DOXYCYCLINE CONTROL OF PRION PROTEIN TRANSGENE EXPRESSION MODULATES PRION DISEASE IN MICE

Conversion of the cellular prion protein (PrPC) into the pathogenic is oform (PrPSc) is the fundamental event underlying transmission and pat hogenesis of prion diseases. To control the expression of PrPC in tran sgenic (Tg) mice, we used a tetracycline controlled transactivator (tT A) driven by the PrP gene control elements and a tTA-responsive promot er linked to a PrP gene [Gossen, M. and Bujard, Ii, (1992) Proc, Natl. Acad. Sci. USA 89, 5547-5551]. Adult Tg mice showed no deleterious ef fects upon repression of PrPC expression (>90%) by oral doxycycline, b ut the mice developed progressive ataxia at approximate to 50 days aft er 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 to lerated. Use of the tTA system to control PrP expression allowed produ ction of Tg mice with high levels of PrP that otherwise cause many emb ryonic and neonatal deaths. Measurement of PrPSc clearance in Tg mice should be possible, facilitating the development of pharmacotherapeuti cs.