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Chimeric elk/mouse prion proteins in transgenic mice.
Tamgüney, Gültekin; Giles, Kurt; Oehler, Abby; Johnson, Natrina L; DeArmond, Stephen J; Prusiner, Stanley B.
Afiliación
  • Tamgüney G; Department of Neurology, University of California, San Francisco, CA, USA.
  • Giles K; Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA.
  • Oehler A; Department of Neurology, University of California, San Francisco, CA, USA.
  • Johnson NL; Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA.
  • DeArmond SJ; Department of Pathology, University of California, San Francisco, CA, USA.
  • Prusiner SB; Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA.
J Gen Virol ; 94(Pt 2): 443-452, 2013 Feb.
Article en En | MEDLINE | ID: mdl-23100369
Chronic wasting disease (CWD) of deer and elk is a highly communicable neurodegenerative disorder caused by prions. Investigations of CWD are hampered by slow bioassays in transgenic (Tg) mice. Towards the development of Tg mice that will be more susceptible to CWD prions, we created a series of chimeric elk/mouse transgenes that encode the N terminus of elk PrP (ElkPrP) up to residue Y168 and the C terminus of mouse PrP (MoPrP) beyond residue 169 (mouse numbering), designated Elk3M(SNIVVK). Between codons 169 and 219, six residues distinguish ElkPrP from MoPrP: N169S, T173N, V183I, I202V, I214V and R219K. Using chimeric elk/mouse PrP constructs, we generated 12 Tg mouse lines and determined incubation times after intracerebral inoculation with the mouse-passaged RML scrapie or Elk1P CWD prions. Unexpectedly, one Tg mouse line expressing Elk3M(SNIVVK) exhibited incubation times of <70 days when inoculated with RML prions; a second line had incubation times of <90 days. In contrast, mice expressing full-length ElkPrP had incubation periods of >250 days for RML prions. Tg(Elk3M,SNIVVK) mice were less susceptible to CWD prions than Tg(ElkPrP) mice. Changing three C-terminal mouse residues (202, 214 and 219) to those of elk doubled the incubation time for mouse RML prions and rendered the mice resistant to Elk1P CWD prions. Mutating an additional two residues from mouse to elk at codons 169 and 173 increased the incubation times for mouse prions to >300 days, but made the mice susceptible to CWD prions. Our findings highlight the role of C-terminal residues in PrP that control the susceptibility and replication of prions.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Priones / Enfermedad Debilitante Crónica Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Gen Virol Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Priones / Enfermedad Debilitante Crónica Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Gen Virol Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido