Genetics of prion diseases and prion diversity in mice.

Linkage of the prion protein (PrP) and scrapie incubation time genes in mice provided strong evidence for the central role of PrP in determining susceptibility to prion disorders. Considerable evidence now argues that the prion protein and incubation time genes are identical. The mouse prion protein gene (Prn-p) may act both quantitatively and qualitatively in modulating prion incubation time. Differences at positions 108 and 189 between PrP-A and PrP-B allotypes can place constraints on interaction between the normal cellular and the scrapie-specific isoforms of PrP (PrPC and PrPSc), although the supply of PrPC available for post-translational conversion to PrPSc can also influence incubation time. Results using transgenic (Tg) mice in studies on scrapie 'strains' or isolates suggest that incubation time characteristics of scrapie isolates can be explained by these two properties of PrP. The final section of this report discusses the novel finding that uninoculated Tg mice overexpressing wild-type (wt) PrP transgenes spontaneously develop a late-onset degenerative neuromyopathy, broadening the spectrum of prion diseases and providing new information on PrP function in both normal and pathological states.