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

Abstract

Conversion of the cellular prion protein (PrP^C) into the pathogenic isoform (PrP^Sc) is the fundamental event underlying transmission and pathogenesis of prion diseases. To control the expression of PrP^C 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 PrP^C 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 PrP^Sc, they showed no neurologic dysfunction, indicating that low levels of PrP^Sc 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 PrP^Sc clearance in Tg mice should be possible, facilitating the development of pharmacotherapeutics.