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 (PrPSc) 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 PrPSc are required for infectivity. In this article, we discuss these recent reports under the context of the protein-only hypothesis and their implications.
Acknowledgements
This work was supported in parts by NIH grants R01 NS049173 and P01 IA077774 to C.S.
Figures and Tables
Figure 1 Diagram of multiple species in equilibrium with PrPC. Depending on the solution conditions, PrPC can form different types of aggregates. Amorphous aggregates arise from nonspecific protein aggregation pathways through the denatured state. Under partially denaturing conditions, PrPc can also form amyloid-type of structures which appear not to be infectious in animal models. The formation of PrPSc 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 PrPC 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.
![Figure 1 Diagram of multiple species in equilibrium with PrPC. Depending on the solution conditions, PrPC can form different types of aggregates. Amorphous aggregates arise from nonspecific protein aggregation pathways through the denatured state. Under partially denaturing conditions, PrPc can also form amyloid-type of structures which appear not to be infectious in animal models. The formation of PrPSc 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 PrPC 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.](/cms/asset/c521778b-eb46-4c2f-8b6d-7d917e570f34/kprn_a_10911960_f0001.gif)
Table 1 Strategies successfully used for de novo generation of infectious prions in vitro