PrP knockout mice in which only the open reading frame was disrupted (‘Zürich 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,‘Zürich II’, with a 2.9 kb Prnp deletion, developed this phenotype at∼ 10 months (50% morbidity). A single Prnp allele abolished the syndrome. Compound Zürich I/Zürich II heterozygotes had half the Dpl of Zürich II mice and developed symptoms 6 months later. Zürich II mice transgenic for a Prnd‐containing cosmid expressed Dpl at twice the level and became ataxic∼ 5 months earlier. Thus, Dpl levels in brain and onset of the ataxic syndrome are inversely correlated.