Generation of prions in vitro and the protein-only hypothesis

Abstract

Prions are self-propagating proteinaceous infectious agents capable of transmitting disease in the absence of nucleic acids. The nature of the infectious agent in prion diseases has been at the center of passionate debate for the past 30 years. However, recent reports on the in vitro generation of prions have settled all doubts that the misfolded prion protein (PrP(Sc)) is the key component in propagating infectivity. However, we still do not understand completely the mechanism of prion replication and whether or not other cellular factors besides PrP(Sc) are required for infectivity. In this article, we discuss these recent reports under the context of the protein-only hypothesis and their implications.

Figure 1

Diagram of multiple species in equilibrium with PrP^C. Depending on the solution conditions, PrP^C can form different types of aggregates. Amorphous aggregates arise from nonspecific protein aggregation pathways through the denatured state. Under partially denaturing conditions, PrP^c can also form amyloid-type of structures which appear not to be infectious in animal models. The formation of PrP^Sc is depicted as an exquisite time-dependent misfolding process with the putative presence of an intermediate. The bell-shaped curves represent the apparent high energy barriers precluding PrP^C from forming infectious aggregates under normal conditions. These barriers may be associated to complex processes such as β-helix folding and nucleation. The presence of co-factors such as poly-anions, lipids and yet unknown molecules can also modulate these reactions.