PrPC was distinguished from PrPSc operationally, by the solubility in detergents and sensitivity to protease digestion of PrPC in contrast to the sedimentibility and partial resistance to proteases of PrPSc. PrPSc has a higher degree of β-sheet than PrPC

The prion hypothesis [1] is now 20 years old. In its original protein-only version, which is the one generally accepted when the term ‘prion’ or ‘prion hypothesis’ is used, protein was proposed as the sole component of the infectious agent causing the transmissible spongiform encephalopathies (TSEs), including scrapie in sheep, bovine spongiform encephalopathy (BSE) and Creutzfeldt–Jakob disease (CJD). However, despite stimulation from the prion and other hypotheses [2,3], the physicochemical and biological properties of the TSE infectious agent remain to be reconciled with the structure and biochemical properties of PrP. The nature of the causal agent continues to be the subject of debate. The prion hypothesis was proposed because of the failure to identify a TSE-specific nucleic acid or to demonstrate its presence. Soon after publication of the prion hypothesis, the PrP protein was discovered [4]. Evidence accrued showing that PrP and TSE infectivity co-purified [5], and it was suggested that PrP was the essential component of the infectious agent – i.e. that TSE infections were caused by an infectious protein, PrP [6]. In 1985, the DNA encoding PrP was sequenced and it emerged that PrP is a host glycoprotein [7]. The normal form of the protein, PrPC, whose function is still unknown, is anchored to the cell surface by a glycolipid moiety. If PrP was the infectious agent it was predicted that it had to undergo a post-translational covalent or conformational change in structure [8]. Mutational change to PrP could occur, initiating conformational change. Germline mutations of the PrP sequence are proposed to cause familial TSEs. Mutation might also occur in a somatic cell and initiate ‘sporadic prion disease’. This continues to stand as the essence of the prion hypothesis: that the host protein, PrP, is induced to alter its conformation into an ‘infectious form’. Change is initiated spontaneously by mutated PrP, which is more susceptible to conformational change, or exogenously by PrP that is already in the abnormal form. Despite its widespread acceptance, the prion hypothesis has yet to be reconciled with several properties of TSE agents, most notably the diversity in biological and biochemical properties of different TSE strains (Box 1). Here, a simpler explanation is sought by re-examining the case for a host-independent nucleic acid genome that carries the genetic information determining TSE strain properties and their diversity.