Deletion of N-terminal residues 23-88 from prion protein (PrP) abrogates the potential to rescue PrP-deficient mice from PrP-like protein/Doppel-induced neurodegeneration

Accumulating evidence has suggested that prion protein (PrP) is neuroprotective and that a PrP-like protein/ Doppel (PrPLP/Dpl) is neurotoxic. A line of PrP-deficient mice, Ngsk Prnp(0/0), ectopically expressing PrPLP/Dpl in neurons, exhibits late-onset ataxia because of Purkinje cell death that is prevented by a transgene encoding wild-type mouse PrP. To elucidate the mechanisms of neurodegeneration in these mice, we introduced five types of PrP transgene, namely one heterologous hamster, two mouse/hamster chimeric genes, and two mutants, each of which encoded PrP lacking residues 23 - 88 (MHM2.del23-88) or with E199K substitution (Mo.E199K), into Ngsk Prnp(0/0) mice. Only MHM2.del23-88 failed to rescue the mice from the Purkinje cell death. The transgenic mice, MHM2.del23-88/ Ngsk Prnp(0/0), expressed several times more PrP than did wild-type (Prnp(+/+)) mice and PrPLP/Dpl at an equivalent level to Ngsk Prnp(0/0) mice. Little difference was observed in the pathology and onset of ataxia between Ngsk Prnp(0/0) and MHM2.del23-88/Ngsk Prnp(0/0). No detergent-insoluble PrPLP/Dpl was detectable in the central nervous system of Ngsk Prnp(0/0) mice even after the onset of ataxia. Our findings provide evidence that the N-terminal residues 23-88 of PrP containing the unique octapeptide-repeat region is crucial for preventing Purkinje cell death in Prnp(0/0) mice expressing PrPLP/Dpl in the neuron.