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Acta Neuropathologica Communications
Published in: Acta Neuropathologica Communications 1/2015

Open Access 01-12-2015 | Research

Two alternative pathways for generating transmissible prion disease de novo

Authors: Natallia Makarava, Regina Savtchenko, Ilia V. Baskakov

Published in: Acta Neuropathologica Communications | Issue 1/2015

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Abstract

Introduction

Previous studies established that prion disease with unique strain-specific phenotypes could be induced by in vitro-formed recombinant PrP (rPrP) fibrils with structures different from that of authentic prions, or PrPSc. To explain the etiology of prion diseases, new mechanism proposed that in animals the transition from rPrP fibrils to PrPSc consists of two main steps: the first involves fibril-induced formation of atypical PrPres, a self-replicating but clinically silent state, and the second consists of atypical PrPres-dependent formation of PrPSc via rare deformed templating events.

Results

In the current study, atypical PrPres with characteristics similar to those of brain-derived atypical PrPres was generated in vitro. Upon inoculation into animals, in vitro-generated atypical PrPres gave rise to PrPSc and prion disease with a phenotype similar to those induced by rPrP fibrils. Significant differences in the sialylation pattern between atypical PrPres and PrPSc suggested that only a small sub-fraction of the PrPC that is acceptable as a substrate for PrPSc could be also recruited by atypical PrPres. This can explain why atypical PrPres replicates slower than PrPSc and why PrPSc outcompetes atypical PrPres.

Conclusions

This study illustrates that transmissible prion diseases with very similar disease phenotypes could be produced via two alternative procedures: direct inoculation of recombinant PrP amyloid fibrils or in vitro-produced atypical PrPres. Moreover, this work showed that preparations of atypical PrPres free of PrPSc can give rise to transmissible diseases in wild type animals and that atypical PrPres generated in vitro is an adequate model for brain-derived atypical PrPres.
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Literature
1.
2.
Cohen FE, Prusiner SB. Pathologic conformations of prion proteins. Annu Rev Biochem. 1998;67:793–819.CrossRefPubMed
3.
4.
Zhang Z, Zhang Y, Wang F, Wang X, Xu Y, Yang H, et al. De novo generation of infectious prions with bacterially expressed recombinant prion protein. Faseb J. 2013;27:4768–75.PubMedCentralCrossRefPubMed
5.
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 Acad Natl Sci U S A. 2012;109:8546–51.CrossRef
6.
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. ProcAcadNatlSciUSA. 2012;109:E1938–46.CrossRef
7.
Legname G, Baskakov IV, Nguyen HOB, Riesner D, Cohen FE, DeArmond SJ, et al. Synthetic mammalian prions. Science. 2004;305:673–6.CrossRefPubMed
8.
Colby DW, Giles K, Legname G, Wille H, Baskakov IV, DeArmond SJ, et al. Design and construction of diverse mammalian prion strains. ProcAcadNatlSciUSA. 2009;106:20417–22.CrossRef
9.
Colby DW, Wain R, Baskakov IV, Legname G, Palmer CG, Nguyen HO, et al. Protease-sensitive synthetic prions. PLoS Pathogen. 2010;6:e1000736.CrossRef
10.
Makarava N, Kovacs GG, Bocharova OV, Savtchenko R, Alexeeva I, Budka H, et al. Recombinant prion protein induces a new transmissible prion disease in wild type animals. Acta Neuropathol. 2010;119:177–87.PubMedCentralCrossRefPubMed
11.
Makarava N, Kovacs GG, Savtchenko R, Alexeeva I, Ostapchenko VG, Budka H, et al. A New Mechanism for Transmissible Prion Diseases. J Neurosci. 2012;32:7345–55.PubMedCentralCrossRefPubMed
12.
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 Pathogen. 2011;7:e1002419.CrossRef
13.
Wille H, Bian W, McDonald M, Kendall A, Colby DW, Bloch L, et al. Natural and synthetic prion structure from X-ray fiber diffraction. ProcAcadNatlSciUSA. 2009;106:16990–5.CrossRef
14.
Ostapchenko VG, Sawaya MR, Makarava N, Savtchenko R, Nilsson KP, Eisenberg D, et al. Two amyloid states of the prion protein display significantly different folding patterns. J Mol Biol. 2010;400:908–21.PubMedCentralCrossRefPubMed
15.
16.
17.
Gonzalez-Montalban N, Lee YJ, Makarava N, Savtchenko R, Baskakov IV. Changes in prion replication environemnt cause prion strain mutation. Faseb J. 2013;27:3702–10.PubMedCentralCrossRefPubMed
18.
Ghaemmaghami S, Watts JC, Nquyen HO, Hayashi S, DeArmond SJ, Prusiner SB. Conformational transformation and selection of synthetic prion strains. J Mol Biol. 2011;413:527–42.PubMedCentralCrossRefPubMed
19.
Ghaemmaghami S, Colby DW, Nquyen HO, Hayashi S, Oehler A, DeArmond S, et al. Convergent Replication of Mouse Synthetic Prion Strains. Am J Pathol. 2013;182:866–74.PubMedCentralCrossRefPubMed
20.
Berry DB, Lu D, Geva M, Watts JC, Bhardwaj S, Oehler A, et al. Drug resistance confounding prion therapeutics. Proc Acad Natl Sci USA. 2013;110:E4160–9.CrossRef
21.
Mahal SP, Jablonski J, Suponitsky-Kroyter I, Orlschlegel AM, Herva ME, Oldstone M, et al. Propagating of RML prions in mice expressing PrP devoid of GPI anchor leads to formation of a novel, stable prion strain. PLOS Pathog. 2012;8:e1002746.PubMedCentralCrossRefPubMed
22.
Cancellotti E, Mahal SP, Somerville R, Diack A, Brown D, Piccardo P, et al. Post-translational changes to PrP alter transmissible spongiform encephalopathy strain properties. EMBO J. 2013;32:756–69.PubMedCentralCrossRefPubMed
23.
24.
Wan W, Bian W, McDonald M, Kijac A, Wemmer DE, Stubbs G. Heterogeneous Seeding of a Prion Structure by a Generic Amyloid Form of the Fungal Prion-forming Domain HET-s(218–289). J Biol Chem. 2013;288:29604–12.PubMedCentralCrossRefPubMed
25.
Kovacs GG, Makarava N, Savtchenko R, Baskakov IV. Atypical and classical forms of the disease-associated state of the prion protein exhibit distinct neuronal tropism, deposition patterns, and lesion profiles. Am J Pathol. 2013;183:1539–47.PubMedCentralCrossRefPubMed
26.
Makarava N, Savtchenko R, Baskakov IV. Selective amplification of classical and atypical prions using modified protein misfolding cyclic amplification. J Biol Chem. 2013;288:33–41.PubMedCentralCrossRefPubMed
27.
Klimova N, Makarava N, Baskakov IV (2015) The diversity and relationship of prion protein self-replicating states. Virus Research in press.
28.
Bocharova OV, Breydo L, Parfenov AS, Salnikov VV, Baskakov IV. In vitro conversion of full length mammalian prion protein produces amyloid form with physical property of PrPSc. JMolBiol. 2005;346:645–59.
29.
Bocharova OV, Makarava N, Breydo L, Anderson M, Salnikov VV, Baskakov IV. Annealing PrP amyloid firbils at high temperature results in extension of a proteinase K resistant core. J Biol Chem. 2006;281:2373–9.CrossRefPubMed
30.
Makarava N, Kovacs GG, Savtchenko R, Alexeeva I, Budka H, Rohwer RG, et al. Stabilization of a prion strain of synthetic origin requires multiple serial passages. J Biol Chem. 2012;287:30205–14.PubMedCentralCrossRefPubMed
31.
Gonzalez-Montalban N, Makarava N, Ostapchenko VG, Savtchenko R, Alexeeva I, Rohwer RG, et al. Highly Efficient Protein Misfolding Cyclic Amplification. PLoS Pathogen. 2011;7:e1001277.CrossRef
32.
Gonzalez-Montalban N, Makarava N, Savtchenko R, Baskakov IV. Relationship between Conformational Stability and Amplification Efficiency of Prions. Biochemistry. 2011;50:7933–40.PubMedCentralCrossRefPubMed
33.
Piro JR, Wang F, Walsh DJ, Rees JR, Ma J, Supattapone S. Seeding Specificity and Ultrastructural Characteristics of Infectious Recombinant Prions. Biochemistry. 2011;50:7111–6.PubMedCentralCrossRefPubMed
34.
Makarava N, Savtchenko R, Alexeeva I, Rohwer RG, Baskakov IV. Fast and ultrasensitive method for quantitating prion infectivity titer. Nature Commun. 2012;3:741.CrossRef
35.
Katorcha E, Makarava N, Savtchenko R, D’Azzo A, Baskakov IV. Sialylation of prion protein controls the rate of prion amplification, the cross-species barrier, the ratio of PrPSc glycoform and prion infectivity. PLOS Pathog. 2014;10:e1004366.PubMedCentralCrossRefPubMed
36.
Stahl N, Baldwin MA, Hecker R, Pan KM, Burlingame AL, Prusiner SB. Glycosylinositol phospholipid anchors of the scrapie and cellular prion proteins contain sialic acid. Biochemistry. 1992;31:5043–53.CrossRefPubMed
37.
Nishina K, Deleault NR, Mahal S, Baskakov I, Luhrs T, Riek R, et al. The Stoichiometry of Host PrPC Glycoforms Modulates the Efficiency of PrPSc formation in vitro. Biochemistry. 2006;45:14129–39.CrossRefPubMed
38.
Zou WQ, Capellari S, Parchi P, Sy MS, Gambetti P, Chen SG. Identification of Novel Proteinase K-resistant C-terminal Fragments of PrP in Creutzfeldt-Jakob Disease. J Biol Chem. 2003;278:40429–36.CrossRefPubMed
39.
Satoh K, Muramoto T, Tanaka T, Kitamoto N, Ironside JW, Nagashima K, et al. Association of an 11–12 kDa protease-resistant prion protein fragment with subtypes of dura graft-associated Creutzfeldt-Jakob disease and other prion diseases. J Gen Virol. 2003;84:2885–93.CrossRefPubMed
40.
Lawson VA, Priola SA, Meade-White K, Lawton M, Chesebro B. Flexible N-terminal region of prion protein influences conformation of protease resistant prion protein isoforms associated with cross-species scrapie infection in vivo and in vitro. J Biol Chem. 2004;279:13689–95.CrossRefPubMed
41.
Biacabe AG, Jacobs JG, Bencsik A, Langeveld JP, Baron TG. H-type bovine spongiform encephalopathy: complex molecular features and similarities with human prion diseases. Prion. 2007;1:61–8.PubMedCentralCrossRefPubMed
42.
Baron T, Bencsik A, Vulin J, Biacabe AG, Morignat E, Verchere J, 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 Pathog. 2008;4:e1000137.PubMedCentralCrossRefPubMed
43.
44.
Giles K, Berry DB, Condello C, Hawley RC, Gallardo-Godoy A, Bryant C, et al. (2015) Different 2-aminothiazole therapeutics produce distinct patterns of scrapie prion neuropathology in mouse brains. J Pharmacol Exp Ther in press.
45.
46.
Soto C, Estrada L, Castilla J. Amyloids, prions and the inherent infectious nature of misfolded protein aggregates. Trends BiochemSci. 2006;31:150–5.CrossRef
47.
Walker LC, Jucker M. Neurodegenerative Diseases: Expanding the Prion Concept. Annu Rev Neurosci. 2015;38:87–103.CrossRefPubMed
Metadata
Title
Two alternative pathways for generating transmissible prion disease de novo
Authors
Natallia Makarava
Regina Savtchenko
Ilia V. Baskakov
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Acta Neuropathologica Communications / Issue 1/2015
Electronic ISSN: 2051-5960
DOI
https://doi.org/10.1186/s40478-015-0248-5

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