Identification of a novel gene encoding a PrP-like protein expressed as chimeric transcripts fused to PrP exon 1/2 in ataxic mouse line with a disrupted PrP gene

1. Mouse lines lacking prion protein (PrPC) have a puzzling phenotypic disc repancy. Some, but not all, developed late-onset ataxia due to Purkinje cel l degeneration. 2. Here, we identified aberrant mRNA species in the brain of Ngsk Prnp(0/0) ataxic, but not in nonataxic Zrch Prnp(0/0) mouse line. These mRNAs were c himeric between the noncoding exons 1 and 2 of the PrP gene (Prnp) and the novel sequence encoding PrP-like protein (PrPLP), a putative membrane glyco protein with 23% identity to PrPC in the primary amino acid structure. The chimeric mRNAs were generated from the disrupted Prnp locus of Ngsk Prnp(0/ 0) mice lacking a part of the Prnp intron 2 and its splice acceptor signal. 3. In the brain of wild-type and Zrch Prnp(0/0) mice, PrPLP mRNA was barely detect able. In contrast, in the brain of Ngsk Prnp(0/0) mice, PrP/PrPLP c himeric mRNAs were expressed in neurons, at a particularly high level in hi ppocampus pyramidal cells and Purkinje cells under the control of the Prnp promoter. 4. In addition to the functional loss of PrPC, ectopic PrPLP expression fro m the chimeric mRNAs could also be involved in the Purkinje cell degenerati on in Ngsk Prnp(0/0) mice.