The nature of transmission in prion diseases

Abstract

Replicating biological information is usually stored only within nucleic acid. The existence of 'strains' of agent in prion disease (scrapie, BSE, CJD) has been taken to indicate an independent genome within the transmissible agent. Other replicable information exists, however, both in biology and elsewhere, including, for example, the 'meme' (the neutral correlate of ideas which replicate in human brains by communication) and the computer virus. From this broader viewpoint, we explore the possibility that 'strain' differences in prion disease reflect biological information stored within the prion protein rather than in nucleic acid. Much of the disease variation in mice (used as evidence for strain differences) can be accounted for by the primary structures of the prion protein of the host (the experimentally infected mouse) and the donor mouse (from which infectious tissue is taken). Information determining residual disease variation (when these factors have been excluded) may reside in different conformational states of host prion protein. Prion protein can adopt different conformational and glycosylation states. The information which these states contain is only partially conserved on transmission between animals, permitting the appearances of both 'strain stability' and 'strain mutation'. Different sources of replicating, biological information including information in the 'agent' (the abnormal form of prion protein) and in the host prion gene (PRNP) are in evolutionary competition. We argue that, in the prion diseases, replicating information is not carried in nucleic acid in either the host or the 'agent' but is carried within the conformational state of the abnormal form of prion protein.