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Molecular Mechanisms Encoding Strains of Prions and Prion-Like Misfolded Proteins

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Prions and Diseases

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Abstract

Yeast, fungal, and mammalian prions determine heritable as well as infectious traits (Shorter J, Lindquist S. Nat Rev Genet, 6:435–450, 2005; Wickner RB, et al. FEMS Yeast Res, 10:980–991, 2010; Prusiner SB, Scott MR, DeArmond SJ, Carlson G. Transmission and replication of prions. In: Prusiner SB (ed). Prion biology and diseases. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 187–242, 2004a). In mammals, prions cause a group of fatal and rapidly progressive neurodegenerative diseases (Prusiner SB, Scott MR, DeArmond SJ, Carlson G. Transmission and replication of prions. In: Prusiner SB (ed). Prion biology and diseases. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 187–242, 2004a), originally described as transmissible spongiform encephalopathies (TSEs) (Gajdusek DC, Gibbs CJ Jr, Alpers M. Nature, 209:794–796, 1966). Variations in prions, which cause different disease phenotypes, are referred to as strains. Mammalian prion strains are differentiated by a number of characteristics, including disease incubation time, clinical symptoms, prion dose–response, proteolytic sensitivity, conformational attributes of pathogenic prion protein (PrPSc), targeted brain anatomical areas, or by Western blot patterns of glycosylated or deglycosylated PrPSc (Puoti G, et al. Lancet Neurol, 11:618–628, 2012; Prusiner SB, et al. Some strategies and methods for the study of prions. In: Prusiner SB (ed). Prion biology and diseases. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 857–920, 2004b; Safar J, et al. Nat Med, 4:1157–1165, 1998a). Remarkable progress in the past decade has produced many lines of evidence arguing that extraordinary phenotypic diversity of human prion diseases arises from structurally distinct prion strains that target, at different progression speeds, variable brain structures and cells (Kim C, et al. Nat Commun, 9, 2018; Safar JG, et al. PLoS Pathog, 11:e1004832, 2015a). This paradigm is supported now with biochemical, genetic, and animal studies, by the recent successful generation of a new synthetic strain of human prions, and by considerable progress in high-resolution structural studies of prions (Kim C, et al. Nat Commun, 9, 2018; Safar JG, et al. PLoS Pathog, 11:e1004832, 2015a). The recent findings of distinct prion-like conformers of amyloid beta (Cohen M, et al. Prion, 9:S76–S77, 2015a (Taylor & Francis Inc., Philadelphia)) and misfolded tau protein expand this concept to Alzheimer’s disease (AD) (Kim C, et al. Sci Transl Med, 14:eabg0253, 2022) and monogenic frontotemporal lobar degeneration (FTLD)-MAPT P301L (Daude N, et al. Acta Neuropathol, 139:1045–1070, 2020) and suggest that distinct strains of misfolded proteins drive the phenotypes and progression rates in a number of neurodegenerative diseases (Kang SG, Eskandari-Sedighi G, Hromadkova L, Safar JG, Westaway D. Front Neurol, 1394, 2020a). The emerging concept pointing to structurally distinct prion-like strains of misfolded proteins as the critical differentiating factor in disease development emphasizes the need for personalized structure- and strain-specific therapeutic approaches.

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Abbreviations

AD :

Alzheimer’s disease

ALS:

amyotrophic lateral sclerosis

CDI :

conformation-dependent immunoassay

CHO:

N-linked complex glycosylation chains

CJD :

Creutzfeldt-Jakob disease

CPA:

cell panel assay

ER:

endoplasmic reticulum

FFI :

fatal familial insomnia

FTLD:

frontotemporal lobar degeneration

GSS :

Gerstmann–Sträussler–Scheinker syndrome

PMCA :

protein misfolding cyclic amplification

PrP :

prion protein

PrPC:

normal or cellular prion protein

PrPSc:

pathogenic prion protein

PRNP :

prion protein gene

rPrPSc :

protease-resistant conformers of pathogenic prion protein (PrP 27-30)

sPrPSc :

protease-sensitive conformers of pathogenic prion protein

sCJD :

sporadic Creutzfeldt–Jakob disease

SFI :

sporadic fatal insomnia

SSCA:

standard scrapie cell assay

TSE :

transmissible spongiform encephalopathy

VPSPr :

variable protease-sensitive prionopathy

WB:

Western blot

References

  • Anfinsen CB. Principles that govern the folding of protein chains. Science. 1973;181:223–30.

    Article  CAS  Google Scholar 

  • Asher DM, et al. Risk of transmissibility from neurodegenerative disease-associated proteins: experimental knowns and unknowns. J Neuropathol Exp Neurol. 2020;79:1141–6.

    Article  CAS  Google Scholar 

  • Barria MA, Mukherjee A, Gonzalez-Romero D, Morales R, Soto C. De novo generation of infectious prions in vitro produces a new disease phenotype. PLoS Pathog. 2009;5:e1000421.

    Article  Google Scholar 

  • Bennett MJ, Schlunegger MP, Eisenberg D. 3D domain swapping: a mechanism for oligomer assembly. Protein Sci. 1995;4:2455–68.

    Article  CAS  Google Scholar 

  • Bergstrom AL, et al. Short-term study of the uptake of PrP(Sc) by the Peyer’s patches in hamsters after oral exposure to scrapie. J Comp Pathol. 2006;134:126–33.

    Article  Google Scholar 

  • Bessen RA, Marsh RF. Biochemical and physical properties of the prion protein from two strains of the transmissible mink encephalopathy agent. J Virol. 1992;66:2096–101.

    Article  CAS  Google Scholar 

  • Bessen RA, Marsh RF. Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J Virol. 1994;68:7859–68.

    Article  CAS  Google Scholar 

  • Bishop MT, Will RG, Manson JC. Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties. Proc Natl Acad Sci U S A. 2010;107:12005–10.

    Article  CAS  Google Scholar 

  • Borchelt DR, Scott M, Taraboulos A, Stahl N, Prusiner SB. Scrapie and cellular prion proteins differ in their kinetics of synthesis and topology in cultured cells. J Cell Biol. 1990;110:743–52.

    Article  CAS  Google Scholar 

  • Braak H, Del Tredici K. Evolutional aspects of Alzheimer’s disease pathogenesis. J Alzheimers Dis. 2013;33(Suppl 1):S155–61.

    Google Scholar 

  • Brown P, et al. Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol. 1994;35:513–29.

    Article  CAS  Google Scholar 

  • Browning SR, et al. Transmission of prions from mule deer and elk with chronic wasting disease to transgenic mice expressing cervid PrP. J Virol. 2004;78:13345–50.

    Article  CAS  Google Scholar 

  • Bruce ME, Dickinson AG. Biological stability of different classes of scrapie agent. In: Prusiner SB, Hadlow WJ, editors. Slow transmissible diseases of the nervous system, vol. 2. New York: Academic; 1979. p. 71–86.

    Google Scholar 

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

    Article  Google Scholar 

  • Büeler H, et al. Mice devoid of PrP are resistant to scrapie. Cell. 1993;73:1339–47.

    Article  Google Scholar 

  • Cali I, et al. The co-existence of PrPSc type 1 and 2 in Sporadic Creutzfeldt-Jakob Disease affects the phenotype and PrPSc conformation. J Neuropathol Exp Neurol. 2009a;68:553. (Lippincott Williams & Wilkins, Philadelphia)

    Google Scholar 

  • Cali I, 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. 2009b;132:2643–58.

    Article  Google Scholar 

  • Carlson GA, et al. Prion isolate specified allotypic interactions between the cellular and scrapie prion proteins in congenic and transgenic mice. Proc Natl Acad Sci U S A. 1994a;91:5690–4.

    Article  CAS  Google Scholar 

  • Carlson GA, DeArmond SJ, Torchia M, Westaway D, Prusiner SB. Genetics of prion diseases and prion diversity in mice. Philos Trans R Soc Lond Ser B Biol Sci. 1994b;343:363–9.

    Article  CAS  Google Scholar 

  • Castilla J, Saa P, Hetz C, Soto C. In vitro generation of infectious scrapie prions. Cell. 2005;121:195–206.

    Article  CAS  Google Scholar 

  • Caughey B, Raymond GJ. The scrapie-associated form of PrP is made from a cell surface precursor that is both protease- and phospholipase-sensitive. J Biol Chem. 1991;266:18217–23.

    Article  CAS  Google Scholar 

  • Caughey B, Raymond GJ, Bessen RA. Strain-dependent differences in b-sheet conformations of abnormal prion protein. J Biol Chem. 1998;273:32230–5.

    Article  CAS  Google Scholar 

  • Caughey B, Baron GS, Chesebro B, Jeffrey M. Getting a grip on prions: oligomers, amyloids, and pathological membrane interactions. Annu Rev Biochem. 2009;78:177–204.

    Article  CAS  Google Scholar 

  • Chandler RL. Encephalopathy in mice produced by inoculation with scrapie brain material. Lancet. 1961;277:1378–9.

    Article  Google Scholar 

  • Chitravas N, et al. Treatable neurological disorders misdiagnosed as Creutzfeldt-Jakob disease. Ann Neurol. 2011;70:437–44.

    Article  Google Scholar 

  • Choi YP, Peden AH, Groner A, Ironside JW, Head MW. Distinct stability states of disease-associated human prion protein identified by conformation-dependent immunoassay. J Virol. 2011;84:12030–8.

    Article  Google Scholar 

  • Choi JK, et al. Amyloid fibrils from the N-terminal prion protein fragment are infectious. Proc Natl Acad Sci U S A. 2016;113:13851–6.

    Article  CAS  Google Scholar 

  • Cobb NJ, Surewicz WK. Prion diseases and their biochemical mechanisms. Biochemistry. 2009;48:2574–85.

    Article  CAS  Google Scholar 

  • Cohen FE, Prusiner SB. Pathologic conformations of prion proteins. Annu Rev Biochem. 1998;67:793–819.

    Article  CAS  Google Scholar 

  • Cohen M, et al. Distinct strains of A beta prions implicated in rapidly progressive Alzheimer disease. Prion. 2015a;9:S76–7. (Taylor & Francis Inc., Philadelphia)

    Google Scholar 

  • Cohen ML, et al. Rapidly progressive Alzheimer’s disease features distinct structures of amyloid-beta. Brain. 2015b;138:1009–22.

    Article  Google Scholar 

  • Colby DW, et al. Protease-sensitive synthetic prions. PLoS Pathog. 2010;6:e1000736.

    Article  Google Scholar 

  • Collinge J, Clarke AR. A general model of prion strains and their pathogenicity. Science. 2007;318:930–6.

    Article  CAS  Google Scholar 

  • 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;383:685–90.

    Article  CAS  Google Scholar 

  • Collinge J, et al. Safety and efficacy of quinacrine in human prion disease (PRION-1 study): a patient-preference trial. Lancet Neurol. 2009;8:334–44.

    Article  CAS  Google Scholar 

  • Cronier S, et al. Detection and characterization of proteinase K-sensitive disease-related prion protein with thermolysin. Biochem J. 2008;416:297–305.

    Article  CAS  Google Scholar 

  • Daude N, et al. Diverse, evolving conformer populations drive distinct phenotypes in frontotemporal lobar degeneration caused by the same MAPT-P301L mutation. Acta Neuropathol. 2020;139:1045–70.

    Article  CAS  Google Scholar 

  • DeArmond SJ, et al. Selective neuronal targeting in prion disease. Neuron. 1997;19:1337–48.

    Article  CAS  Google Scholar 

  • Deleault NR, et al. Protease-resistant prion protein amplification reconstituted with partially purified substrates and synthetic polyanions. J Biol Chem. 2005;280:26873–9.

    Article  CAS  Google Scholar 

  • Deleault NR, Harris BT, Rees JR, Supattapone S. Formation of native prions from minimal components in vitro. Proc Natl Acad Sci U S A. 2007;104:9741–6.

    Article  CAS  Google Scholar 

  • Deleault NR, Kascsak R, Geoghegan JC, Supattapone S. Species-dependent differences in cofactor utilization for formation of the protease-resistant prion protein in vitro. Biochemistry. 2010.

    Google Scholar 

  • Deleault NR, et al. Isolation of phosphatidylethanolamine as a solitary cofactor for prion formation in the absence of nucleic acids. Proc Natl Acad Sci U S A. 2012;109:8546–51.

    Article  CAS  Google Scholar 

  • Dickinson AG, Fraser HG. Scrapie: pathogenesis in inbred mice: an assessment of host control and response involving many strains of agent. In: ter Meulen V, Katz M, editors. Slow virus infections of the central nervous system. New York: Springer; 1977. p. 3–14.

    Chapter  Google Scholar 

  • Dickinson AG, Outram GW. Genetic aspects of unconventional virus infections: the basis of the virino hypothesis. In: Bock G, Marsh J, editors. Novel infectious agents and the central nervous system. Ciba foundation symposium 135. Chichester: Wiley; 1988. p. 63–83.

    Google Scholar 

  • Dickinson AG, Fraser H, Meikle VMH, Outram GW. Competition between different scrapie agents in mice. Nat New Biol. 1972;237:244–5.

    Article  CAS  Google Scholar 

  • Drummond E, et al. Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer’s disease. Acta Neuropathol. 2017;133:933–54.

    Article  CAS  Google Scholar 

  • Duque Velásquez C, et al. Chronic wasting disease (CWD) prion strains evolve via adaptive diversification of conformers in hosts expressing prion protein polymorphisms. J Biol Chem. 2020;295:4985–5001.

    Article  Google Scholar 

  • Endo T, Groth D, Prusiner SB, Kobata A. Diversity of oligosaccharide structures linked to asparagines of the scrapie prion protein. Biochemistry. 1989;28:8380–8.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Gajdusek DC, Gibbs CJ Jr, Alpers M. Experimental transmission of a kuru-like syndrome to chimpanzees. Nature. 1966;209:794–6.

    Article  CAS  Google Scholar 

  • Gallardo G, Holtzman DM. Amyloid-β and Tau at the crossroads of Alzheimer’s disease. Adv Exp Med Biol. 2019;1184:187–203.

    Article  CAS  Google Scholar 

  • Gambetti P, Kong Q, Zou W, Parchi P, Chen SG. Sporadic and familial CJD: classification and characterisation. Br Med Bull. 2003;66:213–39.

    Article  CAS  Google Scholar 

  • Geoghegan JC, et al. Selective incorporation of polyanionic molecules into hamster prions. J Biol Chem. 2007;282:36341–53.

    Article  CAS  Google Scholar 

  • Geoghegan JC, Miller MB, Kwak AH, Harris BT, Supattapone S. Trans-dominant inhibition of prion propagation in vitro is not mediated by an accessory cofactor. PLoS Pathog. 2009;5:e1000535.

    Article  Google Scholar 

  • Ghaemmaghami S, et al. Cell division modulates prion accumulation in cultured cells. Proc Natl Acad Sci U S A. 2007;104:17971–6.

    Article  CAS  Google Scholar 

  • Gibbs CJ Jr, et al. Creutzfeldt-Jakob disease (spongiform encephalopathy): transmission to the chimpanzee. Science. 1968;161:388–9.

    Article  Google Scholar 

  • Giles K, et al. Human prion strain selection in transgenic mice. Ann Neurol. 2010;68:151–61.

    Article  CAS  Google Scholar 

  • Haldiman T, et al. Co-existence of distinct prion types enables conformational evolution of human PrPSc by competitive selection. J Biol Chem. 2013;288:29846–61.

    Article  CAS  Google Scholar 

  • Head MW, et al. Prion protein heterogeneity in sporadic but not variant Creutzfeldt-Jakob disease: UK cases 1991–2002. Ann Neurol. 2004;55:851–9.

    Article  CAS  Google Scholar 

  • Hill AF, et al. The same prion strain causes vCJD and BSE. Nature. 1997;389:448–50.

    Article  CAS  Google Scholar 

  • Jones EM, Surewicz WK. Fibril conformation as the basis of species- and strain-dependent seeding specificity of mammalian prion amyloids. Cell. 2005;121:63–72.

    Article  CAS  Google Scholar 

  • Kaneko K, et al. Evidence for protein X binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation. Proc Natl Acad Sci U S A. 1997;94:10069–74.

    Article  CAS  Google Scholar 

  • Kang S-G, Eskandari-Sedighi G, Hromadkova L, Safar JG, Westaway D. Cellular biology of tau diversity and pathogenic conformers. Front Neurol. 2020a;1394

    Google Scholar 

  • Kang SG, Eskandari-Sedighi G, Hromadkova L, Safar JG, Westaway D. Cellular biology of Tau diversity and pathogenic conformers. Front Neurol. 2020b;11:590199.

    Article  Google Scholar 

  • Karapetyan YE, et al. Prion strain discrimination based on rapid in vivo amplification and analysis by the cell panel assay. PLoS One. 2009;4:e5730.

    Article  Google Scholar 

  • Kaufman SK, Del Tredici K, Thomas TL, Braak H, Diamond MI. Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer’s disease and PART. Acta Neuropathol. 2018;136:57–67.

    Article  CAS  Google Scholar 

  • Kellings K, Meyer N, Mirenda C, Prusiner SB, Riesner D. Further analysis of nucleic acids in purified scrapie prion preparations by improved return refocussing gel electrophoresis (RRGE). J Gen Virol. 1992;73:1025–9.

    Article  CAS  Google Scholar 

  • Kellings K, Prusiner SB, Riesner D. Nucleic acids in prion preparations: unspecific background or essential component? Philos Trans R Soc Lond Ser B Biol Sci. 1994;343:425–30.

    Article  CAS  Google Scholar 

  • Kim JI, et al. Mammalian prions generated from bacterially expressed prion protein in the absence of any mammalian cofactors. J Biol Chem. 2010;285:14083–7.

    Article  CAS  Google Scholar 

  • Kim C, et al. Protease-sensitive conformers in broad spectrum of distinct PrPSc structures in sporadic Creutzfeldt-Jakob disease are indicator of progression rate. PLoS Pathog. 2011a;7:e1002242.

    Article  CAS  Google Scholar 

  • Kim C, et al. Protease-sensitive conformers in broad spectrum of distinct PrP structures in Sporadic Creutzfeldt-Jakob disease are indicator of progression rate. PLoS Pathog. 2011b;7:e1002242.

    Article  CAS  Google Scholar 

  • Kim C, et al. Small protease sensitive oligomers of PrP(Sc) in distinct human prions determine conversion rate of PrP(C). PLoS Pathog. 2012;8:e1002835.

    Article  CAS  Google Scholar 

  • Kim C, et al. Artificial strain of human prions created in vitro. Nat Commun. 2018;9

    Google Scholar 

  • Kim C, et al. Distinct populations of highly potent TAU seed conformers in rapidly progressing Alzheimer’s disease. Sci Transl Med. 2022;14:eabg0253.

    Article  CAS  Google Scholar 

  • Kimberlin RH, Walker CA. Pathogenesis of mouse scrapie: effect of route of inoculation on infectivity titres and dose-response curves. J Comp Pathol. 1978;88:39–47.

    Article  CAS  Google Scholar 

  • 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;68:1875–81.

    Article  Google Scholar 

  • King DJ, Safar JG, Legname G, Prusiner SB. Thioaptamer interactions with prion proteins: sequence-specific and non-specific binding sites. J Mol Biol. 2007;369:1001–14.

    Article  CAS  Google Scholar 

  • Kiselar JG, Maleknia SD, Sullivan M, Downard KM, Chance MR. Hydroxyl radical probe of protein surfaces using synchrotron X-ray radiolysis and mass spectrometry. Int J Radiat Biol. 2002;78:101–14.

    Article  CAS  Google Scholar 

  • Kiselar JG, Datt M, Chance MR, Weiss MA. Structural analysis of proinsulin hexamer assembly by hydroxyl radical footprinting and computational modeling. J Biol Chem. 2011;286:43710–6.

    Article  CAS  Google Scholar 

  • Klingeborn M, Race B, Meade-White KD, Chesebro B. Lower specific infectivity of protease-resistant prion protein generated in cell-free reactions. Proc Natl Acad Sci U S A. 2011;108:E1244–53.

    Article  CAS  Google Scholar 

  • Kocisko DA, et al. Cell-free formation of protease-resistant prion protein. Nature. 1994;370:471–4.

    Article  CAS  Google Scholar 

  • Korth C, et al. Abbreviated incubation times for human prions in mice expressing a chimeric mouse—human prion protein transgene. Proc Natl Acad Sci U S A. 2003;100:4784–9.

    Article  CAS  Google Scholar 

  • Kovacs GG, et al. Immunohistochemistry for the prion protein: comparison of different monoclonal antibodies in human prion disease subtypes. Brain Pathol. 2002;12:1–11.

    Article  CAS  Google Scholar 

  • Legname G, et al. Synthetic mammalian prions. Science. 2004;305:673–6.

    Article  CAS  Google Scholar 

  • Legname G, et al. Strain-specified characteristics of mouse synthetic prions. Proc Natl Acad Sci U S A. 2005;102:2168–73.

    Article  CAS  Google Scholar 

  • Legname G, et al. Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes. Proc Natl Acad Sci U S A. 2006;103:19105–10.

    Article  CAS  Google Scholar 

  • Lewis V, et al. Australian sporadic CJD analysis supports endogenous determinants of molecular-clinical profiles. Neurology. 2005;65:113–8.

    Article  CAS  Google Scholar 

  • Li J, Browning S, Mahal SP, Oelschlegel AM, Weissmann C. Darwinian evolution of prions in cell culture. Science. 2010;327:869–72.

    Article  CAS  Google Scholar 

  • Li Q, et al. Structural attributes of mammalian prion infectivity: Insights from studies with synthetic prions. J Biol Chem. 2018;293:18494–503.

    Article  CAS  Google Scholar 

  • Liu H, et al. Distinct conformers of amyloid beta accumulate in the neocortex of patients with rapidly progressive Alzheimer’s disease. J Biol Chem. 2021:101267.

    Google Scholar 

  • Mahal SP, et al. Prion strain discrimination in cell culture: the cell panel assay. Proc Natl Acad Sci U S A. 2007;104:20908–13.

    Article  CAS  Google Scholar 

  • Makarava N, et al. Recombinant prion protein induces a new transmissible prion disease in wild-type animals. Acta Neuropathol. 2010;119:177–87.

    Article  CAS  Google Scholar 

  • Masters CL, Selkoe DJ. Biochemistry of amyloid beta-protein and amyloid deposits in Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2:a006262.

    Article  Google Scholar 

  • Meyer N, et al. Search for a putative scrapie genome in purified prion fractions reveals a paucity of nucleic acids. J Gen Virol. 1991;72:37–49.

    Article  CAS  Google Scholar 

  • Mishra RS, et al. Protease-resistant human prion protein and ferritin are cotransported across Caco-2 epithelial cells: implications for species barrier in prion uptake from the intestine. J Neurosci. 2004;24:11280–90.

    Article  CAS  Google Scholar 

  • Monari L, et al. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism. Proc Natl Acad Sci U S A. 1994;91:2839–42.

    Article  CAS  Google Scholar 

  • Morales R, Abid K, Soto C. The prion strain phenomenon: molecular basis and unprecedented features. Biochim Biophys Acta. 2007;1772:681–91.

    Article  CAS  Google Scholar 

  • Noble GP, et al. A structural and functional comparison between infectious and non-infectious autocatalytic recombinant PrP conformers. PLoS Pathog. 2015;11:e1005017.

    Article  Google Scholar 

  • Paravastu AK, Leapman RD, Yau WM, Tycko R. Molecular structural basis for polymorphism in Alzheimer’s beta-amyloid fibrils. Proc Natl Acad Sci U S A. 2008;105:18349–54.

    Article  CAS  Google Scholar 

  • Parchi P, et al. Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann Neurol. 1996;39:767–78.

    Article  CAS  Google Scholar 

  • Parchi P, et al. Typing prion isoforms. Nature. 1997;386:232–3.

    Article  CAS  Google Scholar 

  • Pattison IH, Millson GC. Scrapie produced experimentally in goats with special reference to the clinical syndrome. J Comp Pathol. 1961;71:101–8.

    Article  CAS  Google Scholar 

  • Peretz D, et al. Strain-specified relative conformational stability of the scrapie prion protein. Protein Sci. 2001;10:854–63.

    Article  CAS  Google Scholar 

  • Petkova AT, et al. A structural model for Alzheimer’s beta-amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci U S A. 2002;99:16742–7.

    Article  CAS  Google Scholar 

  • Pillai JA, Appleby BS, Safar J, Leverenz JB. Rapidly progressive Alzheimer’s disease in two distinct autopsy cohorts. J Alzheimers Dis. 2018;64:973–80.

    Article  Google Scholar 

  • Pirisinu L, et al. A new method for the characterization of strain-specific conformational stability of protease-sensitive and protease-resistant PrP. PLoS One. 2011;5:e12723.

    Article  Google Scholar 

  • Piro JR, et al. Prion protein glycosylation is not required for strain-specific neurotropism. J Virol. 2009;83:5321–8.

    Article  CAS  Google Scholar 

  • Piro JR, et al. Seeding specificity and ultrastructural characteristics of infectious recombinant prions. Biochemistry. 2011;50:7111–6.

    Article  CAS  Google Scholar 

  • Polymenidou M, et al. Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease. Lancet Neurol. 2005;4:805–14.

    Article  CAS  Google Scholar 

  • Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science. 1982;216:136–44.

    Article  CAS  Google Scholar 

  • Prusiner SB. Prion diseases and the BSE crisis. Science. 1997;278:245–51.

    Article  CAS  Google Scholar 

  • Prusiner SB. Prions (Les Prix Nobel Lecture). In: Frängsmyr T, editor. Les Prix Nobel. Stockholm: Almqvist & Wiksell International; 1998a. p. 268–323.

    Google Scholar 

  • Prusiner SB. Prions Proc Natl Acad Sci USA. 1998b;95:13363–83.

    Article  CAS  Google Scholar 

  • Prusiner SB. Shattuck lecture – neurodegenerative diseases and prions. N Engl J Med. 2001;344:1516–26.

    Article  CAS  Google Scholar 

  • Prusiner SB, editor. Prion biology and diseases, 1050. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 2004.

    Google Scholar 

  • Prusiner SB, et al. Measurement of the scrapie agent using an incubation time interval assay. Ann Neurol. 1982;11:353–8.

    Article  CAS  Google Scholar 

  • Prusiner SB, et al. Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell. 1990;63:673–86.

    Article  CAS  Google Scholar 

  • Prusiner SB, Scott MR, DeArmond SJ, Cohen FE. Prion protein biology. Cell. 1998;93:337–48.

    Article  CAS  Google Scholar 

  • Prusiner SB, Tremblay P, Safar J, Torchia M, DeArmond SJ. Bioassays of prions. In: Prusiner SB, editor. Prion biology and diseases. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 1999a. p. 113–45.

    Google Scholar 

  • Prusiner SB, Scott MR, DeArmond SJ, Carlson G. Transmission and replication of prions. In: Prusiner SB, editor. Prion biology and diseases. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 1999b. p. 147–90.

    Google Scholar 

  • Prusiner SB, Scott MR, DeArmond SJ, Carlson G. Transmission and replication of prions. In: Prusiner SB, editor. Prion biology and diseases. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 2004a. p. 187–242.

    Google Scholar 

  • Prusiner SB, et al. Some strategies and methods for the study of prions. In: Prusiner SB, editor. Prion biology and diseases. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 2004b. p. 857–920.

    Google Scholar 

  • Puoti G, et al. Sporadic Creutzfeldt-Jakob disease: co-occurrence of different types of PrP(Sc) in the same brain. Neurology. 1999;53:2173–6.

    Article  CAS  Google Scholar 

  • Puoti G, et al. Sporadic human prion diseases: molecular insights and diagnosis. Lancet Neurol. 2012;11:618–28.

    Article  CAS  Google Scholar 

  • Qiang W, Yau WM, Lu JX, Collinge J, Tycko R. Structural variation in amyloid-beta fibrils from Alzheimer’s disease clinical subtypes. Nature. 2017.

    Google Scholar 

  • Safar JG. Molecular mechanisms encoding quantitative and qualitative traits of prion strains. In: Zou WAGP, editor. Prions and diseases, vol. 1. New York: Springer; 2012a.

    Google Scholar 

  • Safar JG. Molecular pathogenesis of sporadic prion diseases in man. Prion. 2012b;6:108–15.

    Article  CAS  Google Scholar 

  • Safar J, Prusiner SB. Molecular studies of prion diseases. Prog Brain Res. 1998;117:421–34.

    Article  CAS  Google Scholar 

  • Safar J, Roller PP, Ruben GC, Gajdusek DC, Gibbs CJ Jr. Secondary structure of proteins associated in thin films. Biopolymers. 1993a;33:1461–76.

    Article  CAS  Google Scholar 

  • Safar J, Roller PP, Gajdusek DC, Gibbs CJ Jr. Thermal stability and conformational transitions of scrapie amyloid (prion) protein correlate with infectivity. Protein Sci. 1993b;2:2206–16.

    Article  CAS  Google Scholar 

  • Safar J, Roller P, Gajdusek D, Gibbs C Jr. Conformational transitions, dissociation, and unfolding of scrapie amyloid (prion) protein. J Biol Chem. 1993c;268:20276–84.

    Article  CAS  Google Scholar 

  • Safar J, Roller PP, Gajdusek DC, Gibbs CJ Jr. Scrapie amyloid (prion) protein has the conformational characteristics of an aggregated molten globule folding intermediate. Biochemistry. 1994a;33:8375–83.

    Article  CAS  Google Scholar 

  • Safar J, Roller P, Ruben G, Gajdusek D, GIBBS C. Conformational pathways of scrapie amyloid (prion) protein and the structure-function relationship with infectivity. Neurobiol Aging. 1994b;15:S157–8. (Elsevier Science Inc., New York).

    Article  Google Scholar 

  • Safar J, et al. Eight prion strains have PrPSc molecules with different conformations. Nat Med. 1998a;4:1157–65.

    Article  CAS  Google Scholar 

  • Safar J, et al. Eight prion strains have PrPSc molecules with different conformations. Nat Med. 1998b;4:1157–65.

    Article  CAS  Google Scholar 

  • Safar J, Cohen FE, Prusiner SB. Quantitative traits of prion strains are enciphered in the conformation of the prion protein. Arch Virol Suppl. 2000:227–35.

    Google Scholar 

  • Safar JG, et al. Measuring prions causing bovine spongiform encephalopathy or chronic wasting disease by immunoassays and transgenic mice. Nat Biotechnol. 2002;20:1147–50.

    Article  CAS  Google Scholar 

  • Safar JG, et al. Search for a prion-specific nucleic acid. J Virol. 2005a;79:10796–806.

    Article  CAS  Google Scholar 

  • Safar JG, et al. Diagnosis of human prion disease. Proc Natl Acad Sci U S A. 2005b;102:3501–6.

    Article  CAS  Google Scholar 

  • Safar JG, et al. Prion clearance in bigenic mice. J Gen Virol. 2005c;86:2913–23.

    Article  CAS  Google Scholar 

  • Safar JG, et al. Transmission and detection of prions in feces. J Infect Dis. 2008;198:81–9.

    Article  CAS  Google Scholar 

  • Safar JG, et al. Conserved properties of human and bovine prion strains on transmission to guinea pigs. Lab Investig. 2011;91:1326–36.

    Article  CAS  Google Scholar 

  • Safar JG, et al. Structural determinants of phenotypic diversity and replication rate of human prions. PLoS Pathog. 2015a;11:e1004832.

    Article  Google Scholar 

  • Safar JG, et al. Structural determinants of phenotypic diversity and replication rate of human prions. PLoS Pathog. 2015b;11:e1004832.

    Article  Google Scholar 

  • Sanders DW, Kaufman SK, Holmes BB, Diamond MI. Prions and protein assemblies that convey biological information in health and disease. Neuron. 2016;89:433–48.

    Article  CAS  Google Scholar 

  • Schmidt C, et al. Clinical features of rapidly progressive Alzheimer’s disease. Dement Geriatr Cogn Disord. 2010;29:371–8.

    Article  CAS  Google Scholar 

  • Schmidt C, et al. Rapidly progressive Alzheimer disease. Arch Neurol. 2011;68:1124–30.

    Article  Google Scholar 

  • Schmidt C, et al. Rapidly progressive Alzheimer’s disease: a multicenter update. J Alzheimers Dis. 2012;30:751–6.

    Article  Google Scholar 

  • Schmidt C, Artjomova S, Hoeschel M, Zerr I. CSF prion protein concentration and cognition in patients with Alzheimer disease. Prion. 2013;7:229–34.

    Article  CAS  Google Scholar 

  • Schoch G, et al. Analysis of prion strains by PrPSc profiling in sporadic Creutzfeldt-Jakob disease. PLoS Med. 2006;3:e14.

    Article  Google Scholar 

  • Scott M, et al. Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques. Cell. 1989;59:847–57.

    Article  CAS  Google Scholar 

  • Scott MR, et al. Propagation of prion strains through specific conformers of the prion protein. J Virol. 1997;71:9032–44.

    Article  CAS  Google Scholar 

  • Scott MR, et al. Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans. Proc Natl Acad Sci U S A. 1999;96:15137–42.

    Article  CAS  Google Scholar 

  • Scott M, et al. Transgenetic investigations of the species barrier and prion strains. In: Prusiner SB, editor. Prion biology and diseases. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 2004. p. 435–82.

    Google Scholar 

  • Scott MR, Peretz D, Nguyen H-OB, DeArmond SJ, Prusiner SB. Transmission barriers for bovine, ovine, and human prions in transgenic mice. J Virol. 2005;79:5259–71.

    Article  CAS  Google Scholar 

  • Shirley BA, editor. Protein stability and folding: theory and practice. Totowa: Humana Press; 1995. p. 377.

    Google Scholar 

  • Shorter J, Lindquist S. Prions as adaptive conduits of memory and inheritance. Nat Rev Genet. 2005;6:435–50.

    Article  CAS  Google Scholar 

  • Siddiqi MK, et al. Structurally distinct external solvent-exposed domains drive replication of major human prions. PLoS Pathog. 2021;17:e1009642.

    Article  CAS  Google Scholar 

  • Stephenson DA, et al. Quantitative trait loci affecting prion incubation time in mice. Genomics. 2000;69:47–53.

    Article  CAS  Google Scholar 

  • Tamguney G, et al. Genes contributing to prion pathogenesis. J Gen Virol. 2008;89:1777–88.

    Article  CAS  Google Scholar 

  • Tanaka M, Collins SR, Toyama BH, Weissman JS. The physical basis of how prion conformations determine strain phenotypes. Nature. 2006;442:585–9.

    Article  CAS  Google Scholar 

  • Taraboulos A, et al. Acquisition of protease resistance by prion proteins in scrapie-infected cells does not require asparagine-linked glycosylation. Proc Natl Acad Sci U S A. 1990;87:8262–6.

    Article  CAS  Google Scholar 

  • Taraboulos A, et al. Regional mapping of prion proteins in brains. Proc Natl Acad Sci U S A. 1992;89:7620–4.

    Article  CAS  Google Scholar 

  • Telling GC. Transgenic mouse models of prion diseases. Methods Mol Biol. 2008;459:249–63.

    Article  CAS  Google Scholar 

  • Telling GC, et al. Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric human-mouse prion protein. Proc Natl Acad Sci U S A. 1994;91:9936–40.

    Article  CAS  Google Scholar 

  • Telling GC, et al. Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science. 1996;274:2079–82.

    Article  CAS  Google Scholar 

  • Theint T, Nadaud PS, Surewicz K, Surewicz WK, Jaroniec CP. 13C and 15N chemical shift assignments of mammalian Y145Stop prion protein amyloid fibrils. Biomol NMR Assign. 2017;11:75–80.

    Article  CAS  Google Scholar 

  • Tremblay P, et al. Mutant PrPSc conformers induced by a synthetic peptide and several prion strains. J Virol. 2004;78:2088–99.

    Article  CAS  Google Scholar 

  • Trevitt CR, Collinge J. A systematic review of prion therapeutics in experimental models. Brain. 2006;129:2241–65.

    Article  Google Scholar 

  • Tuzi NL, et al. Host PrP glycosylation: a major factor determining the outcome of prion infection. PLoS Biol. 2008;6:e100.

    Article  Google Scholar 

  • Tzaban S, et al. Protease-sensitive scrapie prion protein in aggregates of heterogeneous sizes. Biochemistry. 2002;41:12868–75.

    Article  CAS  Google Scholar 

  • Uro-Coste E, et al. Beyond PrP9res) type 1/type 2 dichotomy in Creutzfeldt-Jakob disease. PLoS Pathog. 2008;4:e1000029.

    Google Scholar 

  • Wadsworth JDF, et al. Strain-specific prion-protein conformation determined by metal ions. Nat Cell Biol. 1999;1:55–9.

    Article  CAS  Google Scholar 

  • Wang F, Wang X, Yuan CG, Ma J. Generating a prion with bacterially expressed recombinant prion protein. Science. 2010;327:1132–5.

    Article  CAS  Google Scholar 

  • Watts JC, Westaway D. The prion protein family: diversity, rivalry, and dysfunction. Biochim Biophys Acta. 2007;1772:654–72.

    Article  CAS  Google Scholar 

  • Weissmann C. The state of the prion. Nat Rev Microbiol. 2004;2:861–71.

    Article  CAS  Google Scholar 

  • Wickner RB, et al. Prion amyloid structure explains templating: how proteins can be genes. FEMS Yeast Res. 2010;10:980–91.

    Article  CAS  Google Scholar 

  • Zhang Z, et al. De novo generation of infectious prions with bacterially expressed recombinant prion protein. FASEB J. 2013;27:4768–75.

    Article  CAS  Google Scholar 

  • Zou WQ, et al. Identification of novel proteinase K-resistant C-terminal fragments of PrP in Creutzfeldt-Jakob disease. J Biol Chem. 2003;278:40429–36.

    Article  CAS  Google Scholar 

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Acknowledgments

The authors are grateful to the patients’ families for donating brain tissue and we thank all the referring physicians and all members of the National Prion Disease Pathology Surveillance Center (NPDPSC), Cleveland, OH, for technical assistance and review of clinical data. Work in the Safar lab was supported by grants from NIH (R01NS103848, 1RF1AG058267, and 1RF1AG061797), the NPDPSC is funded by CDC (NU38CK00048), and the CWRU proteomic MS core is funded by NIH (P30CA043703). This research used beamline 17-BM of the National Synchrotron Light Source II, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Brookhaven National Laboratory under Contract No. DE-SC0012704.

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Authors and Affiliations

  1. School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    Lenka Hromadkova, M. Khursheed Siddiqi & He Liu

  2. Department of Pathology, School of Medicine, Department of Neurology, School of Medicine, Cleveland Center for Membrane & Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    Jiri G. Safar

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  1. Lenka Hromadkova
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  2. M. Khursheed Siddiqi
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  4. Jiri G. Safar
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Correspondence to Jiri G. Safar .

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  1. Departments of Pathology and Neurology, National Prion Disease Pathology Surveillance Center, National Center for Regenerative Medicine Case Western Reserve University, School of Medicine, Cleveland, OH, USA

    Wen-Quan Zou

  2. Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Pierluigi Gambetti

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Hromadkova, L., Siddiqi, M.K., Liu, H., Safar, J.G. (2023). Molecular Mechanisms Encoding Strains of Prions and Prion-Like Misfolded Proteins. In: Zou, WQ., Gambetti, P. (eds) Prions and Diseases. Springer, Cham. https://doi.org/10.1007/978-3-031-20565-1_7

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