Transmissible and genetic prion diseases share a common pathway of neurodegeneration

Prion diseases can be infectious, sporadic and genetic(1-4). The infectious forms of these diseases, including bovine spongiform encephalopathy and Creutzfeldt-Jakob disease, are usually characterized by the accumulation in the brain of the transmissible pathogen, an abnormally folded isoform of the prion protein (PrP) termed PrPSc. However, certain inherited PrP mutations appear to cause neurodegeneration in the absence of PrPSc (refs 5-8), working instead by favoured synthesis of (PrP)-Pr-Ctm, a transmembrane form of PrP (ref. 9). The relationship between the neurodegeneration seen in transmissible prion diseases involving PrPSc and that associated with (PrP)-Pr-Ctm has remained unclear. Here we find that the effectiveness of accumulated PrPSc in causing neurodegenerative disease depends upon the predilection of host-encoded PrP to be made in the (PrP)-Pr-Ctm form. Furthermore, the time course of PrPSc accumulation in transmissible prion disease is followed closely by increased generation of (PrP)-Pr-Ctm. Thus, the accumulation of PrPSc appears to modulate in trans the events involved in generating or metabolising (PrP)-Pr-Ctm. Together, these data suggest that the events of (PrP)-Pr-Ctm-mediated neurodegeneration may represent a common step in the pathogenesis of genetic and infectious prion diseases.