Prion diseases can be infectious, sporadic and genetic^,,,. 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 PrP^Sc. However, certain inherited PrP mutations appear to cause neurodegeneration in the absence of PrP^Sc (refs ,,,), working instead by favoured synthesis of ^CtmPrP, a transmembrane form of PrP (ref. ). The relationship between the neurodegeneration seen in transmissible prion diseases involving PrP^Sc and that associated with ^CtmPrP has remained unclear. Here we find that the effectiveness of accumulated PrP^Sc in causing neurodegenerative disease depends upon the predilection of host-encoded PrP to be made in the ^CtmPrP form. Furthermore, the time course of PrP^Sc accumulation in transmissible prion disease is followed closely by increased generation of ^CtmPrP. Thus, the accumulation of PrP^Sc appears to modulate in trans the events involved in generating or metabolising ^CtmPrP. Together, these data suggest that the events of ^CtmPrP-mediated neurodegeneration may represent a common step in the pathogenesis of genetic and infectious prion diseases.