Cell
Volume 63, Issue 4, 16 November 1990, Pages 673-686
Journal home page for Cell

Article
Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication

https://doi.org/10.1016/0092-8674(90)90134-ZGet rights and content

Abstract

Transgenic (Tg) mice expressing both Syrian hamster (Ha) and mouse (Mo) prion protein (PrP) genes were used to probe the mechanism of scrapie prion replication. Four Tg lines expressing HaPrP exhibited distinct incubation times ranging from 48 to 277 days, which correlated inversely with HaPrP mRNA and HaPrPC. Bioassays of Tg brain extracts showed that the prion inoculum dictates which prions are synthesized de novo. Tg mice inoculated with Ha prions had ∼109 ID50 units of Ha prions per gram of brain and <10 units of Mo prions. Conversely, Tg mice inoculated with Mo prions synthesized Mo prions but not Ha prions. Similarly, Tg mice inoculated with Ha prions exhibited neuropathologic changes characteristic of hamsters with scrapie, while Mo prions produced changes similar to those in non-Tg mice. Our results argue that species specificity of scrapie prions resides in the PrP sequence and prion synthesis is initiated by a species-specific interaction between PrPSc in the inoculum and homologous PrPC.

References (89)

  • O.E. Ijsselmuiden et al.

    Optimizing the solid-phase immunofiltration assay: a rapid alternative to immunoassays

    J. Immunol. Meth.

    (1989)
  • R.H. Kimberlin et al.

    Pathogenesis of mouse scrapie: effect of route of inoculation on infectivity titres and dose-response curves

    J. Comp. Pathol.

    (1978)
  • M.P. McKinley et al.

    A protease-resistant protein is a structural component of the scrapie prion

    Cell

    (1983)
  • J. Monod et al.

    On the nature of allosteric transitions: a plausible model

    J. Mol. Biol.

    (1965)
  • B. Oesch et al.

    A cellular gene encodes scrapie PrP 27–30 protein

    Cell

    (1985)
  • M. Scott et al.

    Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques

    Cell

    (1989)
  • N. Stahl et al.

    Scrapie prion protein contains a phosphatidylinositol glycolipid

    Cell

    (1987)
  • J. Uhl et al.

    Quantitation of related proteins by Western blot analysis

    J. Immunol. Meth.

    (1988)
  • D. Westaway et al.

    Distinct prion proteins in short and long scrapie incubation period mice

    Cell

    (1987)
  • J.M. Aiken et al.

    Evidence of mitochondrial involvement in scrapie infection

    J. Virol.

    (1989)
  • R.A. Barry et al.

    Monoclonal antibodies to the cellular and scrapie prion proteins

    J. Infect. Dis.

    (1986)
  • R.A. Barry et al.

    Immunology of prions

  • R.A. Barry et al.

    Antibodies to the scrapie protein decorate prion rods

    J. Immunol.

    (1985)
  • C. Bellinger-Kawahara et al.

    Purified scrapie prions resist inactivation by UV irradiation

    J. Virol.

    (1987)
  • J.M. Bockman et al.

    Immunoblotting of Creutzfeldt-Jakob disease prion proteins: host species-specific epitopes

    Ann. Neurol.

    (1987)
  • D.R. Borchelt et al.

    Scrapie and cellular prion proteins differ in their kinetics of synthesis and topology in cultured cells

    J. Cell Biol.

    (1990)
  • H. Braig et al.

    Scrapie: concept of a virus-induced amyloidosis of the brain

    EMBO J.

    (1985)
  • M.E. Bruce et al.

    Genetic control of amyloid plaque production and incubation period in scrapie-infected mice

    J. Neuropathol. Exp. Neurol.

    (1985)
  • M.E. Bruce et al.

    Biological evidence that the scrapie agent has an independent genome

    J. Gen. Virol.

    (1987)
  • M.E. Bruce et al.

    Cerebral amyloidosis in scrapie in the mouse: effect of agent strain and mouse genotype

    Neuropathol. Appl. Neurobiol.

    (1976)
  • D.A. Butler et al.

    Scrapie-infected murine neuroblastoma cells produce protease-resistant prion proteins

    J. Virol.

    (1988)
  • G.A. Carlson et al.

    Genetics and polymorphism of the mouse prion gene complex: the control of scrapie incubation time

    Mol. Cell. Biol.

    (1988)
  • G.A. Carlson et al.

    Primary structure of prion protein may modify scrapie isolate properties

  • B. Caughey et al.

    Prion protein biosynthesis in scrapie-infected and uninfected neuroblastoma cells

    J. Virol.

    (1989)
  • B. Caughey et al.

    Normal and scrapie-associated forms of prion protein differ in their sensitivities to phospholipase and proteases in intact neuroblastoma cells

    J. Virol.

    (1990)
  • M. Czub et al.

    Replication of the scrapie agent in hamsters infected intracerebrally confirms the pathogenesis of an amyfoid-inducing virosis

    J. Gen. Virol.

    (1988)
  • S.J. DeArmond et al.

    Molecular pathology of prion diseases

  • S.J. DeArmond et al.

    Changes in the localization of brain prion proteins during scrapie infection

    Neurology

    (1987)
  • A.G. Dickinson et al.

    The scrapie replication-site hypothesis and its implications for pathogenesis

  • J.R. Duguid et al.

    Isolation of cDNAs of scrapie-modulated RNAs by subtractive hybridization of a cDNA library

  • C.M. Eklund et al.

    Pathogenesis of scrapie virus infection in the mouse

    J. Infect. Dis.

    (1967)
  • T. Endo et al.

    Diversity of oligosaccharide structures linked to asparagines of the scrapie prion protein

    Biochemistry

    (1989)
  • P.A. Evans et al.

    Proline isomerization in staphylococcal nuclease characterized by NMR and site-directed mutagenesis

    Nature

    (1987)
  • R.O. Fox et al.

    Multiple conformations of a protein demonstrated by magnetization transfer NMR spectroscopy

    Nature

    (1986)
  • Cited by (0)

    View full text