The prion gene complex encoding PrPC and Doppel: insights from mutational analysis

The prion protein gene, Prnp, encodes PrPSc, the major structural component of prions, infectious pathogens causing a number of disorders including sc rapie and bovine spongiform encephalopathy (or BSE). Missense mutations in the human Prnp gene cause inherited prion diseases such as familial Creutzf eldt-Jakob disease. In uninfected animals Prnp encodes a glycophosphatidyli nositol (GPI)-anchored protein denoted PrPC and in prion infections PrPC is converted to PrPSc by templated refolding. Though Prnp is conserved in mam malian species, attempts to verify interactions of putative PrP binding pro teins by genetic means have proven frustrating and the ZrchI and Npu lines of Prnp gene-ablated mice (Prnp(0/0) mice) lacking PrPC remain healthy thro ughout development. This indicates that PrPC serves a function that is not apparent in a laboratory setting or that other molecules have overlapping f unctions. Current possibilities involve shuttling or sequestration of synap tic Cu(II) via binding to N-terminal octapeptide residues and/or signal tra nsduction involving the fyn kinase. A new point of entry into the issue of prion protein function has emerged from identification of a paralogue, Prnd , with 24% coding sequence identity to Prnp. Prnd lies downstream of Prnp a nd encodes the doppel (DpI) protein. Like PrPC, Dpl is presented on the cel l surface via a GPI anchor and has three a-helices: however, it lacks the c onformationally plastic and octapeptide repeat domains present in its well- known relative. Interestingly, Dpl is overexpressed in the Ngsk and Rcm0 li nes of Prnp(0/0) mice via intergenic splicing events. These lines of Prnp(0 /0) mice exhibit ataxia and apoptosis of cerebellar cells, indicating that ectopic synthesis of Dpl protein is toxic to central nervous system neurons : this inference has now been confirmed by the construction of transgenic m ice expressing Dpl under the direct control of the PrP promoter. Remarkably , Dpl-programmed ataxia is rescued by wild-type Prnp transgenes. The intera ction between the Prnp and Prnd genes in mouse cerebellar neurons may have a physical correlate in competition between Dpl and PrPC within a common bi ochemical pathway that when mis-regulated leads to apoptosis. (C) 2001 Publ ished by Elsevier Science B.V.