Originally Published on Cell | 25 May 2012
The once heretical concept that a misfolded protein is the infectious agent responsible for prion diseases is now widely accepted. Recent exciting research has led not only to the end of the skepticism that proteins can transmit disease, but also to expanding the concept that transmissible proteins might be at the root of some of the most prevalent human illnesses. At the same time, the idea that biological information can be transmitted by propagation of protein misfolding raises the possibility that heritable protein agents may be operating as epigenetic factors in normal biological functions and participating in evolutionary adaptation.
The discovery that proteins can behave like infectious agents to transmit disease is a signiﬁcant milestone in biology. The unorthodox prion hypothesis was proposed decades ago to explain the surprising transmission mechanisms of a group of rare diseases known as transmissible spongiform encephalopa-thies (TSEs), or prion diseases (Grifﬁth, 1967; Prusiner, 1982). The prion hypothesis states that the infectious agent in TSEs is composed exclusively of a misfolded form of the prion protein (PrPSc), which replicates in infected individuals by transforming the normal version of the prion protein (PrPC) into more of the misfolded isoform (Prusiner, 1998). This hypothesis remained controversial for decades, but recent studies have settled all doubts by demonstrating that infectious material can be generated in vitro, in the absence of genetic material, by replication of the protein misfolding process (Legname et al., 2004; Castilla et al., 2005; Deleault et al., 2007; Wang et al., 2010).
Despite the obvious differences between prions and conventional infectious micro-organisms (such as bacteria or viruses), prions exhibit the typical characteristics of bona ﬁde infectious agents, namely, exponential multiplication in an appropriate host; transmission between individuals by various routes, including food borne and blood borne; titration by infectivity bioassays; resistance to biological clearance mechanisms; penetration of biological membrane barriers; ‘‘mutation’’ by structural changes forming diverse strains; and transmission controlled by species barriers. Although prions fulﬁll the Koch’s postulates for infectious agents, it remains surprising that a single protein possesses the complexity and ﬂexibility required to act like living micro-organ-isms that transmit disease.
Prion replication requires exposure to tiny quantities of PrPSc, present in the infectious material, to trigger the autocatalytic conversion of host PrPC to PrPSc. This process follows a crystal-lization-like model in which the infectious particle (a small PrPSc aggregate) acts as a nucleus to recruit monomeric PrPC into the growing PrPSc polymer (Lansbury and Caughey, 1995). A key step in prion replication is the breakage of large PrPSc aggregates into many smaller seeding-competent polymers that amplify the prion replication process, resulting in the exponential accumulation of PrPSc (Saborio et al., 2001). This seeding-nucle-ation mechanism of prion propagation has been reproduced in vitro to ‘‘cultivate’’ prions with infectious properties when inoc-ulated into animals (Castilla et al., 2005; Deleault et al., 2007; Wang et al., 2010). Additional research is needed to elucidate the precise mechanisms and cellular factors required for prion replication in vivo as well as the detailed structure of the infec-tious folding of the prion protein (Soto, 2011).