Doppel-induced Purkinje cell death is stoichiometrically abrogated by prion protein.

Mice devoid of prion protein (PrP) exhibiting ataxia and Purkinje cell degeneration, such as Ngsk Prnp(-/-) mice, ectopically express PrP-like protein, Dpl, in neurons including Purkinje cells. In this study, two types of transgenic (tg) mice expressing Dpl in neurons, tg(N-Dpl), or Purkinje cells only, tg(P-Dpl), were generated on the background of non-ataxic Zrch I Prnp(-/-) mice. In contrast to the tg mice with the Prnp(+/+) background, both tg mice with the Prnp(-/-) alleles developed Purkinje cell degeneration after incubation periods inversely correlated to the levels of Dpl. Some tg mice hemizygous for Prnp allele also developed disease but much later than those carrying the Prnp(-/-) alleles. This indicates that Dpl expressed by Purkinje cells itself is toxic to the cells, and that the neurotoxicity is stoichiometrically antagonized by PrP.