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De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis

Academic Article
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Overview

authors

  • Sigurdson, Christina
  • Nilsson, K. P. R.
  • Hornemann, S.
  • Heikenwalder, M.
  • Manco, G.
  • Schwarz, P.
  • Ott, D.
  • Rulicke, T.
  • Liberski, P. P.
  • Julius, C.
  • Falsig, J.
  • Stitz, L.
  • Wuthrich, Kurt
  • Aguzzi, A.

publication date

  • January 2009

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Most transmissible spongiform encephalopathies arise either spontaneously or by infection. Mutations of PRNP, which encodes the prion protein, PrP, segregate with phenotypically similar diseases. Here we report that moderate overexpression in transgenic mice of mPrP(170N,174T), a mouse PrP with two point mutations that subtly affect the structure of its globular domain, causes a fully penetrant lethal spongiform encephalopathy with cerebral PrP plaques. This genetic disease was reproduced with 100% attack rate by intracerebral inoculation of brain homogenate to tga20 mice overexpressing WT PrP, and from the latter to WT mice, but not to PrP-deficient mice. Upon successive transmissions, the incubation periods decreased and PrP became more protease-resistant, indicating the presence of a strain barrier that was gradually overcome by repeated passaging. This shows that expression of a subtly altered prion protein, with known 3D structure, efficiently generates a prion disease.

subject areas

  • Animals
  • Gene Transfer Techniques
  • Mice
  • Mice, Transgenic
  • Point Mutation
  • Prion Diseases
  • Prions
  • Protein Conformation
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Research

keywords

  • amyloid
  • neurodegeneration
  • prion
  • species barrier
  • transgenic mice
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Identity

PubMed Central ID

  • PMC2629180

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0810680105

PubMed ID

  • 19073920
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Additional Document Info

start page

  • 304

end page

  • 309

volume

  • 106

issue

  • 1

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