Abstract
Although the prion protein (PrP) was discovered in the early 1980s, there is still a considerable lack of knowledge of the normal function of the PrP protein and its precise role in the infectious process of transmissible spongiform encephalopathies (TSEs) or prion diseases. The production and use of a multitude of transgenic mice expressing different forms of PrP has enabled us to increase our knowledge of PrP in health and disease. Using mice expressing PrP from different species, we are able to define the strain of TSE agent infecting a wide range of hosts and model the transmission potential of each agent within and between species. Transgenic mouse models are also utilised in investigating the normal function of PrP, the impact of differential glycosylation in PrP biology and the genetics underlying disease susceptibility. Advances in transgenic technologies have enabled us to control both spatial and temporal expression of PrP, allowing us to define the mechanisms and routes of disease pathogenesis. Transgenic mice also play a vital role in understanding the mechanisms of neurodegeneration in the TSEs, which may also lead to a better understanding of the other protein misfolding diseases such as Alzheimer’s disease.
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Notes
- 1.
Gene targeting is a technique that uses homologous recombination to alter an endogenous gene
- 2.
Sporadic CJD is subclassified via the codon 129 genotype of the host and typed by biochemical properties
References
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(23):6358–6366
Baker CA, Martin D, Manuelidis L (2002) Microglia from Creutzfeldt-Jakob disease-infected brains are infectious and show specific mRNA activation profiles. J Virol 76(21):10905–10913. doi:10.1128/jvi.76.21.10905-10913.2002
Barron RM, Thomson V, Jamieson E, Melton DW, Ironside J, Will R, Manson JC (2001) Changing a single amino acid in the N-terminus of murine PrP alters TSE incubation time across three species barriers. EMBO J 20(18):5070–5078
Beringue V, Herzog L, Reine F, Le Dur A, Casalone C, Vilotte JL, Laude H (2008) Transmission of atypical bovine prions to mice transgenic for human prion protein. Emerg Infect Dis 14(12):1898–1901
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(5):393–398
Bishop MT, Ritchie DL, Will RG, Ironside JW, Head MW, Thomson V, Bruce M, Manson JC (2008) No major change in vCJD agent strain after secondary transmission via blood transfusion. PLoS One 3(8):e2878. doi:10.1371/journal.pone.0002878
Bishop MT, Will RG, Manson JC (2010) Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties. Proc Natl Acad Sci U S A 107(26):12005–12010. doi:10.1073/pnas.1004688107 [pii]
Blattler T, Brandner S, Raeber AJ, Klein MA, Voigtlander T, Weissmann C, Aguzzi A (1997) PrP-expressing tissue required for transfer of scrapie infectivity from spleen to brain. Nature 389(6646):69–73
Bradford BM, Tuzi NL, Feltri ML, McCorquodale C, Cancellotti E, Manson JC (2009) Dramatic reduction of PrP C level and glycosylation in peripheral nerves following PrP knock-out from Schwann cells does not prevent transmissible spongiform encephalopathy neuroinvasion. J Neurosci 29(49):15445–15454. doi:29/49/15445 [pii] 10.1523/JNEUROSCI.4195-09.2009
Brown DR, Herms J, Kretzschmar HA (1994a) Mouse cortical cells lacking cellular PrP survive in culture with a neurotoxic PrP fragment. Neuroreport 5(16):2057–2060
Brown P, Gibbs CJ Jr, Rodgers-Johnson P, Asher DM, Sulima MP, Bacote A, Goldfarb LG, Gajdusek DC (1994b) Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol 35(5):513–529. doi:10.1002/ana.410350504
Bruce MB, Will RG, Fraser H (1999) Comparison of the biological characteristics of BSE and CJD in mice. In: Iqbal K, Swaab DF, Winblad B, Wisniewski HM (eds) Alzheimer’s disease and related disorders. Wiley, Chichester, pp 553–560
Bruce ME, McBride PA, Jeffrey M, Scott JR (1994) PrP in pathology and pathogenesis in scrapie-infected mice. Mol Neurobiol 8(2–3):105–112. doi:10.1007/BF02780660
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(6650):498–501
Bueler H, Fischer M, Lang Y, Bluethmann H, Lipp HP, DeArmond SJ, Prusiner SB, Aguet M, Weissmann C (1992) Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356(6370):577–582. doi:10.1038/356577a0
Cali I, Castellani R, Yuan J, Al-Shekhlee A, Cohen ML, Xiao X, Moleres FJ, Parchi P, Zou WQ, Gambetti P (2006) Classification of sporadic Creutzfeldt-Jakob disease revisited. Brain 129(Pt 9):2266–2277
Cancellotti E, Bradford BM, Tuzi NL, Hickey RD, Brown D, Brown KL, Barron RM, Kisielewski D, Piccardo P, Manson JC (2010) Glycosylation of PrPC determines timing of neuroinvasion and targeting in the brain following transmissible spongiform encephalopathy infection by a peripheral route. J Virol 84(7):3464–3475. doi:10.1128/JVI.02374-09 [pii]
Cancellotti E, Wiseman F, Tuzi NL, Baybutt H, Monaghan P, Aitchison L, Simpson J, Manson JC (2005) Altered glycosylated PrP proteins can have different neuronal trafficking in brain but do not acquire scrapie-like properties. J Biol Chem 280(52):42909–42918
Chesebro B, Race R, Kercher L (2005) Scrapie pathogenesis in brain and retina: Effects of prion protein expression in neurons and astrocytes. J Neurovirol 11(5):476–480. doi:doi:10.1080/13550280500187583
Collinge J, Palmer MS, Dryden AJ (1991) Genetic predisposition to iatrogenic Creutzfeldt-Jakob disease. Lancet 337(8755):1441–1442. doi:0140-6736(91)93128-V [pii]
Cronier S, Laude H, Peyrin J-M (2004) Prions can infect primary cultured neurons and astrocytes and promote neuronal cell death. Proc Natl Acad Sci U S A 101(33):12271–12276. doi:10.1073/pnas.0402725101
Dickinson AG, Meikle VMH, Fraser H (1968) Identification of a gene which controls the incubation period of some strains of scrapie agent in mice. J Comp Pathol 78(3):293–299
Eloit M, Adjou K, Coulpier M, Fontaine JJ, Hamel R, Lilin T, Messiaen S, Andreoletti O, Baron T, Bencsik A, Gaelle Biacabe A, Beringue V, Laude H, Le Dur A, Vilotte JL, Comoy E, Deslys JP, Grassi J, Simon S, Lantier F, Sarradin P (2005) BSE agent signatures in a goat. Veterinary Record 156(16):523–524. doi:10.1136/vr.156.16.523-b
Follet J, Lemaire-Vieille C, Blanquet-Grossard F, Podevin-Dimster V, Lehmann S, Chauvin JP, Decavel JP, Varea R, Grassi J, Fontes M, Cesbron JY (2002) PrP expression and replication by Schwann cells: implications in prion spreading. J Virol 76(5):2434–2439
Fraser H, Bruce ME, Chree A, McConnell I, Wells GA (1992) Transmission of bovine spongiform encephalopathy and scrapie to mice. J Gen Virol 73(Pt 8):1891–1897
Hill AF, Desbruslais M, Joiner S, Sidle KC, Gowland I, Collinge J, Doey LJ, Lantos P (1997) The same prion strain causes vCJD and BSE. Nature 389(6650):448–450. doi:10.1038/38925
Hill AF, Joiner S, Wadsworth JD, Sidle KC, Bell JE, Budka H, Ironside JW, Collinge J (2003) Molecular classification of sporadic Creutzfeldt-Jakob disease. Brain 126(Pt 6):1333–1346
Ilieva H, Polymenidou M, Cleveland DW (2009) Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J Cell Biol 187(6):761–772. doi:10.1083/jcb.200908164
Jeffrey M, Goodsir CM, Bruce ME, McBride PA, Scott JR (1994) Infection-specific prion protein (PrP) accumulates on neuronal plasmalemma in scrapie-infected mice. Ann N Y Acad Sci 724(1):327–330. doi:10.1111/j.1749-6632.1994.tb38923.x
Jeffrey M, Goodsir CM, Race RE, Chesebro B (2004) Scrapie-specific neuronal lesions are independent of neuronal PrP expression. Ann Neurol 55(6):781–792. doi:10.1002/ana.20093
Jeffrey M, Martin S, Gonzalez L, Foster J, Langeveld JP, van Zijderveld FG, Grassi J, Hunter N (2006) Immunohistochemical features of PrP(d) accumulation in natural and experimental goat transmissible spongiform encephalopathies. J Comp Pathol 134(2–3):171–181. doi:S0021-9975(05)00121-0 [pii] 10.1016/j.jcpa.2005.10.003
Kercher L, Favara C, Chan CC, Race R, Chesebro B (2004) Differences in scrapie-induced pathology of the retina and brain in transgenic mice that express hamster prion protein in neurons, astrocytes, or multiple cell types. Am J Pathol 165(6):2055–2067. doi:10.1016/S0002-9440(10)63256-7 [pii]
Kercher L, Favara C, Striebel JF, LaCasse R, Chesebro B (2007) Prion protein expression differences in microglia and astroglia influence scrapie-induced neurodegeneration in the retina and brain of transgenic mice. J Virol 81(19):10340–10351. doi:10.1128/JVI.00865-07 [pii]
Kimberlin RH, Cole S, Walker CA (1987) Temporary and permanent modifications to a single strain of mouse scrapie on transmission to rats and hamsters. J Gen Virol 68(7):1875–1881. doi:10.1099/0022-1317-68-7-1875
Kimberlin RH, Walker CA (1979) Pathogenesis of scrapie: agent multiplication in brain at the first and second passage of hamster scrapie in mice. J Gen Virol 42(1):107–117. doi:10.1099/0022-1317-42-1-107
Kingsbury D, Kasper K, Stites D, Watson J, Hogan R, Prusiner S (1983) Genetic control of scrapie and Creutzfeldt-Jakob disease in mice. J Immunol 131(1):491–496
Kretzschmar HA, Prusiner SB, Stowring LE, DeArmond SJ (1986) Scrapie prion proteins are synthesized in neurons. Am J Pathol 122(1):1–5
Llewelyn CA, Hewitt PE, Knight RSG, Amar K, Cousens S, Mackenzie J, Will RG (2004) Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 363(9407):417–421
Lloyd SE, Onwuazor ON, Beck JA, Mallinson G, Farrall M, Targonski P, Collinge J, Fisher EMC (2001) Identification of multiple quantitative trait loci linked to prion disease incubation period in mice. Proc Natl Acad Sci 98(11):6279–6283. doi:10.1073/pnas.101130398
Lloyd SE, Thompson SR, Beck JA, Linehan JM, Wadsworth JD, Brandner S, Collinge J, Fisher EM (2004) Identification and characterization of a novel mouse prion gene allele. Mamm Genome 15(5):383–389. doi:10.1007/s00335-004-3041-5
Mallucci G, Dickinson A, Linehan J, Klohn PC, Brandner S, Collinge J (2003) Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science 302(5646):871–874. doi:10.1126/science.1090187 302/5646/871 [pii]
Mallucci GR, White MD, Farmer M, Dickinson A, Khatun H, Powell AD, Brandner S, Jefferys JG, Collinge J (2007) Targeting cellular prion protein reverses early cognitive deficits and neurophysiological dysfunction in prion-infected mice. Neuron 53(3):325–335. doi:S0896-6273(07)00008-6 [pii] 10.1016/j.neuron.2007.01.005
Manolakou K, Beaton J, McConnell I, Farquar C, Manson J, Hastie ND, Bruce M, Jackson IJ (2001) Genetic and environmental factors modify bovine spongiform encephalopathy incubation period in mice. Proc Natl Acad Sci U S A 98(13):7402–7407. doi:10.1073/pnas.121172098 [pii]
Manson JC, Clarke AR, Hooper ML, Aitchison L, McConnell I, Hope J (1994a) 129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal. Mol Neurobiol 8(2–3):121–127. doi:10.1007/BF02780662
Manson JC, Clarke AR, McBride PA, McConnell I, Hope J (1994b) PrP gene dosage determines the timing but not the final intensity or distribution of lesions in scrapie pathology. Neurodegeneration 3(4):331–340
Manson JC, Jamieson E, Baybutt H, Tuzi NL, Barron R, McConnell I, Somerville R, Ironside J, Will R, Sy MS, Melton DW, Hope J, Bostock C (1999) A single amino acid alteration (101L) introduced into murine PrP dramatically alters incubation time of transmissible spongiform encephalopathy. EMBO J 18(23):6855–6864
McBride PA, Schulz-Schaeffer WJ, Donaldson M, Bruce M, Diringer H, Kretzschmar HA, Beekes M (2001) Early spread of scrapie from the gastrointestinal tract to the central nervous system involves autonomic fibers of the splanchnic and vagus nerves. J Virol 75(19):9320–9327. doi:10.1128/JVI.75.19.9320-9327.2001
Moore RC, Hope J, McBride PA, McConnell I, Selfridge J, Melton DW, Manson JC (1998) Mice with gene targetted prion protein alterations show that Prnp, Sinc and Prni are congruent. Nat Genet 18(2):118–125
Moser M, Colello RJ, Pott U, Oesch B (1995) Developmental expression of the prion protein gene in glial cells. Neuron 14(3):509–517
Muramoto T, Kitamoto T, Tateishi J, Goto I (1993) Accumulation of abnormal prion protein in mice infected with Creutzfeldt-Jakob disease via intraperitoneal route: a sequential study. Am J Pathol 143(5):1470–1479
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(3):e1001319. doi:10.1371/journal.ppat.1001319
Palmer MS, Dryden AJ, Hughes JT, Collinge J (1991) Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature 352(6333):340–342. doi:10.1038/352340a0
Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I, Budka H, Kopp N, Piccardo P, Poser S, Rojiani A, Streichemberger N, Julien J, Vital C, Ghetti B, Gambetti P, Kretzschmar H (1999) Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 46(2):224–233
Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW (2004) Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 364(9433):527–529
Plinston C, Hart P, Chong A, Hunter N, Foster J, Piccardo P, Manson JC, Barron RM (2011) Increased susceptibility of human-PrP transgenic mice to bovine spongiform encephalopathy infection following passage in sheep. J Virol 85(3):1174–1181. doi:10.1128/JVI.01578-10 [pii]
Priola SA, Lawson VA (2001) Glycosylation influences cross-species formation of protease-resistant prion protein. EMBO J 20(23):6692–6699. doi:10.1093/emboj/20.23.6692
Race RE, Priola SA, Bessen RA, Ernst D, Dockter J, Rall GF, Mucke L, Chesebro B, Oldstone MB (1995) Neuron-specific expression of a hamster prion protein minigene in transgenic mice induces susceptibility to hamster scrapie agent. Neuron 15(5):1183–1191. doi:0896-6273(95)90105-1 [pii]
Raeber AJ, Race RE, Brandner S, Priola SA, Sailer A, Bessen RA, Mucke L, Manson J, Aguzzi A, Oldstone MB, Weissmann C, Chesebro B (1997) Astrocyte-specific expression of hamster prion protein (PrP) renders PrP knockout mice susceptible to hamster scrapie. EMBO J 16(20):6057–6065
Ritchie DL, Boyle A, McConnell I, Head MW, Ironside JW, Bruce ME (2009) Transmissions of variant Creutzfeldt-Jakob disease from brain and lymphoreticular tissue show uniform and conserved bovine spongiform encephalopathy-related phenotypic properties on primary and secondary passage in wild-type mice. J Gen Virol 90(Pt 12):3075–3082. doi:10.1099/vir.0.013227-0 [pii]
Sandberg MK, Al-Doujaily H, Sigurdson CJ, 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 overexpressing human prion protein. The Journal of General Virology 91(Pt 10):2651–2657. doi:10.1099/vir.0.024380-0 [pii]
Scott M, Foster D, Mirenda C, Serban D, Coufal F, Walchli M, Torchia M, Groth D, Carlson G, DeArmond SJ, Westaway D, Prusiner SB (1989) Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques. Cell 59(5):847–857. doi:0092-8674(89)90608-9 [pii]
Taraboulos A, Serban D, Prusiner SB (1990) Scrapie prion proteins accumulate in the cytoplasm of persistently infected cultured cells. J Cell Biol 110(6):2117–2132. doi:10.1083/jcb.110.6.2117
Tuzi NL, Cancellotti E, Baybutt H, Blackford L, Bradford B, Plinston C, Coghill A, Hart P, Piccardo P, Barron RM, Manson JC (2008) Host PrP glycosylation: a major factor determining the outcome of prion infection. PLoS Biol 6(4):e100. doi:07-PLBI-RA-2655 [pii] 10.1371/journal.pbio.0060100
Tuzi NL, Clarke AR, Bradford B, Aitchison L, Thomson V, Manson JC (2004) Cre-loxP mediated control of PrP to study transmissible spongiform encephalopathy diseases. Genesis 40(1):1–6
Uro-Coste E, Cassard H, Simon S, Lugan S, Bilheude JM, Perret-Liaudet A, Ironside JW, Haik S, Basset-Leobon C, Lacroux C, Peoch K, Streichenberger N, Langeveld J, Head MW, Grassi J, Hauw JJ, Schelcher F, Delisle MB, Andreoletti O (2008) Beyond PrP9res) type 1/type 2 dichotomy in Creutzfeldt-Jakob disease. PLoS Pathog 4(3):e1000029. doi:10.1371/journal.ppat.1000029
van Keulen LJM, Schreuder BEC, Meloen RH, Poelen-van den Berg M, Mooij-Harkes G, Vromans MEW, Langeveld JPM (1995) Immumohistochemical detection and localization of prion protein in brain tissue of sheep with natural scrapie. Veter Pathol Online 32(3):299–308. doi:10.1177/030098589503200312
Weissmann C, Bueler H, Fischer M, Sailer A, Aguzzi A, Aguet M (1994a) PrP-deficient mice are resistant to scrapie. Ann N Y Acad Sci 724:235–240
Weissmann C, Bueler H, Fischer M, Sauer A, Aguet M (1994b) Susceptibility to scrapie in mice is dependent on PrPC. Philos Trans R Soc Lond 343(1306):431–433. doi:10.1098/rstb.1994.0040
Westaway D, Goodman PA, Mirenda CA, McKinley MP, Carlson GA, Prusiner SB (1987) Distinct prion proteins in short and long scrapie incubation period mice. Cell 51(4):651–662
Westaway D, Mirenda CA, Foster D, Zebarjadian Y, Scott M, Torchia M, Yang SL, Serban H, DeArmond SJ, Ebeling C et al (1991) Paradoxical shortening of scrapie incubation times by expression of prion protein transgenes derived from long incubation period mice. Neuron 7(1):59–68. doi:0896-6273(91)90074-A [pii]
Wilson R, Plinston C, Hunter N, Casalone C, Corona C, Tagliavini F, Suardi S, Ruggerone M, Moda F, Graziano S, Sbriccoli M, Cardone F, Pocchiari M, Ingrosso L, Baron T, Richt J, Andreoletti O, Simmons M, Lockey R, Manson JC, Barron RM (2012) Chronic wasting disease and atypical forms of bovine spongiform encephalopathy and scrapie are not transmissible to mice expressing wild-type levels of human prion protein. J Gen Virol 93(7):1624–1629
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Diack, A.B., Wilson, R., Cancellotti, E., Bradford, B., Bishop, M., Manson, J.C. (2013). Transgenic Mice Modelling. In: Zou, WQ., Gambetti, P. (eds) Prions and Diseases. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5338-3_10
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