Onset of ataxia and Purkinje cell loss in PrP null mice inversely correlated with Dpl level in brain

PrP knockout mice in which only the open reading frame was disrupted ('Zurich I') remained healthy. However, more extensive deletions resulted in ataxia, Purkinje cell loss and ectopic expression in brain of Doppel (Dpl), encoded by the downstream gene, Prnd. A new PrP knockout line,'Zurich II', with a 2.9 kb Prnp deletion, developed this phenotype at similar to 10 months (50% morbidity), A single Prnp allele abolished the syndrome. Compound Zurich I/Zurich II heterozygotes had half the Dpl of Zurich II mice and developed symptoms 6 months later. Zurich II mice transgenic for a Prnd-containing cosmid expressed Dpl at twice the level and became ataxic similar to5 months earlier. Thus, Dpl levels in brain and onset of the ataxic syndrome are inversely correlated.