NR AIAI
AU Mastrangelo,P.; Westaway,D.
TI Biology of the prion gene complex
QU Biochemistry and Cell Biology 2001; 79(5): 613-28
PT journal article; review; review, academic
AB The prion protein gene Prnp encodes PrPsc, the major structural component of prions, infectious pathogens causing a number of disorders including scrapie and bovine spongiform encephalopathy (BSE). Missense mutations in the human Prnp gene, PRNP, cause inherited prion diseases such as familial Creutzfeldt-Jakob Disease. In uninfected animals, Prnp encodes a GPI-anchored protein denoted PrPc, and in prion infections, PrPc is converted to PrPsc by templated refolding. Although Prnp is conserved in mammalian species, attempts to verify interactions of putative PrP-binding proteins by genetic means have proven frustrating in that two independent lines of Prnp gene ablated mice (Prnp0/0 mice: ZrchI and Npu) lacking PrPc remain healthy throughout development. This indicates that PrPc serves a function that is not apparent in a laboratory setting or that other molecules have overlapping functions. Shuttling or sequestration of synaptic Cu(II) via binding to N-terminal octapeptide residues and (or) signal transduction involving the fyn kinase are possibilities currently under consideration. A new point of entry into the issue of prion protein function has emerged from identification of a paralog, Prnd, with 25% coding sequence identity to Prnp. Prnd lies downstream of Prnp and encodes the Dpl protein. Like PrPc, Dpl is presented on the cell surface via a GPI anchor and has three alpha-helices: however, it lacks the conformationally plastic and octapeptide repeat domains present in its well-known relative. Interestingly, Dpl is overexpressed in two other lines of Prnp0/0 mice (Ngsk and Rcm0) via intergenic splicing events. These lines of Prnp0/0 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 mice expressing Dpl under the direct control of the PrP promoter. Remarkably, Dpl-programmed ataxia is rescued by wt Prnp transgenes. The interaction between the Prnp and Prnd genes in mouse cerebellar neurons may have a physical correlate in competition between Dpl and PrPc within a common biochemical pathway that, when misregulated, leads to apoptosis.
ZR 150
MH Animal; Cell Death; Creutzfeldt-Jakob Syndrome/genetics; Human; Mice; Models, Genetic; Models, Molecular; Neurodegenerative Diseases/genetics; Neurons/metabolism; Polymorphism (Genetics); Prion Diseases/*genetics/metabolism; Prions/*genetics/metabolism; Protein Binding; Scrapie/genetics; Support, Non-U.S. Gov't
AD Centre for Research in Neurodegenerative Diseases, University of Toronto, ON, Canada.
SP englisch
PO Kanada