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New developments in prion disease research using genetically modified mouse models

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Abstract

While much of what we know about the general principles of protein-based information transfer derives from studies of experimentally adapted rodent prions, these laboratory strains are limited in their ability to recapitulate features of human and animal prions and the diseases they produce. Here, we review how recent approaches using genetically modified mice have informed our understanding of naturally occurring prion diseases, their strain properties, and the factors controlling their transmission and evolution. In light of the increasing importance of chronic wasting disease, the application of mouse transgenesis to study this burgeoning and highly contagious prion disorder, in particular recent insights derived from gene-targeting approaches, will be a major focus of this review.

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References

  • Angers R, Christiansen J, Nalls AV, Kang HE, Hunter N, Hoover E, Mathiason CK, Sheetz M, Telling GC (2014) Structural effects of PrP polymorphisms on intra- and interspecies prion transmission. Proc Natl Acad Sci USA 111:11169–11174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Angers RC, Browning SR, Seward TS, Sigurdson CJ, Miller MW, Hoover EA, Telling GC (2006) Prions in skeletal muscles of deer with chronic wasting disease. Science 311:1117

    Article  CAS  PubMed  Google Scholar 

  • Angers RC, Kang HE, Napier D, Browning S, Seward T, Mathiason C, Balachandran A, McKenzie D, Castilla J, Soto C, Jewell J, Graham C, Hoover EA, Telling GC (2010) Prion strain mutation determined by prion protein conformational compatibility and primary structure. Science 328:1154–1158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Angers RC, Seward TS, Napier D, Green M, Hoover E, Spraker T, O’Rourke K, Balachandran A, Telling GC (2009) Chronic wasting disease prions in elk antler velvet. Emerg Infect Dis 15:696–703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arifin MI, Hannaoui S, Chang SC, Thapa S, Schatzl HM, Gilch S (2021) Cervid prion protein polymorphisms: role in chronic wasting disease pathogenesis. Int J Mol Sci 22

  • Asante EA, Linehan JM, Desbruslais M, Joiner S, Gowland I, Wood AL, Welch J, Hill AF, Lloyd SE, Wadsworth JD, Collinge J (2002) BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein. Embo J 21:6358–6366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Babelhadj B, di Bari MA, Pirisinu L, Chiappini B, Gaouar SBS, Riccardi G, Marcon S, Agrimi U, Nonno R, Vaccari G (2018) Prion disease in dromedary camels, Algeria. Emerg Infect Dis 24:1029–1036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barria MA, Telling GC, Gambetti P, Mastrianni JA, Soto C (2011) Generation of a new form of human PrP(Sc) in vitro by interspecies transmission from cervid prions. J Biol Chem 286:7490–7495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Benestad SL, Mitchell G, Simmons M, Ytrehus B, Vikoren T (2016) First case of chronic wasting disease in Europe in a Norwegian free-ranging reindeer. Vet Res 47:88

    Article  PubMed  PubMed Central  Google Scholar 

  • Benestad SL, Sarradin P, Thu B, Schonheit J, Tranulis MA, Bratberg B (2003) Cases of scrapie with unusual features in Norway and designation of a new type, Nor98. Vet Rec 153:202–208

    Article  CAS  PubMed  Google Scholar 

  • Benestad SL, Telling GC (2018) Chronic wasting disease: an evolving prion disease of cervids. Handb Clin Neurol 153:135–151

    Article  PubMed  Google Scholar 

  • Beringue V, Herzog L, Jaumain E, Reine F, Sibille P, le Dur A, Vilotte JL, Laude H (2012) Facilitated cross-species transmission of prions in extraneural tissue. Science 335:472–475

    Article  CAS  PubMed  Google Scholar 

  • Beringue V, Herzog L, Reine F, le Dur A, Casalone C, Vilotte JL, Laude H (2008a) Transmission of atypical bovine prions to mice transgenic for human prion protein. Emerg Infect Dis 14:1898–1901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beringue V, le Dur A, Tixador P, Reine F, Lepourry L, Perret-Liaudet A, Haik S, Vilotte JL, Fontes M, Laude H (2008b) Prominent and persistent extraneural infection in human PrP transgenic mice infected with variant CJD. PLoS ONE 3:e1419

    Article  PubMed  PubMed Central  Google Scholar 

  • Bessen RA, Marsh RF (1994) Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J Virol 68:7859–7868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bian J, Christiansen JR, Moreno JA, Kane SJ, Khaychuk V, Gallegos J, Kim S, Telling GC (2019) Primary structural differences at residue 226 of deer and elk PrP dictate selection of distinct CWD prion strains in gene-targeted mice. Proc Natl Acad Sci U S A 116:12478–12487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bian J, Khaychuk V, Angers RC, Fernandez-Borges N, Vidal E, Meyerett-Reid C, Kim S, Calvi CL, Bartz JC, Hoover EA, Agrimi U, Richt JA, CASTILLA J, Telling GC (2017) Prion replication without host adaptation during interspecies transmissions. Proc Natl Acad Sci USA 114:1141–1146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bian J, Kim S, Kane SJ, Crowell J, Sun JL, Christiansen J, Saijo E, Moreno JA, Dilisio J, Burnett E, Pritzkow S, Gorski D, Soto C, Kreeger TJ, Balachandran A, Mitchell G, Miller MW, Nonno R, Vikoren T, Vage J, Madslien K, Tran L, Vuong TT, Benestad SL, Telling GC (2021) Adaptive selection of a prion strain conformer corresponding to established North American CWD during propagation of novel emergent Norwegian strains in mice expressing elk or deer prion protein. PLoS Pathog 17:e1009748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bishop MT, Hart P, Aitchison L, Baybutt HN, Plinston C, Thomson V, Tuzi NL, Head MW, Ironside JW, Will RG, Manson JC (2006) Predicting susceptibility and incubation time of human-to-human transmission of vCJD. Lancet Neurol 5:393–398

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bosque PJ, Ryou C, Telling G, Peretz D, Legname G, Dearmond SJ, Prusiner SB (2002) Prions in skeletal muscle. Proc Natl Acad Sci U S A 99:3812–3817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Browning SR, Mason GL, Seward T, Green M, Eliason GA, Mathiason C, Miller MW, Williams ES, Hoover E, Telling GC (2004) Transmission of prions from mule deer and elk with chronic wasting disease to transgenic mice expressing cervid PrP. J Virol 78:13345–13350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, McCardle L, Chree A, Hope J, Birkett C, Cousens S, Fraser H, Bostock CJ (1997) Transmissions to mice indicate that “new variant” CJD is caused by the BSE agent. Nature 389:498–501

    Article  CAS  PubMed  Google Scholar 

  • Büeler H, Raeber A, Sailer A, Fischer M, Aguzzi A, Weissmann C (1994) High prion and PrPSc levels but delayed onset of disease in scrapie-inoculated mice heterozygous for a disrupted PrP gene. Mol Med 1:19–30

    Article  PubMed  Google Scholar 

  • Buschmann A, Groschup MH (2005) Highly bovine spongiform encephalopathy-sensitive transgenic mice confirm the essential restriction of infectivity to the nervous system in clinically diseased cattle. J Infect Dis 192:934–942

    Article  PubMed  Google Scholar 

  • Cancellotti E, Barron RM, Bishop MT, Hart P, Wiseman F, Manson JC (2007) The role of host PrP in transmissible spongiform encephalopathies. Biochim Biophys Acta 1772:673–680

    Article  CAS  PubMed  Google Scholar 

  • Cassard H, Torres JM, Lacroux C, Douet JY, Benestad SL, Lantier F, Lugan S, Lantier I, Costes P, Aron N, Reine F, Herzog L, Espinosa JC, Beringue V, Andreoletti O (2014) Evidence for zoonotic potential of ovine scrapie prions. Nat Commun 5:5821

    Article  CAS  PubMed  Google Scholar 

  • Castilla J, Gutierrez Adan A, Brun A, Pintado B, Ramirez MA, Parra B, Doyle D, Rogers M, Salguero FJ, Sanchez C, Sanchez-Vizcaino JM, Torres JM (2003) Early detection of PrPres in BSE-infected bovine PrP transgenic mice. Arch Virol 148:677–691

    Article  CAS  PubMed  Google Scholar 

  • Cervenakova L, Rohwer R, Williams S, Brown P, Gajdusek DC (1997) High sequence homology of the PrP gene in mule deer and Rocky Mountain elk. Lancet 350:219–220

    Article  CAS  PubMed  Google Scholar 

  • Christen B, Perez DR, Hornemann S, Wuthrich K (2008) NMR structure of the bank vole prion protein at 20 degrees C contains a structured loop of residues 165–171. J Mol Biol

  • Collinge J (1999) Variant Creutzfeldt-Jakob disease. Lancet 354:317–323

    Article  CAS  PubMed  Google Scholar 

  • Collinge J, Clarke AR (2007) A general model of prion strains and their pathogenicity. Science 318:930–936

    Article  CAS  PubMed  Google Scholar 

  • Collinge J, Palmer MS, Sidle KC, Hill AF, Gowland I, Meads J, Asante E, Bradley R, Doey LJ, Lantos PL (1995) Unaltered susceptibility to BSE in transgenic mice expressing human prion protein. Nature 378:779–783

    Article  CAS  PubMed  Google Scholar 

  • Collinge J, Sidle KC, Meads J, Ironside J, Hill AF (1996) Molecular analysis of prion strain variation and the aetiology of “new variant” CJD. Nature 383:685–690

    Article  CAS  PubMed  Google Scholar 

  • Comoy EE, Casalone C, Lescoutra-Etchegaray N, Zanusso G, Freire S, Marce D, Auvre F, Ruchoux MM, Ferrari S, Monaco S, Sales N, Caramelli M, Leboulch P, Brown P, Lasmezas CI, Deslys JP (2008) Atypical BSE (BASE) transmitted from asymptomatic aging cattle to a primate. PLoS ONE 3:e3017

    Article  PubMed  PubMed Central  Google Scholar 

  • Comoy EE, Mikol J, Luccantoni-Freire S, Correia E, Lescoutra-Etchegaray N, Durand V, Dehen C, Andreoletti O, Casalone C, Richt JA, Greenlee JJ, Baron T, Benestad SL, Brown P, Deslys JP (2015) Transmission of scrapie prions to primate after an extended silent incubation period. Sci Rep 5:11573

    Article  PubMed  PubMed Central  Google Scholar 

  • Comoy EE, Mikol J, Ruchoux MM, Durand V, Luccantoni-Freire S, Dehen C, Correia E, Casalone C, Richt JA, Greenlee JJ, Torres JM, Brown P, Deslys JP (2013) Evaluation of the zoonotic potential of transmissible mink encephalopathy. Pathogens 2:520–532

    Article  PubMed  PubMed Central  Google Scholar 

  • Czub S, Schulz-Schaeffer W, Stahl-Hennig C, Beekes M, Schaetzl H, Motzkus D (2017) First evidence of intracranial and peroral transmission of Chronic Wasting Disease (CWD) into Cynomolgus macaques. PRION 2017 Conference abstract

  • Davenport KA, Christiansen JR, Bian J, Young M, Gallegos J, Kim S, Balachandran A, Mathiason CK, Hoover EA, Telling GC (2018) Comparative analysis of prions in nervous and lymphoid tissues of chronic wasting disease-infected cervids. J Gen Virol 99:753–758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davenport KA, Henderson DM, Bian J, Telling GC, Mathiason CK, Hoover EA (2015) Insights into chronic wasting disease and bovine spongiform encephalopathy species barriers by use of real-time conversion. J Virol 89:9524–9531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Denkers ND, Seelig DM, Telling GC, Hoover EA (2010) Aerosol and nasal transmission of chronic wasting disease in cervidized mice. J Gen Virol 91:1651–1658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Denkers ND, Telling GC, Hoover EA (2011) Minor oral lesions facilitate transmission of chronic wasting disease. J Virol 85:1396–1399

    Article  CAS  PubMed  Google Scholar 

  • Di Bari MA, Nonno R, Castilla J, D’Agostino C, Pirisinu L, Riccardi G, Conte M, Richt J, Kunkle R, Langeveld J, Vaccari G, Agrimi U (2013) Chronic wasting disease in bank voles: characterisation of the shortest incubation time model for prion diseases. PLoS Pathog 9:e1003219

    Article  PubMed  PubMed Central  Google Scholar 

  • Duque Velasquez C, Kim C, Herbst A, Daude N, Garza MC, Wille H, Aiken J, McKenzie D (2015) Deer prion proteins modulate the emergence and adaptation of chronic wasting disease strains. J Virol 89:12362–12373

    Article  PubMed  PubMed Central  Google Scholar 

  • Gossert AD, Bonjour S, Lysek DA, Fiorito F, Wuthrich K (2005) Prion protein NMR structures of elk and of mouse/elk hybrids. Proc Natl Acad Sci U S A 102:646–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Green KM, Browning SR, Seward TS, Jewell JE, Ross DL, Green MA, Williams ES, Hoover EA, Telling GC (2008a) The elk PRNP codon 132 polymorphism controls cervid and scrapie prion propagation. J Gen Virol 89:598–608

    Article  CAS  PubMed  Google Scholar 

  • Green KM, Castilla J, Seward TS, Napier DL, Jewell JE, Soto C, Telling GC (2008b) Accelerated high fidelity prion amplification within and across prion species barriers. PLoS Pathog 4:e1000139

    Article  PubMed  PubMed Central  Google Scholar 

  • Haley NJ, Mathiason CK, Carver S, Telling GC, Zabel MD, Hoover EA (2012) Sensitivity of protein misfolding cyclic amplification versus immunohistochemistry in ante-mortem detection of chronic wasting disease. J Gen Virol 93:1141–1150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haley NJ, Mathiason CK, Carver S, Zabel M, Telling GC, Hoover EA (2011) Detection of chronic wasting disease prions in salivary, urinary, and intestinal tissues of deer: potential mechanisms of prion shedding and transmission. J Virol 85:6309–6318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hannaoui S, Triscott E, Duque Velasquez C, Chang SC, Arifin MI, Zemlyankina I, Tang X, Bollinger T, Wille H, McKenzie D, Gilch S (2021) New and distinct chronic wasting disease strains associated with cervid polymorphism at codon 116 of the Prnp gene. PLoS Pathog 17:e1009795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hannaoui S, Zemlyankina I, Chang SC, Arifin MI, Béringue V, McKenzie D, Schatzl HM, Gilch S (2022) Transmission of cervid prions to humanized mice demonstrates the zoonotic potential of CWD. bioRxiv 04.19.488833

  • Hecker R, Taraboulos A, Scott M, Pan K-M, Torchia M, Jendroska K, Dearmond SJ, Prusiner SB (1992) Replication of distinct prion isolates is region specific in brains of transgenic mice and hamsters. Genes Dev 6:1213–1228

    Article  CAS  PubMed  Google Scholar 

  • Hill AF, Desbruslais M, Joiner S, Sidle KCL, Gowland I, Collinge J, Doey LJ, Lantos P (1997) The same prion strain causes vCJD and BSE. Nature 389:448–450

    Article  CAS  PubMed  Google Scholar 

  • Hill AF, Joiner S, Linehan J, Desbruslais M, Lantos PL, Collinge J (2000) Species-barrier-independent prion replication in apparently resistant species. Proc Natl Acad Sci U S A 97:10248–10253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoyt F, Standke HG, Artikis E, Schwartz CL, Hansen B, Li K, Hughson AG, Manca M, Thomas OR, Raymond GJ, Race B, Baron GS, Caughey B, Kraus A (2022) Cryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains. Nat Commun

  • Huor A, Espinosa JC, Vidal E, Cassard H, Douet JY, Lugan S, Aron N, Marin-Moreno A, Lorenzo P, Aguilar-Calvo P, Badiola J, Bolea R, Pumarola M, Benestad SL, Orge L, Thackray AM, Bujdoso R, Torres JM, Andreoletti O (2019) The emergence of classical BSE from atypical/Nor98 scrapie. Proc Natl Acad Sci USA

  • Kim TY, Shon HJ, Joo YS, Mun UK, Kang KS, Lee YS (2005) Additional cases of chronic wasting disease in imported deer in Korea. J Vet Med Sci 67:753–759

    Article  PubMed  Google Scholar 

  • Kimberlin RH, Walker CA, Fraser H (1989) The genomic identity of different strains of mouse scrapie is expressed in hamsters and preserved on reisolation in mice. J Gen Virol 70:2017–2025

    Article  PubMed  Google Scholar 

  • Kitamoto T, Mohri S, Ironside JW, Miyoshi I, Tanaka T, Kitamoto N, Itohara S, Kasai N, Katsuki M, Higuchi J, Muramoto T, Shin RW (2002) Follicular dendritic cell of the knock-in mouse provides a new bioassay for human prions. Biochem Biophys Res Commun 294:280–286

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi A, Asano M, Mohri S, Kitamoto T (2007) Cross-sequence transmission of sporadic Creutzfeldt-Jakob disease creates a new prion strain. J Biol Chem 282:30022–30028

    Article  CAS  PubMed  Google Scholar 

  • Kong Q, Huang S, Zou W, Vanegas D, Wang M, Wu D, Yuan J, Zheng M, Bai H, Deng H, Chen K, Jenny AL, O’Rourke K, Belay ED, Schonberger LB, Petersen RB, SY, M. S., Chen, S. G. & Gambetti, P. (2005) Chronic wasting disease of elk: transmissibility to humans examined by transgenic mouse models. J Neurosci 25:7944–7949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kraus A, Hoyt F, Schwartz CL, Hansen B, Artikis E, Hughson AG, Raymond GJ, Race B, Baron GS, Caughey B (2021) High-resolution structure and strain comparison of infectious mammalian prions. Mol Cell 81(4540–4551):e6

    Google Scholar 

  • Kurt TD, Seelig DM, Schneider JR, Johnson CJ, Telling GC, Heisey DM, Hoover EA (2011) Alteration of the chronic wasting disease species barrier by in vitro prion amplification. J Virol 85:8528–8537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kurt TD, Telling GC, Zabel MD, Hoover EA (2009) Trans-species amplification of PrP(CWD) and correlation with rigid loop 170N. Virology 387:235–243

    Article  CAS  PubMed  Google Scholar 

  • Lafauci G, Carp RI, Meeker HC, Ye X, Kim JI, Natelli M, Cedeno M, Petersen RB, Kascsak R, Rubenstein R (2006) Passage of chronic wasting disease prion into transgenic mice expressing Rocky Mountain elk (Cervus elaphus nelsoni) PrPC. J Gen Virol 87:3773–3780

    Article  CAS  PubMed  Google Scholar 

  • Le Dur A, Lai TL, Stinnakre MG, Laisne A, Chenais N, Rakotobe S, Passet B, Reine F, Soulier S, Herzog L, Tilly G, Rezaei H, Beringue V, Vilotte JL, Laude H (2017) Divergent prion strain evolution driven by PrP(C) expression level in transgenic mice. Nat Commun 8:14170

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee YH, Sohn HJ, Kim MJ, Kim HJ, Park KJ, Lee WY, Yun EI, Tark DS, Choi YP, Cho IS, Balachandran A (2013) Experimental chronic wasting disease in wild type VM mice. J Vet Med Sci 75:1107–1110

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Ma J, Wollmann R, Lindquist S (2002) Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol. Science 298:1781–1785

    Article  CAS  PubMed  Google Scholar 

  • Manka SW, Zhang W, Wenborn A, Betts J, JOiner S, Saibil HR, Collinge J, Wadsworth JDF (2022) 2.7 Å cryo-EM structure of ex vivo RML prion fibrils. Nat Commun

  • Marsh RF, Hanson RP (1979) On the origin of transmissible mink encephalopathy. In: Prusiner SB, & Hadlow WJ (eds.) Slow transmissible diseases of the nervous system, Vol. 1. New York: Academic Press

  • Mathiason CK, Hayes-Klug J, Hays SA, Powers J, Osborn DA, Dahmes SJ, Miller KV, Warren RJ, Mason GL, Telling GC, Young AJ, Hoover EA (2010) B cells and platelets harbor prion infectivity in the blood of deer infected with chronic wasting disease. J Virol 84:5097–5107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meade-White K, Race B, TRifilo M, Bossers A, Favara C, Lacasse R, Miller M, Williams E, Oldstone M, Race R, Chesebro B (2007) Resistance to chronic wasting disease in transgenic mice expressing a naturally occurring allelic variant of deer prion protein. J Virol 81:4533–4539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mestre-Frances N, Nicot S, Rouland S, Biacabe AG, Quadrio I, Perret-Liaudet A, Baron T, Verdier JM (2012) Oral transmission of L-type bovine spongiform encephalopathy in primate model. Emerg Infect Dis 18:142–145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miller M, Williams E, Hobbs N, Wolfe L (2004) Environmental sources of prion transmission in mule deer. Emerging Infectious Diseases [serial on the Internet] 10

  • Miller MW, Williams ES, McCarty CW, Spraker TR, Kreeger TJ, Larsen CT, Thorne ET (2000) Epizootiology of chronic wasting disease in free-ranging cervids in Colorado and Wyoming. J Wildl Dis 36:676–690

    Article  CAS  PubMed  Google Scholar 

  • Moore RC, Hope J, McBride PA, McConnell I, Selfridge J, Melton DW, Manson JC (1998) Mice with gene targetted prion protein alterations show that Prn-p, Sinc and Prni are congruent. Nat Genet 18:118–125

    Article  CAS  PubMed  Google Scholar 

  • Nichols TA, Spraker TR, Gidlewski T, Powers JG, Telling GC, Vercauteren KC, Zabel MD (2012) Detection of prion protein in the cerebrospinal fluid of elk (Cervus canadensis nelsoni) with chronic wasting disease using protein misfolding cyclic amplification. J Vet Diagn Invest 24:746–749

    Article  PubMed  Google Scholar 

  • Nichols TA, Spraker TR, Rigg TD, Meyerett-Reid C, Hoover C, Michel B, Bian J, Hoover E, Gidlewski T, Balachandran A, O’Rourke K, Telling GC, Bowen R, Zabel MD, Vercauteren KC (2013) Intranasal Inoculation of white-tailed deer (Odocoileus virginianus) with lyophilized chronic wasting disease prion particulate complexed to montmorillonite clay. PLoS ONE 8:e62455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nonno R, di Bari MA, Cardone F, Vaccari G, Fazzi P, Dell’Omo G, Cartoni C, Ingrosso L, Boyle A, Galeno R, Sbriccoli M, Lipp HP, Bruce M, Pocchiari M, Agrimi U (2006) Efficient transmission and characterization of Creutzfeldt-Jakob disease strains in bank voles. PLoS Pathog 2:e12

    Article  PubMed  PubMed Central  Google Scholar 

  • Nonno R, di Bari MA, Pirisinu L, D'Agostino C, Vanni I, Chiappini B, Marcon S, Riccardi G, Tran L, Vikoren T, Vage J, Madslien K, Mitchell G, Telling GC, Benestad SL, Agrimi U (2020) Studies in bank voles reveal strain differences between chronic wasting disease prions from Norway and North America. Proc Natl Acad Sci USA

  • Osterholm MT, Anderson CJ, Zabel MD, Scheftel JM, Moore KA, Appleby BS (2019) Chronic wasting disease in cervids: implications for prion transmission to humans and other animal species. mBio 10

  • Outram GW, Fraser H, Wilson DT (1973) Scrapie in mice. Some effects on the brain lesion profile of ME7 agent due to genotype of donor, route of injection and genotype of recipient. J Comp Pathol 83:19–28

    Article  CAS  PubMed  Google Scholar 

  • Padilla D, Beringue V, Espinosa JC, Andreoletti O, Jaumain E, Reine F, Herzog L, Gutierrez-Adan A, Pintado B, Laude H, Torres JM (2011) Sheep and goat BSE propagate more efficiently than cattle BSE in human PrP transgenic mice. PLoS Pathog 7:e1001319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peretz D, Williamson RA, Legname G, Matsunaga Y, Vergara J, Burton DR, Dearmond SJ, Prusiner SB, Scott MR (2002) A change in the conformation of prions accompanies the emergence of a new prion strain. Neuron 34:921–932

    Article  CAS  PubMed  Google Scholar 

  • Pirisinu L, Tran L, Chiappini B, Vanni I, di Bari MA, Vaccari G, Vikoren T, Madslien KI, Vage J, Spraker T, Mitchell G, Balachandran A, Baron T, Casalone C, Rolandsen CM, Roed KH, Agrimi U, Nonno R, Benestad SL (2018) Novel type of chronic wasting disease detected in moose (Alces alces), Norway. Emerg Infect Dis 24:2210–2218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pritzkow S, Gorski D, Ramirez F, Telling GC, Benestad SL, Soto C (2021) North American and Norwegian chronic wasting disease prions exhibit different potential for interspecies transmission and zoonotic risk. J Infect Dis

  • Pritzkow S, Morales R, Moda F, Khan U, Telling GC, Hoover E, Soto C (2015) Grass plants bind, retain, uptake, and transport infectious prions. Cell Rep 11:1168–1175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prusiner SB (1998) Prions (Les Prix Nobel Lecture). In: FRÄNGSMYR, T. (ed.) Les Prix Nobel. Stockholm, Sweden: Almqvist & Wiksell International

  • Prusiner SB, Scott M, Foster D, Pan K-M, Groth D, Mirenda C, Torchia M, Yang S-L, Serban D, Carlson GA, Hoppe PC, Westaway D, Dearmond SJ (1990) Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell 63:673–686

    Article  CAS  PubMed  Google Scholar 

  • Pulford B, Spraker TR, Wyckoff AC, Meyerett C, Bender H, Ferguson A, Wyatt B, Lockwood K, Powers J, Telling GC, Wild MA, Zabel MD (2012) Detection of PrPCWD in feces from naturally exposed Rocky Mountain elk (Cervus elaphus nelsoni) using protein misfolding cyclic amplification. J Wildl Dis 48:425–434

    Article  CAS  PubMed  Google Scholar 

  • Race B, Meade-White K, Race R, Chesebro B (2009a) Prion infectivity in fat of deer with chronic wasting disease. J Virol 83:9608–9610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Race B, Meade-White KD, Miller MW, Barbian KD, Rubenstein R, Lafauci G, Cervenakova L, Favara C, Gardner D, Long D, Parnell M, Striebel J, Priola SA, Ward A, Williams ES, Race R, Chesebro B (2009b) Susceptibilities of nonhuman primates to chronic wasting disease. Emerg Infect Dis 15:1366–1376

    Article  PubMed  PubMed Central  Google Scholar 

  • Race B, Meade-White KD, Phillips K, Striebel J, Race R, Chesebro B (2014) Chronic wasting disease agents in nonhuman primates. Emerg Infect Dis 20:833–837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Race B, Williams K, Chesebro B (2019) Transmission studies of chronic wasting disease to transgenic mice overexpressing human prion protein using the RT-QuIC assay. Vet Res 50:6

    Article  PubMed  PubMed Central  Google Scholar 

  • Race BL, Meade-White KD, Ward A, Jewell J, Miller MW, Williams ES, Chesebro B, Race RE (2007) Levels of abnormal prion protein in deer and elk with chronic wasting disease. Emerg Infect Dis 13:824–830

    Article  PubMed  PubMed Central  Google Scholar 

  • Race R, Chesebro B (1998) Scrapie infectivity found in resistant species. Nature 392:770

    Article  CAS  PubMed  Google Scholar 

  • Race R, Meade-White K, Raines A, Raymond GJ, Caughey B, Chesebro B (2002) Subclinical scrapie infection in a resistant species: persistence, replication, and adaptation of infectivity during four passages. J Infect Dis 186(Suppl 2):S166–S170

    Article  PubMed  Google Scholar 

  • Race R, Raines A, Raymond GJ, Caughey B, Chesebro B (2001) 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. J Virol 75:10106–10112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rane NS, Chakrabarti O, Feigenbaum L, Hegde RS (2010) Signal sequence insufficiency contributes to neurodegeneration caused by transmembrane prion protein. J Cell Biol 188:515–526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robinson AL, Williamson H, Guere ME, Tharaldsen H, Baker K, Smith SL, Perez-Espona S, Krojerova-Prokesova J, Pemberton JM, Goldmann W, Houston F (2019) Variation in the prion protein gene (PRNP) sequence of wild deer in Great Britain and mainland Europe. Vet Res 50:59

    Article  PubMed  PubMed Central  Google Scholar 

  • Roh IS, Kim YC, Won SY, Jeong MJ, Park KJ, Park HC, Lee YR, Kang HE, Sohn HJ, Jeong BH (2022) First report of a strong association between genetic polymorphisms of the prion protein gene (PRNP) and susceptibility to chronic wasting disease in sika deer (Cervus nippon). Transbound Emerg Dis

  • Safar JG, Scott M, Monaghan J, Deering C, Didorenko S, Vergara J, Ball H, Legname G, Leclerc E, Solforosi L, Serban H, Groth D, Burton DR, Prusiner SB, Williamson RA (2002) Measuring prions causing bovine spongiform encephalopathy or chronic wasting disease by immunoassays and transgenic mice. Nat Biotechnol 20:1147–1150

    Article  CAS  PubMed  Google Scholar 

  • Saijo E, Kang HE, Bian J, Bowling KG, Browning S, Kim S, Hunter N, Telling GC (2013) Epigenetic dominance of prion conformers. PLoS Pathog 9:e1003692

    Article  PubMed  PubMed Central  Google Scholar 

  • Sandberg M, Al-Doujaily H, Sigurdson C, Glatzel M, O'Malley C, Powell C, Asante EA, Linehan JM, Brandner S, Wadsworth JD, Collinge J (2010) Chronic wasting disease prions are not transmissible to transgenic mice over-expressing human prion protein. J Gen Virol

  • Scott M, Groth D, Foster D, Torchia M, Yang S-L, Dearmond SJ, Prusiner SB (1993) Propagation of prions with artificial properties in transgenic mice expressing chimeric PrP genes. Cell 73:979–988

    Article  CAS  PubMed  Google Scholar 

  • Scott MR, Safar J, Telling G, Nguyen O, Groth D, Torchia M, Koehler R, Tremblay P, Walther D, Cohen FE, Dearmond SJ, Prusiner SB (1997) Identification of a prion protein epitope modulating transmission of bovine spongiform encephalopathy prions to transgenic mice. Proc Natl Acad Sci USA 94:14279–14284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scott MR, Will R, Ironside J, Nguyen HO, Tremblay P, Dearmond SJ, Prusiner SB (1999) Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans. Proc Natl Acad Sci USA 96:15137–15142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seelig DM, Mason GL, Telling GC, Hoover EA (2010) Pathogenesis of chronic wasting disease in cervidized transgenic mice. Am J Pathol 176:2785–2797

    Article  PubMed  PubMed Central  Google Scholar 

  • Seelig DM, Mason GL, Telling GC, Hoover EA (2011) Chronic wasting disease prion trafficking via the autonomic nervous system. Am J Pathol 179:1319–1328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shikiya RA, Langenfeld KA, Eckland TE, Trinh J, Holec SAM, Mathiason CK, Kincaid AE, Bartz JC (2017) PrPSc formation and clearance as determinants of prion tropism. PLoS Pathog 13:e1006298

    Article  PubMed  PubMed Central  Google Scholar 

  • Sigurdson CJ, Nilsson KP, Hornemann S, Heikenwalder M, Manco G, Schwarz P, Ott D, Rulicke T, Liberski PP, Julius C, Falsig J, Stitz L, Wuthrich K, Aguzzi A (2009) De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis. Proc Natl Acad Sci USA 106:304–309

    Article  CAS  PubMed  Google Scholar 

  • Smith JD, Moylan JS, Hardin BJ, Chambers MA, Estus S, Telling GC, Reid MB (2011) Prion protein expression and functional importance in skeletal muscle. Antioxidants & redox signaling

  • Sohn HJ, Kim JH, Choi KS, Nah JJ, Joo YS, Jean YH, Ahn SW, Kim OK, Kim DY, Balachandran A (2002) A case of chronic wasting disease in an elk imported to Korea from Canada. J Vet Med Sci 64:855–858

    Article  PubMed  Google Scholar 

  • Sun JL, Kim S, Crowell J, Webster BK, Raisley EK, Lowe DC, Bian J, Korpenfelt SL, Benestad SL, Telling GC (2023) Novel prion strain as cause of chronic wasting disease in a moose, Finland. Emerg Infect Dis 29:323–332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taguchi Y, Mohri S, Ironside JW, Muramoto T, Kitamoto T (2003) Humanized knock-in mice expressing chimeric prion protein showed varied susceptibility to different human prions. Am J Pathol 163:2585–2593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tamguney G, Giles K, Bouzamondo-Bernstein E, Bosque PJ, Miller MW, Safar J, Dearmond SJ, Prusiner SB (2006) Transmission of elk and deer prions to transgenic mice. J Virol 80:9104–9114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Telling GC (2011) Transgenic mouse models and prion strains. Top Curr Chem 305:79–99

    Article  CAS  PubMed  Google Scholar 

  • Telling GC (2022) The shape of things to come: structural insights into how prion proteins encipher heritable information. In press, Nature Communications

    Google Scholar 

  • Telling GC, Parchi P, Dearmond SJ, Cortelli P, Montagna P, Gabizon R, Mastrianni J, Lugaresi E, Gambetti P, Prusiner SB (1996) Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274:2079–2082

    Article  CAS  PubMed  Google Scholar 

  • Telling GC, Scott M, Hsiao KK, Foster D, Yang SL, Torchia M, Sidle KC, Collinge J, Dearmond SJ, Prusiner SB (1994) Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric human-mouse prion protein. Proc Natl Acad Sci USA 91:9936–9940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Telling GC, Scott M, Mastrianni J, Gabizon R, Torchia M, Cohen FE, Dearmond SJ, Prusiner SB (1995) Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell 83:79–90

    Article  CAS  PubMed  Google Scholar 

  • Torres JM, Espinosa JC, Aguilar-Calvo P, Herva ME, Relano-Gines A, Villa-Diaz A, Morales M, Parra B, Alamillo E, Brun A, Castilla J, Molina S, Hawkins SA, Andreoletti O (2014) Elements modulating the prion species barrier and its passage consequences. PLoS ONE 9:e89722

    Article  PubMed  PubMed Central  Google Scholar 

  • Wadsworth JD, Asante EA, Desbruslais M, Linehan JM, Joiner S, Gowland I, Welch J, Stone L, Lloyd SE, Hill AF, Brandner S, Collinge J (2004) Human prion protein with valine 129 prevents expression of variant CJD phenotype. Science 306:1793–1796

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Qin K, Camacho MV, Cali I, Yuan J, Shen P, Greenlee J, Kong Q, Mastrianni JA, Zou WQ (2021) Generation of human chronic wasting disease in transgenic mice. Acta Neuropathol Commun 9:158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  • Watts JC, Giles K, Stohr J, Oehler A, Bhardwaj S, Grillo SK, Patel S, Dearmond SJ, Prusiner SB (2012) Spontaneous generation of rapidly transmissible prions in transgenic mice expressing wild-type bank vole prion protein. Proc Natl Acad Sci USA 109:3498–3503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wells GAH, Scott AC, Johnson CT, Gunning RF, Hancock RD, Jeffrey M, Dawson M, Bradley R (1987) A novel progressive spongiform encephalopathy in cattle. Vet Rec 121:419–420

    Article  CAS  PubMed  Google Scholar 

  • Will RG, Cousens SN, Farrington CP, Smith PG, Knight RSG, Ironside JW (1999) Deaths from variant Creutzfeldt-Jakob disease. Lancet 353:979

    Article  CAS  PubMed  Google Scholar 

  • Williams ES, YOUNG S (1980) Chronic wasting disease of captive mule deer: a spongiform encephalopathy. J Wildl Dis 16:89–98

    Article  CAS  PubMed  Google Scholar 

  • Williams ES, Young S (1993) Neuropathology of chronic wasting disease of mule deer (Odocoileus hemionus) and Elk (Cervus elaphus nelsoni). Vet Pathol 30:36–45

    Article  CAS  PubMed  Google Scholar 

  • Wilson GA, Nakada SM, Bollinger TK, Pybus MJ, Merrill EH, Coltman DW (2009) Polymorphisms at the PRNP gene influence susceptibility to chronic wasting disease in two species of deer (Odocoileus spp.) in western Canada. J Toxicol Environ Health A 72:1025–1029

    Article  CAS  PubMed  Google Scholar 

  • Yuan Q, Eckland T, Telling G, Bartz J, Bartelt-Hunt S (2015) Mitigation of prion infectivity and conversion capacity by a simulated natural process–repeated cycles of drying and wetting. PLoS Pathog 11:e1004638

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by grants 1R01NS121682, 1R01NS109376, and PO1-0011877A from the National Institutes of Health.

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  1. Prion Research Center, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, USA

    Julianna L. Sun & Glenn C. Telling

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Sun, J.L., Telling, G.C. New developments in prion disease research using genetically modified mouse models. Cell Tissue Res 392, 33–46 (2023). https://doi.org/10.1007/s00441-023-03761-x

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