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Transgenesis Applied to Transmissible Spongiform Encephalopathies

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Abstract

Transmissible spongiform encephalopathies (TSE) are fatal neurodegenerative disorders present in various mammals. TSEs have been studies intensively, even more so following the BSE crisis and the subsequent threat of a human nvCJD epidemic. In the ‘protein-only’ hypothesis, the infectious agent, called prion, is assumed to be a misfolded host protein. Transgenesis has mainly been applied to study the role of this protein, its structure–function relationship with respect to its pathogenic properties and to assess the genetic origin of the well-recognised species barrier effect. This approach has somewhat supplemented the lack of in vitro models. This review will try to summarise the impressive work that has been done in this field. Although many questions remain unanswered, transgenic experiments have and will still improve our knowledge on this disease and might help us to develop critically needed therapeutic approaches.

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References

  • Aguzzi A, Brandner S, Fischer MB, Furukawa H, Glatzel M, Hawkins C et al. (2001) Spongiform encephalopathies: insight from transgenic models. Adv Virus Res 56: 313–352.

    Google Scholar 

  • Asante EA and Collinge J (2001) Transgenic studies of the influence of the PrP structure on TSE diseases. Adv Prot Chem 57: 273–311.

    Google Scholar 

  • Barron RM, Thomson V, Jamieson E, Melton DW, Ironside J, Will R et al. (2001) Changing a single amino acid in the N-terminus of murine PrP alters TSE incubation time across three species barriers. EMBO J 20: 5070–5078.

    Google Scholar 

  • Behrens A and Aguzzi A (2002) Small is not beautiful: antagonizing functions for the prion protein PrPC and its homologue Dpl. Trends Neurosci 25: 150–154.

    Google Scholar 

  • Behrens A, Brandner S, Genoud N and Aguzzi A (2001) Normal neurogenesis and scrapie pathogenesis in neural grafts lacking the prion protein homologue Doppel. EMBO Rep 2: 347–352.

    Google Scholar 

  • Blättler T, Brandner S, Raeber AJ, Klein MA, Voigtlander T, Weissmann C et al. (1997) PrP-expressing tissue required for. transfer of scrapie infectivity from spleen to brain. Nature 389: 69–73.

    Google Scholar 

  • Bosque PJ, Ryou C, Telling G, Peretz D, Legname G, DeArmond SJ et al. (2002) Prions in skeletal muscle. Proc Natl Acad Sci USA 99: 3812–3817.

    Google Scholar 

  • Brandner S, Isenmann S, Raeber A, Fischer M, Sailer A, Kobayashi Y et al. (1996) Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature 379: 339–343.

    Google Scholar 

  • Brown DR (2000) PrPsc-like prion protein peptide inhibits the function of cellular prion protein. Biochem J 352: 511–518.

    Google Scholar 

  • Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R et al. (1997) The cellular prion protein binds copper in vivo. Nature 390: 684–687.

    Google Scholar 

  • Brown KL, Stewart K, Ritchie DL, Mabbott NA, Williams A, Fraser H et al. (1999) Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dentritic cells. Nat Med 5: 1308–1312.

    Google Scholar 

  • Bruce ME, McConnell I, Fraser H and Dickinson AG (1991) The disease characteristics of scrapie in Sinc congenic mouse lines: implications for the nature of the agent and host control of pathogenesis. J GenVirol72: 595–603.

    Google Scholar 

  • Büeler H, Fischer M, Lang Y, Bluethmann H, Lipp HP, DeArmond SJ et al. (1992) Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356: 577–582.

    Google Scholar 

  • Büeler H, Aguzzi A, Sailer A, Greiner RA, Autenried P, Aguet M et al. (1993) Mice devoid of PrP are resistant to scrapie. Cell 73: 1339–1347.

    Google Scholar 

  • Büeler H, Raeber A, Sailer A, Fischer M, Aguzzi A and 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.

    Google Scholar 

  • Buschmann A, Pfaff E, Reifenberg K, Müller HM and Groschup MH (2000) Detection of cattle-derived BSE prions using transgenic mice overexpressing bovine PrPc. Arch Virol Suppl 16: 75–86.

    Google Scholar 

  • Carlson GA, Kingsbury DT, Goodman PA, Coleman S, Marshall ST, DeArmond S et al. (1986) Linkage of prion protein and scrapie incubation time genes. Cell 46: 503–511.

    Google Scholar 

  • Carlson GA, Ebeling C, Yang SL, Telling G, Torchia M, Groth D et al. (1994) Prion isolate specified allotypic interactions between the cellular and scrapie prion proteins in congenic and transgenic mice. Proc Natl Acad Sci USA 91: 5690–5694.

    Google Scholar 

  • Chiesa R, Piccardo P, Ghetti B and Harris DA (1998) Neurological illness in transgenic mice expressing a prion protein with an insertional mutation. Neuron 21: 1339–1351.

    Google Scholar 

  • Chiesa R, Drisaldi B, Quaglio E, Migheli A, Piccardo P, Ghetti B et al. (2000) Accumulation of protease-resistant prion protein (PrP) and apoptosis of cerebellar granule cells in transgenic mice expressing a PrP insertional mutation. Proc Natl Acad Sci USA 97: 5574–5579.

    Google Scholar 

  • Colling SB, King TM, Collinge J and Jefferys JGR (1995) Prion protein null mice: abnormal intrinsic properties of hippocampal CA1 pyramidal cells. Brain Res Assoc Abst 12: 49.

    Google Scholar 

  • Collinge J (2001) Prion diseases of humans and animals: their causes and molecular basis. Annu Rev Neurosci 24: 519–550.

    Google Scholar 

  • Collinge J and Hawke S (1998) B lymphocytes in prion neuroinvasion: central or peripheral players? Nat Med 4: 1369–1370.

    Google Scholar 

  • Collinge J, Whittington MA, Sidle KC, Smith CJ, Palmer MS, Clarke AR et al. (1994) Prion protein is necessary for normal synaptic function. Nature 370: 295–297.

    Google Scholar 

  • Collinge J, Palmer MS, Sidle KCL, Hill AF, Gowland I, Meads J et al. (1995) Unaltered susceptibility to BSE in transgenic mice expressing human prion protein. Nature 378: 779–783.

    Google Scholar 

  • Comincini S, Castiglioni BM, Foti GM, Del Vecchio I and Ferretti L (2001) Isolation and molecular characterization of rasfadin, a novel gene in the vicinity of the bovine prion gene. Mamm Genome 12: 150–156.

    Google Scholar 

  • Crozet C, Flamant F, Bencsik A, Aubert D, Samarut J and Baron T (2001) Efficient transmission of two different sheep scrapie isolates in transgenic mice expressing the ovine PrP gene. J Virol 75: 5328–5334.

    Google Scholar 

  • DeArmond SJ, Sanchez H, Yehiely F, Qiu Y, Ninchak-Casey A, Daggett V et al. (1997) Selective neuronal targeting in prion disease. Neuron 19: 1337–1348.

    Google Scholar 

  • Denning C, Burl S, Ainslie A, Bracken J, Dinnyes A, Fletcher J et al. (2001) Deletion of the á (1,3) galactosyl transferase (GGTA1) gene and the prion protein (PrP) gene in sheep. Nat Biotechnol 19: 559–562.

    Google Scholar 

  • Dickinson AG and MacKay JMK (1964) Genetical control of the incubation period in mice of the neurological disease, scrapie. Heredity 19: 279–288.

    Google Scholar 

  • Elsen JM, Amigues Y, Schelcher F, Ducrocq V, Andreoletti O, Eychenne F et al. (1999) Genetic susceptibility and transmission factors in scrapie: detailed analysis of an epidemic in a closed flock of Romanov. Arch Virol 144: 431–445.

    Google Scholar 

  • Fischer M, Rülicke T, Raeber A, Sailer A, Moser M, Oesch B et al. (1996) Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO J 15: 1255–1264.

    Google Scholar 

  • Fischer MB, Roeckl C, Parizek P, Schwarz HP and Aguzzi A (2000) Binding of diseaseassociated prion protein to plasminogen. Nature 408: 479–483.

    Google Scholar 

  • Flechsig E, Shmerling D, Hegyi I, Raeber AJ, Fischer M, Cozzio A et al. (2000) Prion protein devoid of the octapeptide repeat region restores susceptibility to scrapie in PrP knockout mice. Neuron 27: 399–408.

    Google Scholar 

  • Glatzel M and Aguzzi A (2000) PrP C expression in the peripheral nervous system is a determinant of prion neuroinvasion. J Gen Virol 81: 2813–2821.

    Google Scholar 

  • Glatzel M, Heppner FL, Albers KM and Aguzzi A (2001) Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron 31: 25–34.

    Google Scholar 

  • Goldmann W, Hunter N, Foster JD, Salbaum JM, Beyreuther K and Hope J (1990) Two alleles of a neural protein gene linked to scrapie in sheep. Biochemistry 87: 2476–2480.

    Google Scholar 

  • Goldmann W, Hunter N, Smith G, Foster J and Hope J (1994) PrP genotype and agents effects in scrapie: change in allelic interaction with different isolates of agent in sheep, a natural host of scrapie. J GenVirol75: 989–995.

    Google Scholar 

  • Gomi H, Yokoyama T, Fujimoto K, Ikeda T, Katoh A, Itoh T et al. (1995) Mice devoid of the glial fibrillary acidic protein develop normally and are susceptible to scrapie prions. Neuron 14: 29–41.

    Google Scholar 

  • Hegde RS, Mastrianni JA, Scott MR, DeFea KA, Tremblay P, Torchia M et al. (1998) A transmembrane form of the prion protein in neurodegenerative disease. Science 279: 827–834.

    Google Scholar 

  • Hedge RS, Tremblay P, Groth D, DeArmond SJ, Prusiner SB and Lingappa VR (1999) Transmissible and genetic prion disease share a common pathway of neurodegeneration. Nature 402: 822–826.

    Google Scholar 

  • Heppner FL, Mushahl C, Arrighi I, Klein MA, Rülicke T, Oesch B et al. (2001) Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies. Science 294: 178–182.

    Google Scholar 

  • Hernandez-Sanchez J, Waddington D, Wiener P, Haley CS and Williams JL (2002) Genome-wide search for markers. associated with bovine spongiform encephalopathy. Mamm Genome 13: 164–168.

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  • Hsiao KK, Baker HF, Crow TJ, Poulter M, Owen F, Terwilliger JD et al. (1989) Linkage of a prion protein missense variant to Gerstmann-Straussler syndrome. Nature 338: 342–345.

    Google Scholar 

  • Hsiao KK, Groth D, Scott M, Yang SL, Serban H, Rapp D et al. (1994) Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein. Proc Natl Acad Sci USA 91: 9126–9130.

    Google Scholar 

  • Kaeser PS, Klein MA, Schwarz and Aguzzi A. (2001) Efficient lymphoreticular prion propagation requires PrPc in stromal and hematopoietic cells. J Virol75: 7097–7106.

    Google Scholar 

  • Kaneko K, Zulianello L, Scott M, Cooper CM, Wallace AC, James TL et al. (1997) Evidence for protein X binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation. Proc Natl Acad Sci USA 94: 10069–10074.

    Google Scholar 

  • Keshet GI, Ovadia H, Taraboulos A and Gabizon R (1999) Scrapie-infected mice and PrP knockout mice share abnormal localization and activity of neuronal nitric oxide synthase. J Neurochem 72: 1224–1231.

    Google Scholar 

  • Kimberlin RH, Cole S and Walker CA (1986) Transmissible mink encephalopathy (TME) in Chinese hamsters: identification of two strains of TME and comparison with scrapie. Neuropathol Appl Neurobiol 12: 197–206.

    Google Scholar 

  • Kimberlin RH, Cole S and Walker CA (1987) Temporary and permanent modifications to a single strain of mouse scrapie on transmission to rats and hamsters. J GenVirol68: 1875–1881.

    Google Scholar 

  • Klein MA, Frigg R, Flechsig E, Raeber AJ, Kalinke U, Bluethmann H et al. (1997) A crucial role for B cells in neuroinvasive scrapie. Nature 390: 687–690.

    Google Scholar 

  • Klein MA, Frigg R, Raeber AJ, Flechsig E, Hegyi I, Zinkernagel RM et al. (1998) PrP expression in B lymphocytes is not required for prion neuroinvasion. Nat Med 4: 1429–1433.

    Google Scholar 

  • Klein MA, Kaeser PS, Schwarz P, Weyd H, Xenarios I, Zinkernagel RM et al. (2001) Complement facilitates early prion pathogenesis. Nat Med 7: 488–492.

    Google Scholar 

  • Kretzschmar HA, Prusiner SB, Stowring LE and DeArmond SJ (1986) Scrapie prion proteins are synthesized in neurons. Am J Pathol 122: 1–5.

    Google Scholar 

  • Kuwahara C, Takeuchi AM, Nishimura T, Haraguchi K, Kubosaki A, Matsumoto Y et al. (1999) Prions prevent neuronal cell death. Nature 400: 225–226.

    Google Scholar 

  • Lasmézas CI, Deslys JP, Robain O, Jaegly A, Beringue V, Peyrin JM et al. (1997) Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science 275: 402–405.

    Google Scholar 

  • Laude H, Vilette D, Le Dur A, Archer F, Soulier S, Besnard N et al. (2002) New in vivo and ex vivo models for the experimental study of sheep scrapie: development and perspectives. CR Biol 325: 49–57.

    Google Scholar 

  • Lemaire-Vieille C, Schulze T, Podevin-Dimster V, Follet J, Bailly Y, Blanquet-Grossard F et al. (2000) Epithelial and endothelial expression of the green fluorescent protein reporter gene under the control of bovine prion protein (PrP) gene regulatory sequences in transgenic mice. Proc Natl Acad Sci USA 97: 5422–5427.

    Google Scholar 

  • Li A, Sakaguchi S, Shigematsu K, Atarashi R, Roy BC, Nakaoke R et al. (2000) Physiological expression of the gene for PrP-like protein, PrPLP/Dpl, by brain endothelial cells and its ectopic expression in neurons of PrP-deficient mice ataxic due to Purkinje cell degeneration. Am J Pathol 157: 1447–1452.

    Google Scholar 

  • Lloyd SE, Onwuazor ON, Beck JA, Mallinson G, Farrall M, Targonski P et al. (2001) Identification of multiple quantitative trait loci linked to prion disease incubation period in mice. Proc Natl Acad Sci USA 98: 6279–6283.

    Google Scholar 

  • Mabbott NA, Williams A, Farquhar CF, Pasparakis M, Kollias G and Bruce ME (2000a) Tumor necrosis factor α-deficient, but not interleukin-6-deficient, mice resist peripheral infection with scrapie. J Virol7: 3338–3344.

    Google Scholar 

  • Mabbott NA, MacKay F, Minns F and Bruce ME (2000) Temporary inactivation of follicular dentritic cells delays neuroinvasion of scrapie. Nat Med 6: 719–720.

    Google Scholar 

  • Mabbott NA, Bruce ME, Botto M, Walport MJ and Pepys MB (2001) Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie. Nat Med 7: 485–487.

    Google Scholar 

  • Mallucci GR, Ratté S, Asante EA, Linehan J, Gowland I, Jefferys JGR et al. (2002) Post-natal knock-out of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration. EMBO J 21: 202–210.

    Google Scholar 

  • Manolakou K, Beaton J, McConnell I, Farquar C, Manson J, Hastie ND et al. (2001) Genetic and environmental factors modify bovine spongiform encephalopathy incubation period in mice. Proc Natl Acad Sci USA 98: 7402–7407.

    Google Scholar 

  • Manson JC, Clarke AR, Hooper ML, Aitchison L, McConnell I and Hope J (1994a) 129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal. Mol Neurobiol 8: 121–127.

    Google Scholar 

  • Manson JC, Clarke AR, McBride PA, McConnell I and Hope J (1994b) PrP gene dosage determines the timing but not the final intensity or distribution of lesions in scrapie pathology. Neurodegeneration 3: 331–340.

    Google Scholar 

  • Manson JC, Hope J, Clarke AR, Johnston A, Black C and MacLeod N (1995) PrP dosage and long term potentiation. Neurodegeneration 4: 113–114.

    Google Scholar 

  • Manson JC, Jamieson E, Baybutt H, Tuzi NL, Barron R, McConnell I et al. (1999) A single amino acid alteration (101L) introduced into murine PrP dramatically alters incubation time of transmissble spongiform encephalopathy. EMBO J 18: 6855–6864.

    Google Scholar 

  • Mastrangelo P and Westaway D (2001) The prion gene complex encoding PrPc and Doppel: insights from mutational analysis. Gene 275: 1–18.

    Google Scholar 

  • Meggio F, Negro A, Sarno S, Ruzzene M, Bertoli A, Sorgato MC et al. (2000) Bovine prion protein as a modulator of protein kinase CK2. Biochem J 352: 191–196.

    Google Scholar 

  • Milhavet O, McMahon HEM, Rachidi W, Nishida N, Katamine S, Mangé A et al. (2000) Prion infection impairs the cellular response to oxidative stress. Proc Natl Acad Sci USA 97: 13937–13942.

    Google Scholar 

  • Mo H, Moore RC, Cohen FE, Westaway D, Prusiner SB, Wright PE et al. (2001) Two different neurodegenerative diseases caused by proteins with similar structures. Proc Natl Acad Sci USA 98: 2352–2357.

    Google Scholar 

  • Montrasio F, Frigg R, Glatzel M, Klein MA, Mackay F, Aguzzi A et al. (2000) Impaired prion replication in spleens of mice lacking functional follicular dentritic cells. Science 288: 1257–1259.

    Google Scholar 

  • Moore RC and Melton DW (1997) Transgenic analysis of prion diseases. Mol Hum Reprod 3: 529–544.

    Google Scholar 

  • Moore RC, Redhead NJ, Selfridge J, Hope J, Manson JC and Melton DW (1995) Double replacement gene targeting for the production of a series of mouse strains with different prion protein gene alterations. Bio/Technology 13: 999–1004.

    Google Scholar 

  • Moore RC, Hope J, McBride PA, McConnell I, Selfridge J, Melton DW et al. (1998) Mice with gene targeted prion protein alterations show that Prnp, Sinc and Prni are congruent. Nat Genet 18: 118–125.

    Google Scholar 

  • Moore RC, Lee IY, Silverman GL, Harrison PM, Strome R, Heinrich C et al. (1999) Ataxia in prion protein (PrP)-deficient mice is associated with upregulation of the novel PrP-like protein Dopple. J Mol Biol 292: 797–817.

    Google Scholar 

  • Moore RC, Mastrangelo P, Bouzamondo E, Heinrich C, Legname G, Prusiner SB et al. (2001) Doppel-induced cerebellar de-generation in transgenic mice. Proc Natl Acad Sci USA 98: 15288–15293.

    Google Scholar 

  • Mouillet-Richard S, Ermonval M, Chebassier C, Laplanche JL, Lehmann S, Launay JM et al. (2000) Signal transduction through prion protein. Science 289: 1925–1928.

    Google Scholar 

  • Muramoto T, Scott M, Cohen FE and Prusiner SB (1996) Recombinant scrapie-like prion protein of 106 amino acids is soluble. Proc Natl Acad Sci USA 93: 15457–15462.

    Google Scholar 

  • Muramoto T, DeArmond SJ, Scott M, Telling GC, Cohen FE and Prusiner SB (1997) Heritable disorder resembling neuronal storage disease in mice expressing prion protein with deletion of an a-helix. Nat Med 3: 750–755.

    Google Scholar 

  • Nishida N, Tremblay P, Sugimoto T, Shigematsu K, Shirabe S, Petromilli C et al. (1999) A mouse prion protein transgene rescues mice deficient for the prion protein gene from Purkinje cell degeneration and demyelination. Lab Invest 79: 689–697.

    Google Scholar 

  • Oldstone MBA, Race R, Thomas D, Lewicki H, Homann D, Smelt S et al. (2002) Lymphotoxin-α-and lymphotoxin-β-deficient mice differ in susceptibility to scrapie: evidence against dendritic cell involvement in neuroinvasion. J Virol76: 4357–4363.

    Google Scholar 

  • Pattison IH (1965) Experiments with scrapie with special reference to the nature of the agent and the pathology of the disease. In: Gajdusek DC, Gibbs Jr CJ and Alpers M (eds), Slow, Latent and Temperate Virus Infections. (pp. 249–257) Washington.

  • Prinz M, Montrasio F, Klein MA, Schwarz P, Priller J, Odermatt B et al. (2002) Lymph nodal prion replication and neuroinvasion in mice devoid of follicular dendritic cells. Proc Natl Acad Sci USA 99: 919–924.

    Google Scholar 

  • Prusiner SB (1982) Novel proteinaceous infectious particles cause scrapie. Science 216: 136–144.

    Google Scholar 

  • Prusiner SB (1991) Molecular biology of prion diseases. Science 252: 1515–1522.

    Google Scholar 

  • Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95: 13363–13383.

    Google Scholar 

  • Prusiner SB, Scott M, Foster D, Pan KM, Groth D, Mirenda C et al. (1990) Transgenic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell 63: 673–686.

    Google Scholar 

  • Prusiner SB, Groth D, Serban A, Koehler R, Foster D, Torchia M et al. (1993) Ablation of the prion protein (PrP) gene in mice prevents scrapie and facilitates production of anti-PrP antibodies. Proc Natl Acad Sci USA 90: 10608–10612.

    Google Scholar 

  • Race RE, Priola SA, Bessen RA, Ernst D, Dockter J, Rall GF et al. (1995) Neuron-specific expression of a Hamster prion protein minigene in transgenic mice induces susceptibility to Hamster scrapie agent. Neuron 15: 1183–1191.

    Google Scholar 

  • Race R, Oldstone M and Chesebro B (2000) Entry versus blockade of brain infection following oral or intraperitoneal scrapie administration: role of prion protein expression in peripheral nerves and spleen. J Viro l74: 828–833.

    Google Scholar 

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

    Google Scholar 

  • Raeber AJ, Race RE, Brandner S, Priola SA, Sailer A, Bessen RA et al. (1997) Astrocyte-specific expression of hamster prion protein PrP renders PrP knockout mice susceptible to hamster scrapie. EMBO J 16: 6057–6065.

    Google Scholar 

  • Raeber AJ, Brandner S, Klein MA, Benninger Y, Musahl C, Frigg R et al. (1998) Transgenic and knockout mice in research on prion diseases. Brain Pathol 8: 715–733.

    Google Scholar 

  • Raeber AJ, Sailer A, Hegyi I, Klein MA, Rülicke T, Fischer M et al. (1999) Ectopic expression of prion protein (PrP) in T lymphocytes or hepatocytes of PrP knockout mice is insufficient to sustain prion replication. Proc Natl Acad Sci USA 96: 3987–3992.

    Google Scholar 

  • Rieger R, Edebhofer F, Lasmezas CI and Weiss S (1997) The human 37 kDa laminin receptor precursor interacts with the prion protein in eukaryotic cells. Nat Med 3: 1383–1388.

    Google Scholar 

  • Riek R, Hornemann S, Wider G, Glockshuber R and Wuthrich K (1997) NMR characterization of the full length recombinant murine prion protein, mPrP (23-231). FEBS Lett 413: 282–288.

    Google Scholar 

  • Rossi D, Cozzio A, Flechsig E, Klein MA, Rülicke T, Aguzzi A et al. (2001) Onset of ataxia and Purkinje cell loss in PrP null mice inversely correlated with Dpl level in brain. EMBO J 20: 694–702.

    Google Scholar 

  • Saborio GP, Permanne B and Soto C (2001) Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 411: 810–813.

    Google Scholar 

  • Sailer A, Büeler H, Fischer M, Aguzzi A and Weissmann C (1994) No propagation of prions in mice devoid of PrP. Cell 77: 967–968.

    Google Scholar 

  • Sakaguchi S, Katamine S, Shigematsu K, Nakatani A, Moriuchi R, Nishida N et al. (1995) Accumulation of proteinase K-resistant prion protein (PrP) is restricted by the expression level of normal PrP in mice inoculated with a mouse-adapted strain of the Creutzfeldt-Jakob disease agent. J Virol69: 7586–7592.

    Google Scholar 

  • Sakaguchi S, Katamine S, Nishida N, Moriuchi R, Shigematsu K, Sugimoto T et al. (1996) Loss of cerebellar Purkinje cells in aged mice homozygous for a disrupted PrP gene. Nature 380: 528–531.

    Google Scholar 

  • Schmitt-Ulms G, Legname G, Baldwin MA, Ball HL, Bradon N, Bosque PJ, et al. (2001) Binding of neural cell adhesion molecules (N-CAMs to the cellular prion protein J Mol Biol 314: 1209–1225.

    Google Scholar 

  • Scott M, Foster D, Mirenda C, Serban D, Coufal F, Wälchli M et al. (1989) Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques. Cell 59: 847–857.

    Google Scholar 

  • Scott MR, Kohler R, Foster D and Prusiner SB (1992) Chimeric prion protein expression in cultured cells and transgenic mice. Protein Sci 1: 986–997.

    Google Scholar 

  • Scott M, Groth D, Foster D, Torchia M, Yang SL, DeArmond SJ et al. (1993) Propagation of prions with artificial properties in transgenic mice expressing chimeric PrP genes. Cell 73: 979–988.

    Google Scholar 

  • Scott MR, Telling GC and Prusiner SB (1996) Transgenetics and gene targeting in studies of prion diseases. Curr Top Microbiol Immunol 207: 95–123.

    Google Scholar 

  • Scott MR, Groth D, Tatzelt J, Torchia M, Tremblay P, DeArmond S et al. (1997a) Propagation of prion strains through specific conformers of the prion protein. J Virol71: 9032–9044.

    Google Scholar 

  • Scott MR, Safar J, Telling G, Nguyen O, Groth D, Torchia M et al. (1997b) Identification of a prion protein epitope modulating transmission of bovine spongiform encephalopathy prions to transgenic mice. Proc Natl Acad Sci USA 94: 14279–14284.

    Google Scholar 

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

    Google Scholar 

  • Shlomchik MJ, Radebold K, Duclos N and Manuelidis L (2001) Neuroinvasion by a Creutzfeldt-Jakob disease agent in the absence of B cells and follicular dentritic cells. Proc Natl Acad Sci USA 98: 9289–9294.

    Google Scholar 

  • Shmerling D, Hegyi I, Fischer M, Blättler T, Brandner S, Götz J et al. (1998) Expression of amino-terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions. Cell 93: 203–214.

    Google Scholar 

  • Silverman GL, Qin K, Moore RC, Yang Y, Mastrangelo P, Tremblay P et al. (2000) Dopple is an N-glycosylated, glycosylphosphatidylinositol-anchored protein. J Biol Chem 275: 26834–26841.

    Google Scholar 

  • Stephenson DA, Chiotti K, Ebeling C, Groth D, DeArmond SJ, Prusiner SB et al. (2000) Quantitative trait loci affecting prion incubation time in mice. Genomics 69: 47–53.

    Google Scholar 

  • Stewart RS, Drisaldi B and Harris DA (2001) A transmembrane form of the prion protein contains an uncleaved signal peptide and is retained in the endoplasmic reticulum Mol Biol Cell12: 881–889.

    Google Scholar 

  • Supattapone S, Bosque P, Muramoto T, Wille H, Aagaard C, Peretz D et al. (1999) Prion protein of 106 residues creates an artificial transmission barrier for prion replication in transgenic mice. Cell 96: 869–878.

    Google Scholar 

  • Supattapone S, Muramoto T, Legname G, Mehlhorn I, Cohen FE, DeArmond SJ et al. (2001) Identification of two prion protein regions that modify scrapie incubation time. J Virol 75: 1408–1413.

    Google Scholar 

  • Symula DJ, Frazer KA, Ueda Y, Denefle P, Stevens ME Wang ZE et al. (1999) Functional screening of an asthma QTL in YAC transgenic mice. Nat Genet 23: 241–244.

    Google Scholar 

  • Tatzelt J, Maeda N, Pekny M, Yang SL, Betsholtz C, Eliasson C et al. (1996) Scrapie in mice deficient in a polipoprotein E or glial fibrillary acidic protein. Neurology 47: 449–453.

    Google Scholar 

  • Telling GC (2000) Prion protein genes and prion diseases: studies in transgenic mice. Neuropathol Appl Neurobiol 26: 209–220.

    Google Scholar 

  • Telling GC, Scott M, Hsiao KK, Foster D, Yang SL, Torchia M et al. (1994) Transmission of Creutzfeld-Jakob disease from humans to transgenic mice expressing chimeric human-mouse prion protein. Proc Natl Acad Sci USA 91: 9936–9940.

    Google Scholar 

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

    Google Scholar 

  • Telling GC, Haga T, Torchia M, Tremblay P, DeArmond SJ and Prusiner SB (1996) Interactions between wild-type and mutant prion proteins modulate neurodegeneration in transgenic mice. Genes Dev 10: 1736–1750.

    Google Scholar 

  • Telling GC, Tremblay P, Torchia M, Dearmond SJ, Cohen FE and Prusiner SB (1997) N-terminally tagged prion protein supports prion propagation in transgenic mice. Protein Sci 6: 825–833.

    Google Scholar 

  • Tobler I, Gaus SE, Deboer T, Achermann P, Fischer M, Rulicke T et al. (1996) Altered cicadian activity rhythms and sleep in mice devoid of prion protein. Nature 380: 639–642.

    Google Scholar 

  • Tremblay P, Meiner Z, Galou M, Heinrich C, Petromilli C, Lisse T et al. (1998) Doxycycline control of prion protein transgene expression modulates prion disease in mice. Proc Natl Acad Sci USA 95: 12580–12585.

    Google Scholar 

  • Tuzi NL, Gall E, Melton D and Manson JC (2002) Expression of Doppel in the CNS of mice does not modulate transmissible spongiform encephalopathy disease. J GenViro l83: 705–711.

    Google Scholar 

  • Vilette D, Andreoletti O, Archer F, Madelaine MF, Vilotte JL, Lehmann S et al. (2001) Ex vivo propagation of infectious sheep scrapie agent in heterologous epithelial cells expressing ovine prion protein. Proc Natl Acad Sci USA 98: 4055–4059.

    Google Scholar 

  • Vilotte JL, Soulier S, Essalmani R, Stinnakre MG, Vaiman D, Lepourry L et al. (2001) Markedly increased susceptibility to natural sheep scrapie of transgenic mice expressing ovine PrP. J Viro l75: 5977–5984.

    Google Scholar 

  • Wadsworth JDF, Jackson GS, Hill AF and Collinge J (1999) Molecular biology of prion propagation. Curr Opin Genet Dev 9: 338–345.

    Google Scholar 

  • Waggoner DJ, Drisaldi B, Bartnikas TB, Casareno RLB, Prohaska JR, Gitlin JD (2000) Brain copper content and cuproenzyme activity do not vary with prion protein expression level. J Biol Chem 275: 7455–7458.

    Google Scholar 

  • Weissmann C (1999) Molecular genetics of transmissible spongi-form encephalopathies. J BiolChem 274: 3–6.

    Google Scholar 

  • Weissmann C and Aguzzi A (1999) PrP's double cause trouble. Science 286: 914–915.

    Google Scholar 

  • Weissmann C, Fischer M, Raeber A, Büeler H, Sailer A, Shmerling D et al. (1998) The use of transgenic mice in the investigation of transmissible spongiform encephalopathies. Rev Sci Tech Off Int Epiz 17: 278–290.

    Google Scholar 

  • Westaway D (1996) Transgenic approaches to prion “species-barrier” effects. In: Baker H and Ridley RM (eds.), Methods in Molecular Medicine: Prion Diseases. (pp. 251-263). Humana Press, Totowa, NJ.

    Google Scholar 

  • Westaway D, Mirenda CA, Foster D, Zebarjadian Y, Scott M, Torchia M et al. (1991) Paradoxical shortening of scrapie incubation times by expression of prion protein transgenes derived from long incubation period mice. Neuron 7: 59–68.

    Google Scholar 

  • Westaway D, DeArmond SJ, Cayetano Canlas J, Groth D, Foster D, Yang SL et al. (1994a) Degeneration of skeletal muscle, peripheral nerves and the central nervous system in transgenic mice overexpressing wild-type prion proteins. Cell 76: 117–129.

    Google Scholar 

  • Westaway D, Zuliani V, Cooper CM, Da Costa M, Neuman S, Jenny AL et al. (1994b) Homozygosity for prion protein alleles encoding glutamine-171 renders sheep susceptibility to natural scrapie. Genes Dev 8: 959–969.

    Google Scholar 

  • Whittington MA, Sidle KC, Gowland I, Meads J, Hill AF, Palmer MS et al. (1995) Rescue of neurophysiological phenotype seen in PrP null mice by transgene encoding human prion protein. Nat Genet 9: 197–201.

    Google Scholar 

  • Zhu Y, Jong MC, Frazer KA, Gong E, Krauss RM, Cheng JF et al. (2000) Genomic interval engineering of mice identifies a novel modulator of triglyceride production. Proc Natl Acad Sci USA 97: 1137–1142.

    Google Scholar 

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Authors and Affiliations

  1. Laboratoire de Génétique Biochimique et Cytogénétique, Institut National de la Recherche Agronomique, 78352, Jouy-en-Josas Cedex, France

    Jean-Luc Vilotte

  2. Unité de Virologie Immunologie Moléculaires, Institut National de la Recherche Agronomique, 78352, Jouy-en-Josas Cedex, France

    Hubert Laude

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  1. Jean-Luc Vilotte
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  2. Hubert Laude
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Correspondence to Jean-Luc Vilotte.

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Vilotte, JL., Laude, H. Transgenesis Applied to Transmissible Spongiform Encephalopathies. Transgenic Res 11, 547–564 (2002). https://doi.org/10.1023/A:1021125510220

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