Frameshifted prion proteins as pathological agents: Quantitative considerations

A quantitatively consistent explanation for the titres of infectivity found in a variety of prion-containing preparations is provided on the basis that the ætiological agents of transmissible spongiform encephalopathy comprise a very small population fraction of prion protein (PrP) variants, which contain frameshifted elements in their N-terminal octapeptide-repeat regions. A mechanism for the replication of frameshifted prions is described and calculations are performed to obtain estimates of the concentration of these PrP variants in normal and infected brain, as well as their enrichment in products of protein misfolding cyclic amplification. These calculations resolve the lack of proper quantitative correlation between measures of infectivity and the presence of conformationally-altered, protease-resistant variants of PrP. Experiments, which could confirm or eventually exclude the role of frameshifted variants in the ætiology of prion disease, are suggested.

► Frameshifting accounts quantitatively for the ætiology of prion disease.
► One per million frameshifted prions may be enough to cause disease.
► The HIV TAR-like element in the PRNP mRNA is likely an effector of frameshifting.
► Precise chemical analyses can decide between the misfolding and frameshifting models.