Disruption of Doppel prevents neurodegeneration in mice with extensive Prnp deletions

The Prnp gene encodes the cellular prion protein PrPC. Removal of its ORF does not result in pathological phenotypes, but deletions extending into the upstream intron result in cerebellar degeneration, possibly because of ectopic cis-activation of the Prnd locus that encodes the PrPC holmologue Doppel (Dpl). To test this hypothesis, we removed Prnd from Prnp(o/o) mice by transallelic meiotic recombination. Balanced loxP-mediated ablation yielded mice lacking both PrPC and Dpl (Prn(o/o)), which developed normally and showed unimpaired immune functions but suffered from male infertility. However, removal of the Prnd locus abolished cerebellar degeneration, proving that this phenotype is caused by Dpl up-regulation. The absence of compound pathological phenotypes in Prn(o/o) mice suggests the existence of alternative compensatory mechanisms. Alternatively, Dpl and PrPC may exert distinct functions despite having partly overlapping expression profiles.