Ectopic expression of the doppel (Dpl) protein, a homologue of the prion pr
otein (PrP), was recently associated with cerebellar Purkinje cell degenera
tion observed in two aging prion protein knock-out (Prnp(0/0)) mouse lines.
We investigated the possible role of Dpl in oxidative metabolism. Two Prnp
(0/0) mouse lines of similar genetic background were studied. One line expr
esses Dpl in the brain and displays Dpl-associated cerebellar abnormalities
. The other has no elevated expression of Dpl and no cerebellar abnormaliti
es. We observed a correlation between Dpl expression and the induction of b
oth heme oxygenase 1 (HO-1) and nitric oxide synthase systems (nNOS and iNO
S). These responses are suggestive of increased oxidative stress in the bra
ins of the Dpl-expressing Prnp(0/0) mice. No induction was observed with Hs
p-60, indicating a specific response by the HO/NOS system. We proposed that
Dpl expression exacerbates oxidative damage that is antagonistic to the pr
otective function of wild-type PrP.