Doxycycline control of prion protein transgene expression modulates prion disease in mice

AUTOR(ES)

Tremblay, Patrick

FONTE

The National Academy of Sciences

RESUMO

Conversion of the cellular prion protein (PrPC) into the pathogenic isoform (PrPSc) is the fundamental event underlying transmission and pathogenesis of prion diseases. To control the expression of PrPC in transgenic (Tg) mice, we used a tetracycline controlled transactivator (tTA) driven by the PrP gene control elements and a tTA-responsive promoter linked to a PrP gene [Gossen, M. and Bujard, H. (1992) Proc. Natl. Acad. Sci. USA 89, 5547–5551]. Adult Tg mice showed no deleterious effects upon repression of PrPC expression (>90%) by oral doxycycline, but the mice developed progressive ataxia at ≈50 days after inoculation with prions unless maintained on doxycycline. Although Tg mice on doxycycline accumulated low levels of PrPSc, they showed no neurologic dysfunction, indicating that low levels of PrPSc can be tolerated. Use of the tTA system to control PrP expression allowed production of Tg mice with high levels of PrP that otherwise cause many embryonic and neonatal deaths. Measurement of PrPSc clearance in Tg mice should be possible, facilitating the development of pharmacotherapeutics.

Documentos Relacionados

• B lymphocyte-restricted expression of prion protein does not enable prion replication in prion protein knockout mice
• Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice.
• Abbreviated incubation times for human prions in mice expressing a chimeric mouse–human prion protein transgene
• 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
• Position-dependent variegation of globin transgene expression in mice.