, S. Nandan, P. T. Lansbury, and B. Caughey, “Non-genetic propagation of strain-specific properties of scrapie prion protein,” Nature, vol. 375, no. 6533, pp. 698–700, 1995.
[92]
G. C. Telling, P. Parchi, S. J. DeArmond et al., “Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity,” Science, vol. 274, no. 5295, pp. 2079–2082, 1996.
[93]
J. Safar, H. Wille, V. Itri et al., “Eight prion strains have molecules with different conformations,” Nature Medicine, vol. 4, no. 10, pp. 1157–1165, 1998.
[94]
A. Thomzig, S. Spassov, M. Friedrich, D. Naumann, and M. Beekes, “Discriminating scrapie and bovine spongiform encephalopathy isolates by infrared spectroscopy of pathological prion protein,” Journal of Biological Chemistry, vol. 279, no. 32, pp. 33847–33854, 2004.
[95]
S. Spassov, M. Beekes, and D. Naumann, “Structural differences between TSEs strains investigated by FT-IR spectroscopy,” Biochimica et Biophysica Acta, vol. 1760, no. 7, pp. 1138–1149, 2006.
[96]
G. Legname, H.-O. B. Nguyen, D. Peretz, F. E. Cohen, S. J. DeArmond, and S. B. Prusiner, “Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 50, pp. 19105–19110, 2006.
[97]
C. Bett, et al., “Biochemical properties of highly neuroinvasive prion strains,” PLoS Pathogens, vol. 8, no. 2, Article ID e100252, 2012.
[98]
J. I. Ayers, C. R. Schutt, R. A. Shikiya, A. Aguzzi, A. E. Kincaid, and J. C. Bartz, “The strain-encoded relationship between replication, stability and processing in neurons is predictive of the incubation period of disease,” PLoS Pathogens, vol. 7, no. 3, Article ID e1001317, 2011.
[99]
M. A. Pastrana, G. Sajnani, B. Onisko et al., “Isolation and characterization of a proteinase K-sensitive fraction,” Biochemistry, vol. 45, no. 51, pp. 15710–15717, 2006.
[100]
J. G. Safar, M. D. Geschwind, C. Deering, et al., “Diagnosis of human prion disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 9, pp. 3501–3506, 2005.
[101]
S. Tzaban, G. Friedlander, O. Schonberger et al., “Protease-sensitive scrapie prion protein in aggregates of heterogeneous sizes,” Biochemistry, vol. 41, no. 42, pp. 12868–12875, 2002.
[102]
P. Parchi, S. G. Chen, P. Brown et al., “Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann-Str？ussler-Scheinker disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 14, pp. 8322–8327, 1998.
[103]
S. L. Benestad, J.-N. Arsac, W. Goldmann, and M. N？remark, “Atypical/Nor98 scrapie: properties of the agent, genetics, and epidemiology,” Veterinary Research, vol. 39, no. 4, article 19, 2008.
[104]
W. Q. Zou, G. Puoti, X. Xiao, et al., “Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein,” Annals of Neurology, vol. 68, no. 2, pp. 162–172, 2010.
[105]
M. Polymenidou, S. Prokop, H. H. Jung et al., “Atypical prion protein conformation in familial prion disease with PRNP P105T mutation,” Brain Pathology, vol. 21, no. 2, pp. 209–214, 2011.
[106]
S. Monaco, M. Fiorini, A. Farinazzo et al., “Allelic origin of protease-sensitive and protease-resistant prion protein isoforms in Gerstmann-Str？ussler-Scheinker disease with the p102l mutation,” PLoS ONE, vol. 7, no. 2, Article ID e32382, 2012.
[107]
X. Xiao, I. Cali, Z. Dong, et al., “Protease-sensitive prions with 144-bp insertion mutations,” Aging, vol. 5, no. 3, pp. 155–173, 2013.
[108]
A. M. Thackray, L. Hopkins, and R. Bujdoso, “Proteinase K-sensitive disease-associated ovine prion protein revealed by conformation-dependent immunoassay,” Biochemical Journal, vol. 401, no. 2, pp. 475–483, 2007.
[109]
C. Kim, T. Haldiman, Y. Cohen et al., “Protease-sensitive conformers in broad spectrum of distinct structures in sporadic Creutzfeldt-Jakob disease are indicator of progression rate,” PLoS Pathogens, vol. 7, no. 9, Article ID e1002242, 2011.
[110]
C. Kim, T. Haldiman, K. Surewicz, et al., “Small protease sensitive oligomers of in distinct human prions determine conversion rate of ,” PLoS Pathogens, vol. 8, no. 8, Article ID e1002835, 2012.
[111]
D. Saverioni, S. Notari, S. Capellari, et al., “Analyses of protease resistance and aggregation state of abnormal prion protein across the spectrum of human prions,” Journal of Biological Chemistry, vol. 288, no. 39, pp. 27972–27985, 2013.
[112]
N. L. Tuzi, E. Cancellotti, H. Baybutt et al., “Host PrP glycosylation: a major factor determining the outcome of prion infection,” PLoS Biology, vol. 6, no. 4, article e100, 2008.
[113]
C. Casalone, G. Zanusso, P. Acutis et al., “Identification of a second bovine amyloidotic spongiform encephalopathy: molecular similarities with sporadic Creutzfeldt-Jakob disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 9, pp. 3065–3070, 2004.
[114]
P. Parchi, S. Capellari, S. G. Chen et al., “Typing prion isoforms,” Nature, vol. 386, no. 6622, pp. 232–234, 1997.
[115]
P. Parchi, R. Castellani, S. Capellari et al., “Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease,” Annals of Neurology, vol. 39, no. 6, pp. 767–778, 1996.
[116]
J. Collinge, K. C. L. Sidle, J. Meads, J. Ironside, and A. F. Hill, “Molecular analysis of prion strain variation and the aetiology of “new variant” CJD,” Nature, vol. 383, no. 6602, pp. 685–690, 1996.
[117]
A. Helenius and M. Aebi, “Intracellular functions of N-linked glycans,” Science, vol. 291, no. 5512, pp. 2364–2369, 2001.
[118]
S. E. O'Connor and B. Imperiali, “Modulation of protein structure and function by asparagine-linked glycosylation,” Chemistry and Biology, vol. 3, no. 10, pp. 803–812, 1996.
[119]
N. J. Cobb and W. K. Surewicz, “Prion diseases and their biochemical mechanisms,” Biochemistry, vol. 48, no. 12, pp. 2574–2585, 2009.
[120]
E. Cancellotti, S. P. Mahal, R. Somerville, et al., “Post-translational changes to PrP alter transmissible spongiform encephalopathy strain properties,” EMBO Journal, vol. 32, no. 5, pp. 756–769, 2013.
[121]
M. Eigen, “On the nature of virus quasispecies,” Trends in Microbiology, vol. 4, no. 6, pp. 216–218, 1996.
[122]
J. Collinge and A. R. Clarke, “A general model of prion strains and their pathogenicity,” Science, vol. 318, no. 5852, pp. 930–936, 2007.
[123]
J. Li, S. Browning, S. P. Mahal, A. M. Oelschlegel, and C. Weissmann, “Darwinian evolution of prions in cell culture,” Science, vol. 327, no. 5967, pp. 869–872, 2010.
[124]
B. T. Ghetti, G. G. Kovacs, and P. Piccardo, “Gerstmann-Str？ussler-Scheinker disease,” in Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders, D. W. Dickson and R. O. Weller, Eds., pp. 364–377, 2011.
[125]
P. Parchi, R. Strammiello, A. Giese, and H. Kretzschmar, “Phenotypic variability of sporadic human prion disease and its molecular basis: past, present, and future,” Acta Neuropathologica, vol. 121, no. 1, pp. 91–112, 2011.
[126]
P. Parchi, S. Capellari, and P. Gambetti, “Fatal familial and sporadic insomnia,” in Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders, D. W. Dickson and R. O. Weller, Eds., pp. 346–349, 2011.
[127]
P. Gambetti, G. Puoti, Q. Kong, and W. Zou, “A new prion diseases: protease-sensitive prionopathy,” in Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders, D. W. Dickson and R. O. Weller, Eds., pp. 350–353, 2011.
[128]
J. W. Ironside, M. W. Head, and R. G. Will, “Variant Creutzfeldt-Jacob disease,” in Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders, D. W. Dickson and R. O. Weller, Eds., pp. 354–363, 2011.
[129]
P. Parchi, W. Zou, W. Wang et al., “Genetic influence on the structural variations of the abnormal prion protein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 18, pp. 10168–10172, 2000.
[130]
P. Parchi, A. Giese, S. Capellari, et al., “Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects,” Annals of Neurology, vol. 46, no. 2, pp. 224–233, 1999.
[131]
P. Parchi, M. Cescatti, S. Notari et al., “Agent strain variation in human prion disease: insights from a molecular and pathological review of the National Institutes of Health series of experimentally transmitted disease,” Brain, vol. 133, no. 10, pp. 3030–3042, 2010.
[132]
I. Cali, R. Castellani, J. Yuan et al., “Classification of sporadic Creutzfeldt-Jakob disease revisited,” Brain, vol. 129, no. 9, pp. 2266–2277, 2006.
[133]
P. Parchi, R. Strammiello, S. Notari et al., “Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of types: an updated classification,” Acta Neuropathologica, vol. 118, no. 5, pp. 659–671, 2009.
[134]
G. Puoti, G. Giaccone, G. Rossi, B. Canciani, O. Bugiani, and F. Tagliavini, “Sporadic Creutzfeldt-Jakob disease: co-occurrence of different types of in the same brain,” Neurology, vol. 53, no. 9, pp. 2173–2176, 1999.
[135]
Y. Murayama, M. Yoshioka, K. Masujin et al., “Sulfated dextrans enhance in vitro amplification of bovine spongiform encephalopathy and enable ultrasensitive detection of bovine ,” PLoS ONE, vol. 5, no. 10, Article ID e13152, 2010.
[136]
N. R. Deleault, B. T. Harris, J. R. Rees, and S. Supattapone, “Formation of native prions from minimal components in vitro,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 23, pp. 9741–9746, 2007.
[137]
S. Notari, S. Capellari, A. Giese et al., “Effects of different experimental conditions on the core generated by protease digestion: implications for strain typing and molecular classification of CJD,” Journal of Biological Chemistry, vol. 279, no. 16, pp. 16797–16804, 2004.
[138]
S. Notari, R. Strammiello, S. Capellari et al., “Characterization of truncated forms of abnormal prion protein in Creutzfeldt-Jakob disease,” Journal of Biological Chemistry, vol. 283, no. 45, pp. 30557–30565, 2008.
[139]
L. Monari, S. G. Chen, P. Brown et al., “Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 7, pp. 2839–2842, 1994.
[140]
T. Pan, M. Colucci, B.-S. Wong et al., “Novel differences between two human prion strains revealed by two-dimensional gel electrophoresis,” Journal of Biological Chemistry, vol. 276, no. 40, pp. 37284–37288, 2001.
[141]
P. Aucouturier, R. J. Kascsak, B. Frangione, and T. Wisniewski, “Biochemical and conformational variability of human prion strains in sporadic Creutzfeldt-Jakob disease,” Neuroscience Letters, vol. 274, no. 1, pp. 33–36, 1999.
[142]
A. Kobayashi, S. Satoh, J. W. Ironside, S. Mohri, and T. Kitamoto, “Type 1 and type 2 human have different aggregation sizes in methionine homozygotes with sporadic, iatrogenic and variant Creutzfeldt-Jakob disease,” Journal of General Virology, vol. 86, no. 1, pp. 237–240, 2005.
[143]
I. Cali, R. Castellani, A. Alshekhlee 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, vol. 132, no. 10, pp. 2643–2658, 2009.
[144]
L. Pirisinu, M. di Bari, S. Marcon et al., “A new method for the characterization of strain-specific conformational stability of protease-sensitive and protease-resistant ,” PLoS ONE, vol. 5, no. 9, Article ID e12723, 2010.
[145]
Y. P. Choi, A. H. Peden, A. Gr？ner, J. W. Ironside, and M. W. Head, “Distinct stability states of disease-associated human prion protein identified by conformation-dependent immunoassay,” Journal of Virology, vol. 84, no. 22, pp. 12030–12038, 2010.
[146]
P. Piccardo, S. R. Dlouhy, P. M. J. Lievens et al., “Phenotypic variability of Gerstmann-Str？ussler-Scheinker disease is associated with prion protein heterogeneity,” Journal of Neuropathology and Experimental Neurology, vol. 57, no. 10, pp. 979–988, 1998.
[147]
P. Piccardo, J. J. Liepnieks, A. William et al., “Prion proteins with different conformations accumulate in Gerstmann-Str？ussler-Scheinker disease caused by A117V and F198S mutations,” American Journal of Pathology, vol. 158, no. 6, pp. 2201–2207, 2001.
[148]
P. Piccardo, C. Seiler, S. R. Dlouhy et al., “Proteinase-K-resistant prion protein isoforms in Gerstmann-Str？ussler-Scheinker disease (Indiana kindred),” Journal of Neuropathology and Experimental Neurology, vol. 55, no. 11, pp. 1157–1163, 1996.
[149]
F. Tagliavini, P. M.-J. Lievens, C. Tranchant et al., “A 7-kDa prion protein (PrP) fragment, an integral component of the PrP region required for infectivity, is the major amyloid protein in Gerstmann-Str？ussler-Scheinker disease A117V,” Journal of Biological Chemistry, vol. 276, no. 8, pp. 6009–6015, 2001.
[150]
F. Tagliavini, F. Prelli, J. Ghiso et al., “Amyloid protein of Gerstmann-Str？ussler-Scheinker disease (Indiana kindred) is an 11？kd fragment of prion protein with an N-terminal glycine at codon 58,” EMBO Journal, vol. 10, no. 3, pp. 513–519, 1991.
[151]
F. Tagliavini, F. Prelli, M. Porro et al., “Amyloid fibrils in Gerstmann-Str？ussler-Scheinker disease (Indiana and Swedish kindreds) express only PrP peptides encoded by the mutant allele,” Cell, vol. 79, no. 4, pp. 695–703, 1994.
[152]
C. Jansen, P. Parchi, S. Capellari et al., “A second case of Gerstmann-Str？ussler-Scheinker disease linked to the G131V mutation in the prion protein gene in a Dutch patient,” Journal of Neuropathology and Experimental Neurology, vol. 70, no. 8, pp. 698–702, 2011.
[153]
P. Gambetti, Z. Dong, J. Yuan et al., “A novel human disease with abnormal prion protein sensitive to protease,” Annals of Neurology, vol. 63, no. 6, pp. 697–708, 2008.
[154]
M. W. Head, S. Lowrie, G. Chohan, R. Knight, D. J. Scoones, and J. W. Ironside, “Variably protease-sensitive prionopathy in a PRNP codon 129 heterozygous UK patient with co-existing tau, α synuclein and Aβ pathology,” Acta Neuropathologica, vol. 120, no. 6, pp. 821–823, 2010.
[155]
M. W. Head, H. M. Yull, D. L. Ritchie, et al., “Variably protease-sensitive prionopathy in the UK: a retrospective review 1991–2008,” Brain, vol. 136, no. 4, pp. 1102–1115, 2013.
[156]
C. Jansen, M. W. Head, W. A. van Gool et al., “The first case of protease-sensitive prionopathy (PSPr) in the Netherlands: a patient with an unusual GSS-like clinical phenotype,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 81, no. 9, pp. 1052–1055, 2010.
[157]
X. Xiao, J. Yuan, S. Ha？k, et al., “Glycoform-selective prion formation in sporadic and familial forms of prion disease,” PLoS ONE, vol. 8, no. 3, Article ID e58786, 2013.
[158]
J. A. Mastrianni, R. Nixon, R. Layzer et al., “Prion protein conformation in a patient with sporadic fatal insomnia,” The New England Journal of Medicine, vol. 340, no. 21, pp. 1630–1638, 1999.
[159]
C. Korth, K. Kaneko, D. Groth et al., “Abbreviated incubation times for human prions in mice expressing a chimeric mouse-human prion protein transgene,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 8, pp. 4784–4789, 2003.
[160]
R. Nonno, M. A. di Bari, F. Cardone et al., “Efficient transmission and characterization of Creutzfeldt-Jakob disease strains in bank voles,” PLoS Pathogens, vol. 2, no. 2, article e12, 2006.
[161]
P. Brown, C. J. Gibbs Jr., P. Rodgers-Johnson et al., “Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease,” Annals of Neurology, vol. 35, no. 5, pp. 513–529, 1994.
[162]
M. T. Bishop, R. G. Will, and J. C. Manson, “Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 26, pp. 12005–12010, 2010.
[163]
F. Moda, S. Suardi, G. di Fede et al., “MM2-thalamic Creutzfeldt-Jakob disease: neuropathological, biochemical and transmission studies identify a distinctive prion strain,” Brain Pathology, vol. 22, no. 5, pp. 662–669, 2012.
[164]
M. E. Bruce, R. G. Will, J. W. Ironside et al., “Transmissions to mice indicate that “new variant” CJD is caused by the BSE agent,” Nature, vol. 389, no. 6650, pp. 498–501, 1997.
[165]
A. F. Hill, M. Desbruslais, S. Joiner et al., “The same prion strain causes vCJD and BSE,” Nature, vol. 389, no. 6650, pp. 448–450, 1997.
[166]
J. D. F. Wadsworth, S. Joiner, J. M. Linehan et al., “Kuru prions and sporadic Creutzfeldt-Jakob disease prions have equivalent transmission properties in transgenic and wild-type mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 10, pp. 3885–3890, 2008.
[167]
J. D. F. Wadsworth, E. A. Asante, M. Desbruslais et al., “Human prion protein with valine 129 prevents expression of variant CJD phenotype,” Science, vol. 306, no. 5702, pp. 1793–1796, 2004.
[168]
E. A. Asante, J. M. Linehan, I. Gowland et al., “Dissociation of pathological and molecular phenotype of variant Creutzfeldt-Jakob disease in transgenic human prion protein 129 heterozygous mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 28, pp. 10759–10764, 2006.
[169]
M. Bishop, P. Hart, L. Aitchison et al., “Predicting susceptibility and incubation time of human-to-human transmission of vCJD,” The Lancet Neurology, vol. 5, no. 5, pp. 393–398, 2006.
[170]
V. Béringue, A. Le Dur, P. Tixador et al., “Prominent and persistent extraneural infection in human PrP transgenic mice infected with variant CJD,” PLoS ONE, vol. 3, no. 1, article e1419, 2008.
[171]
A. Takeuchi, A. Kobayashi, J. W. Ironside, S. Mohri, and T. Kitamoto, “Characterization of variant Creutzfeldt-Jakob disease prions in prion protein-humanized mice carrying distinct codon 129 genotypes,” Journal of Biological Chemistry, vol. 288, no. 30, pp. 21659–21666, 2013.
[172]
J. Tateishi, T. Kitamoto, M. Z. Hoque, and H. Furukawa, “Experimental transmission of Creutzfeldt-Jakob disease and related diseases to rodents,” Neurology, vol. 46, no. 2, pp. 532–537, 1996.
[173]
P. Piccardo, J. C. Manson, D. King, B. Ghetti, and R. M. Barron, “Accumulation of prion protein in the brain that is not associated with transmissible disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 11, pp. 4712–4717, 2007.
[174]
E. A. Asante, J. M. Linehan, M. Smidak, et al., “Inherited prion disease A117V is not simply a proteinopathy but produces prions transmissible to transgenic mice expressing homologous prion protein,” PLoS Pathogens, vol. 9, no. 9, Article ID e100364, 2013.
[175]
R. H. Kimberlin and C. A. Walker, “Characteristics of a short incubation model of scrapie in the golden hamster,” Journal of General Virology, vol. 34, no. 2, pp. 295–304, 1977.
[176]
R. H. Kimberlin and C. A. Walker, “Pathogenesis of scrapie (strain 263k) in hamsters infected intracerebrally, intraperitoneally or intraocularly,” Journal of General Virology, vol. 67, no. 2, pp. 255–263, 1986.
[177]
T. Kuczius, I. Haist, and M. H. Groschup, “Molecular analysis of bovine spongiform encephalopathy and scrapie strain variation,” Journal of Infectious Diseases, vol. 178, no. 3, pp. 693–699, 1998.
[178]
J. Hope, S. C. E. R. Wood, C. R. Birkett et al., “Molecular analysis of ovine prion protein identifies similarities between BSE and an experimental isolate of natural scrapie, CH1641,” Journal of General Virology, vol. 80, no. 1, pp. 1–4, 1999.
[179]
M. Horiuchi, T. Nemoto, N. Ishiguro, H. Furuoka, S. Mohri, and M. Shinagawa, “Biological and biochemical characterization of sheep scrapie in Japan,” Journal of Clinical Microbiology, vol. 40, no. 9, pp. 3421–3426, 2002.
[180]
M. J. Stack, M. J. Chaplin, and J. Clark, “Differentiation of prion protein glycoforms from naturally occurring sheep scrapie, sheep-passaged scrapie strains (CH1641 and SSBP1), Bovine Spongiform Encephalopathy (BSE) cases and Romney and Cheviot breed sheep experimentally inoculated with BSE using two monoclonal antibodies,” Acta Neuropathologica, vol. 104, no. 3, pp. 279–286, 2002.
[181]
T. Baron, C. Crozet, A.-G. Biacabe et al., “Molecular analysis of the protease-resistant prion protein in scrapie and bovine spongiform encephalopathy transmitted to ovine transgenic and wild-type mice,” Journal of Virology, vol. 78, no. 12, pp. 6243–6251, 2004.
[182]
J. Vulin, A.-G. Biacabe, G. Cazeau, D. Calavas, and T. Baron, “Molecular typing of protease-resistant prion protein in transmissible spongiform encephalopathies of small ruminants, France, 2002–2009,” Emerging Infectious Diseases, vol. 17, no. 1, pp. 55–63, 2011.
[183]
T. G. M. Baron, J.-Y. Madec, and D. Calavas, “Similar signature of the prion protein in natural sheep scrapie and bovine spongiform encephalopathy-linked diseases,” Journal of Clinical Microbiology, vol. 37, no. 11, pp. 3701–3704, 1999.
[184]
M. H. Groschup, T. Kuczius, F. Junghans, T. Sweeney, W. Bodemer, and A. Buschmann, “Characterization of BSE and scrapie strains/isolates,” Archives of Virology, no. 16, pp. 217–226, 2000.
[185]
T. Sweeney, T. Kuczius, M. McElroy, M. Gomerez Parada, and M. H. Groschup, “Molecular analysis of Irish sheep scrapie cases,” Journal of General Virology, vol. 81, no. 6, pp. 1621–1627, 2000.
[186]
A. M. Thackray, L. Hopkins, J. Spiropoulos, and R. Bujdoso, “Molecular and transmission characteristics of primary-passaged ovine scrapie isolates in conventional and ovine PrP transgenic mice,” Journal of Virology, vol. 82, no. 22, pp. 11197–11207, 2008.
[187]
T. Baron and A.-G. Biacabe, “Molecular behaviors of “CH1641-Like” sheep scrapie isolates in ovine transgenic mice (TgOvPrP4),” Journal of Virology, vol. 81, no. 13, pp. 7230–7237, 2007.
[188]
S. Nicot and T. G. M. Baron, “Strain-specific proteolytic processing of the prion protein in prion diseases of ruminants transmitted in ovine transgenic mice,” Journal of General Virology, vol. 91, no. 2, pp. 570–574, 2010.
[189]
T. Baron, A. Bencsik, J. Vulin et al., “A C-terminal protease-resistant prion fragment distinguishes ovine “CH1641-like” scrapie from bovine classical and L-type BSE in ovine transgenic mice,” PLoS Pathogens, vol. 4, no. 8, Article ID e1000137, 2008.
[190]
J. D. Foster and A. G. Dickinson, “The unusual properties of CH1641, a sheep-passaged isolate of scrapie,” Veterinary Record, vol. 123, no. 1, pp. 5–8, 1988.
[191]
R. H. Kimberlin and C. A. Walker, “Evidence that the transmission of one source of scrapie agent to hamsters involves separation of agent strains from a mixture,” Journal of General Virology, vol. 39, no. 3, pp. 487–496, 1978.
[192]
M. E. Bruce, A. Boyle, S. Cousens et al., “Strain characterization of natural sheep scrapie and comparison with BSE,” Journal of General Virology, vol. 83, no. 3, pp. 695–704, 2002.
[193]
S. L. Benestad, P. Sarradin, B. Thu, J. Sch？nheit, M. A. Tranulis, and B. Bratberg, “Cases of scrapie with unusual features in Norway and designation of a new type, Nor98,” Veterinary Record, vol. 153, no. 7, pp. 202–208, 2003.
[194]
H. de Bosschere, S. Roels, S. L. Benestad, and E. Vanopdenbosch, “Scrapie case similar to Nor98 diagnosed in Belgium via active surveillance,” Veterinary Record, vol. 155, no. 22, pp. 707–708, 2004.
[195]
D. Gavier-Widén, M. N？remark, S. Benestad et al., “Recognition of the Nor98 variant of scrapie in the Swedish sheep population,” Journal of Veterinary Diagnostic Investigation, vol. 16, no. 6, pp. 562–567, 2004.
[196]
H. Onnasch, H. M. Gunn, B. J. Bradshaw, S. L. Benestad, and H. F. Bassett, “Two Irish cases of scrapie resembling Nor98,” Veterinary Record, vol. 155, no. 20, pp. 636–637, 2004.
[197]
C. M. Loiacono, B. V. Thomsen, S. M. Hall et al., “Nor98 scrapie identified in the United States,” Journal of Veterinary Diagnostic Investigation, vol. 21, no. 4, pp. 454–463, 2009.
[198]
M. Klingeborn, L. Wik, M. Simonsson, L. H. M. Renstr？m, T. Ottinger, and T. Linné, “Characterization of proteinase K-resistant N- and C-terminally truncated PrP in Nor98 atypical scrapie,” Journal of General Virology, vol. 87, no. 6, pp. 1751–1760, 2006.
[199]
D. R. G？tte, S. L. Benestad, H. Laude, A. Zurbriggen, A. Oevermann, and T. Seuberlich, “Atypical scrapie isolates involve a uniform prion species with a complex molecular signature,” PLoS ONE, vol. 6, no. 11, Article ID e27510, 2011.
[200]
L. Pirisinu, R. Nonno, E. Esposito, et al., “Small ruminant nor98 prions share biochemical features with human Gerstmann-Str？ussler-Scheinker disease and variably protease-sensitive prionopathy,” PLoS ONE, vol. 8, no. 6, Article ID e66405, 2013.
[201]
A.-G. Biacabe, J.-L. Laplanche, S. Ryder, and T. Baron, “Distinct molecular phenotypes in bovine prion diseases,” EMBO Reports, vol. 5, no. 1, pp. 110–114, 2004.
[202]
J. G. Jacobs, J. P. M. Langeveld, A.-G. Biacabe et al., “Molecular discrimination of atypical bovine spongiform encephalopathy strains from a geographical region spanning a wide area in Europe,” Journal of Clinical Microbiology, vol. 45, no. 6, pp. 1821–1829, 2007.
[203]
M. Bruce, A. Chree, I. McConnell, J. Foster, G. Pearson, and H. Fraser, “Transmission of bovine spongiform encephalopathy and scrapie to mice: strain variation and the species barrier,” Philosophical Transactions of the Royal Society of London B, vol. 343, no. 1306, pp. 405–411, 1994.
[204]
A. Buschmann, A. Gretzschel, A.-G. Biacabe et al., “Atypical BSE in Germany—proof of transmissibility and biochemical characterization,” Veterinary Microbiology, vol. 117, no. 2–4, pp. 103–116, 2006.
[205]
R. Capobianco, C. Casalone, S. Suardi et al., “Conversion of the BASE prion strain into the BSE strain: the origin of BSE?” PLoS Pathogens, vol. 3, no. 3, article e31, 2007.
[206]
T. Baron, J. Vulin, A.-G. Biacabe et al., “Emergence of classical BSE strain properties during serial passages of H-BSE in wild-type mice,” PLoS ONE, vol. 6, no. 1, Article ID e15839, 2011.
[207]
A.-G. Biacabe, J. G. Jacobs, A. Bencsik, J. P. M. Langeveld, and T. G. M. Baron, “H-type bovine spongiform encephalopathy: complex molecular features and similarities with human prion diseases,” Prion, vol. 1, no. 1, pp. 61–68, 2007.
[208]
J. A. Richt and S. M. Hall, “BSE case associated with prion protein gene mutation,” PLoS Pathogens, vol. 4, no. 9, Article ID e1000156, 2008.
[209]
K. C. Gough and B. C. Maddison, “Prion transmission: prion excretion and occurrence in the environment,” Prion, vol. 4, no. 4, pp. 275–282, 2010.
[210]
R. F. Marsh, A. E. Kincaid, R. A. Bessen, and J. C. Bartz, “Interspecies transmission of chronic wasting disease prions to squirrel monkeys (Saimiri sciureus),” Journal of Virology, vol. 79, no. 21, pp. 13794–13796, 2005.
[211]
E. S. Williams and M. W. Miller, “Transmissible spongiform encephalopathies in non-domestic animals: origin, transmission and risk factors,” Revue Scientifique et Technique, vol. 22, no. 1, pp. 145–156, 2003.
[212]
M. W. Miller and E. S. Williams, “Horizontal prion transmission in mule deer,” Nature, vol. 425, no. 6953, pp. 35–36, 2003.
[213]
R. C. Angers, H.-E. Kang, D. Napier et al., “Prion strain mutation determined by prion protein conformational compatibility and primary structure,” Science, vol. 328, no. 5982, pp. 1154–1158, 2010.
[214]
C. J. Johnson, A. Herbst, C. Duque-Velasquez et al., “Prion protein polymorphisms affect chronic wasting disease progression,” PLoS ONE, vol. 6, no. 3, Article ID e17450, 2011.
[215]
B. Caughey and P. T. Lansbury Jr., “Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders,” Annual Review of Neuroscience, vol. 26, pp. 267–298, 2003.
[216]
C. Haass and D. J. Selkoe, “Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide,” Nature Reviews Molecular Cell Biology, vol. 8, no. 2, pp. 101–112, 2007.
[217]
S. Brandner, S. Isenmann, A. Raeber et al., “Normal host prion protein necessary for scrapie-induced neurotoxicity,” Nature, vol. 379, no. 6563, pp. 339–343, 1996.
[218]
B. Chesebro, M. Trifilo, R. Race et al., “Anchorless prion protein results in infectious amyloid disease without clinical scrapie,” Science, vol. 308, no. 5727, pp. 1435–1439, 2005.
[219]
B. Chesebro, B. Race, K. Meade-White et al., “Fatal transmissible amyloid encephalopathy: a new type of prion disease associated with lack of prion protein membrane anchoring,” PLoS Pathogens, vol. 6, no. 3, Article ID e1000800, 2010.
[220]
B. Race, K. Meade-White, M. B. A. Oldstone, R. Race, and B. Chesebro, “Detection of prion infectivity in fat tissues of scrapie-infected mice,” PLoS Pathogens, vol. 4, no. 12, Article ID e1000232, 2008.
[221]
M. J. Trifilo, T. Yajima, Y. Gu et al., “Prion-induced amyloid heart disease with high blood infectivity in transgenic mice,” Science, vol. 313, no. 5783, pp. 94–97, 2006.
[222]
B. Caughey, G. S. Baron, B. Chesebro, and M. Jeffrey, “Getting a grip on prions: oligomers, amyloids, and pathological membrane interactions,” Annual Review of Biochemistry, vol. 78, pp. 177–204, 2009.
[223]
M. Jeffrey, G. McGovern, S. Sisó, and L. González, “Cellular and sub-cellular pathology of animal prion diseases: relationship between morphological changes, accumulation of abnormal prion protein and clinical disease,” Acta Neuropathologica, vol. 121, no. 1, pp. 113–134, 2011.
[224]
M. Jeffrey, “Review: membrane-associated misfolded protein propagation in natural Transmissible Spongiform Encephalopathies (TSEs), synthetic prion diseases and Alzheimer's disease,” Neuropathology and Applied Neurobiology, vol. 39, no. 3, pp. 196–216, 2013.
[225]
M. Jeffrey, G. McGovern, E. V. Chambers et al., “Mechanism of PrP-amyloid formation in mice without transmissible spongiform encephalopathy,” Brain Pathology, vol. 22, no. 1, pp. 58–66, 2012.
[226]
P. Parchi, S. Capellari, and P. Gambetti, “Intracerebral distribution of the abnormal isoform of the prion protein in sporadic Creutzfeldt-Jakob disease and fatal insomnia,” Microscopy Research and Technique, vol. 50, no. 1, pp. 16–25, 2000.
[227]
P. Parchi, R. B. Petersen, S. G. Chen, et al., “Molecular pathology of fatal familial insomnia,” Brain Pathology, vol. 8, no. 3, pp. 539–548, 1998.
[228]
P. Parchi, R. Castellani, P. Cortelli et al., “Regional distribution of protease-resistant prion protein in fatal familial insomnia,” Annals of Neurology, vol. 38, no. 1, pp. 21–29, 1995.
[229]
C. L. Masters and E. P. Richardson Jr., “Subacute spongiform encephalopathy (Creutzfeldt-Jakob disease). The nature and progression of spongiform change,” Brain, vol. 101, no. 2, pp. 333–344, 1978.
[230]
H. Bueler, M. Fischer, Y. Lang et al., “Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein,” Nature, vol. 356, no. 6370, pp. 577–582, 1992.
[231]
G. R. Mallucci, S. Ratté, E. A. Asante et al., “Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration,” EMBO Journal, vol. 21, no. 3, pp. 202–210, 2002.
[232]
R. Chiesa, P. Piccardo, E. Quaglio et al., “Molecular distinction between pathogenic and infectious properties of the prion protein,” Journal of Virology, vol. 77, no. 13, pp. 7611–7622, 2003.
[233]
A. F. Hill, S. Joiner, J. Linehan, M. Desbruslais, P. L. Lantos, and J. Collinge, “Species-barrier-independent prion replication in apparently resistant species,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 18, pp. 10248–10253, 2000.
[234]
R. Race, A. Raines, G. J. Raymond, B. Caughey, and B. Chesebro, “Long-term subclinical carrier state precedes scrapie replication and adaptation in a resistant species: analogies to bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease in humans,” Journal of Virology, vol. 75, no. 21, pp. 10106–10112, 2001.
[235]
M. K. Sandberg, H. Al-Doujaily, B. Sharps, A. R. Clarke, and J. Collinge, “Prion propagation and toxicity in vivo occur in two distinct mechanistic phases,” Nature, vol. 470, no. 7335, pp. 540–542, 2011.
[236]
A. Aguzzi and J. Falsig, “Prion propagation, toxicity and degradation,” Nature Neuroscience, vol. 15, no. 7, pp. 936–939, 2012.
[237]
B. Caughey and G. S. Baron, “Prions and their partners in crime,” Nature, vol. 443, no. 7113, pp. 803–810, 2006.
[238]
I. H. Solomon, J. A. Schepker, and D. A. Harris, “Prion neurotoxicity: insights from prion protein mutants,” Current Issues in Molecular Biology, vol. 12, no. 2, pp. 51–62, 2010.
[239]
I. H. Solomon, J. E. Huettner, and D. A. Harris, “Neurotoxic mutants of the prion protein induce spontaneous ionic currents in cultured cells,” Journal of Biological Chemistry, vol. 285, no. 34, pp. 26719–26726, 2010.
[240]
M. Jeffrey, G. McGovern, C. M. Goodsir, K. L. Brown, and M. E. Bruce, “Sites of prion protein accumulation in scrapie-infected mouse spleen revealed by immuno-electron microscopy,” Journal of Pathology, vol. 191, no. 3, pp. 323–332, 2000.
[241]
C. Cunningham, R. Deacon, H. Wells et al., “Synaptic changes characterize early behavioural signs in the ME7 model of murine prion disease,” European Journal of Neuroscience, vol. 17, no. 10, pp. 2147–2155, 2003.
[242]
R. Chiesa, P. Piccardo, S. Dossena et al., “Bax deletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 1, pp. 238–243, 2005.
[243]
S. W. Scheff, D. A. Price, F. A. Schmitt, and E. J. Mufson, “Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment,” Neurobiology of Aging, vol. 27, no. 10, pp. 1372–1384, 2006.
[244]
G. Mallucci, A. Dickinson, J. Linehan, P.-C. Kl？hn, S. Brandner, and J. Collinge, “Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis,” Science, vol. 302, no. 5646, pp. 871–874, 2003.
[245]
J. A. Moreno, H. Radford, D. Peretti, et al., “Sustained translational repression by eIF2α-P mediates prion neurodegeneration,” Nature, vol. 485, no. 7399, pp. 507–511, 2012.
[246]
V. Beringue, M. Demoy, C. I. Lasmézas, et al., “Role of spleen macrophages in the clearance of scrapie agent early in pathogenesis,” Journal of Pathology, vol. 190, no. 4, pp. 495–502, 2000.
[247]
K. M. Luhr, E. K. Nordstr？m, P. L？w, H.-G. Ljunggren, A. Taraboulos, and K. Kristensson, “Scrapie protein degradation by cysteine proteases in CD11c+ dendritic cells and GT1-1 neuronal cells,” Journal of Virology, vol. 78, no. 9, pp. 4776–4782, 2004.
[248]
C. Cunningham, D. C. Wilcockson, S. Campion, K. Lunnon, and V. H. Perry, “Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration,” Journal of Neuroscience, vol. 25, no. 40, pp. 9275–9284, 2005.
[249]
A. E. Williams, L. J. Lawson, V. H. Perry, and H. Fraser, “Characterization of the microglial response in murine scrapie,” Neuropathology and Applied Neurobiology, vol. 20, no. 1, pp. 47–55, 1994.
[250]
V. H. Perry, C. Cunningham, and D. Boche, “Atypical inflammation in the central nervous system in prion disease,” Current Opinion in Neurology, vol. 15, no. 3, pp. 349–354, 2002.
[251]
V. H. Perry, C. Cunningham, and C. Holmes, “Systemic infections and inflammation affect chronic neurodegeneration,” Nature Reviews Immunology, vol. 7, no. 2, pp. 161–167, 2007.
[252]
C. Holmes, M. El-Okl, A. L. Williams, C. Cunningham, D. Wilcockson, and V. H. Perry, “Systemic infection, interleukin 1β, and cognitive decline in Alzheimer's disease,” Journal of Neurology Neurosurgery and Psychiatry, vol. 74, no. 6, pp. 788–789, 2003.
