Biology of the prion gene complex

The prion protein gene Prnp encodes PrPSc, the major structural component o f prions, infectious pathogens causing a number of disorders including scra pie and bovine spongiform encephalopathy (BSE). Missense mutations in the h uman Prnp gene, PRNP, cause inherited prion diseases such as familial Creut zfeldt-Jakob Disease. In uninfected animals, Prnp encodes a GPI-anchored pr otein denoted PrPC, and in prion infections, PrPC is converted to PrPSc by templated refolding. Although Prnp is conserved in mammalian species, attem pts to verify interactions of putative PrP-binding proteins by genetic mean s have proven frustrating in that two independent lines of Prnp gene ablate d mice (Prnp(0/0) mice: ZrchI and Npu) lacking PrPC remain healthy througho ut development. This indicates that PrPC serves a function that is not appa rent in a laboratory setting or that other molecules have overlapping funct ions. Shuttling or sequestration of synaptic Cu(II) via binding to N-termin al octapeptide residues and (or) signal transduction involving the fyn kina se are possibilities currently under consideration. A new point of entry in to the issue of prion protein function has emerged from identification of a paralog, Prnd, with 25% coding sequence identity to Prnp. Prnd lies downst ream of Prnp and encodes the Dpl protein. Like PrPC, Dpl is presented on th e cell surface via a GPI anchor and has three alpha-helices: however, it la cks the conformationally plastic and octapeptide repeat domains present in its well-known relative. Interestingly, Dpl is overexpressed in two other l ines of Prnp(0/0) mice (Ngsk and Rcm0) via intergenic splicing events. Thes e lines of Prnp(0/0) mice exhibit ataxia and apoptosis of cerebellar cells, indicating that ectopic synthesis of Dpl protein is toxic to CNS neurons: this inference has now been confirmed by the construction of transgenic mic e expressing Dpl under the direct control of the PrP promoter. Remarkably, Dpl-programmed ataxia is rescued by wt Prnp transgenes. The interaction bet ween the Prnp and Prnd genes in mouse cerebellar neurons may have a physica l correlate in competition between Dpl and PrPC within a common biochemical pathway that, when misregulated, leads to apoptosis.