Infectious prions and proteinopathies

Abstract

Transmissible spongiform encephalopathies (TSEs) are caused by an infectious agent that is thought to consist of only misfolded and aggregated prion protein (PrP). Unlike conventional micro-organisms, the agent spreads and propagates by binding to and converting normal host PrP into the abnormal conformer, increasing the infectious titre. Synthetic prions, composed of refolded fibrillar forms of recombinant PrP (rec-PrP) have been generated to address whether PrP aggregates alone are indeed infectious prions. In several reports, the development of TSE disease has been described following inoculation and passage of rec-PrP fibrils in transgenic mice and hamsters. However in studies described here we show that inoculation of rec-PrP fibrils does not always cause clinical TSE disease or increased infectious titre, but can seed the formation of PrP amyloid plaques in PrP-P101L knock-in transgenic mice (101LL). These data are reminiscent of the "prion-like" spread of misfolded protein in other models of neurodegenerative disease following inoculation of transgenic mice with pre-formed amyloid seeds. Protein misfolding, even when the protein is PrP, does not inevitably lead to the development of an infectious TSE disease. It is possible that most in vivo and in vitro produced misfolded PrP is not infectious and that only a specific subpopulation is associated with infectivity and neurotoxicity.

Keywords: TSE; amyloid; prion; prion-like; synthetic prions.

FIGURE 1.

PrP amyloid plaque seeding in 101LL mice. Recombinant PrP was expressed in E coli and purified before refolding into amyloid fibrils. These preparations were inoculated into 101LL and wildtype mice (A). Animals survived for lifespan, and while no PrP aggregation was observed in wildtype mice (B), large thioflavin fluorescent (D) PrP amyloid plaques were detected in several 101LL mice (C).