Molecular types of Creutzfeldt–Jakob disease

Prions causing Creutzfeldt–Jakob disease (CJD) and related disorders are hypothesized to be composed predominantly of a misfolded form of a normal brain protein, the prion protein (PrP). Decades of experimental data support this assertion. Still, even as experimental evidence for the prion hypothesis has solidified, further investigations into the nature of prions have revealed a diversity that is puzzling given the apparently simple composition of the agent.

In this issue of Neurology, an article by Meissner et al.¹ highlights this strange diversity.

In a proposed model of prion replication, misfolded and aggregated PrP (PrP^Sc) composes the infectious particle. In sporadic CJD, this aggregate initially arises spontaneously from processes related to the thermodynamic instability of the protein’s conformation. PrP^Sc then interacts with normal PrP (PrP^C), causing it to misfold, presumably by recruiting it into the abnormal aggregate. The aggregate grows and at some point fractures, increasing the number of aggregates. The process repeats, and PrP^Sc thus propagates throughout the CNS. Recent experiments with mammalian prions synthesized in vitro and studies of analogous proteins in yeast support the notion that prions are composed solely of aggregated PrP.^2,3

Given this simple composition, the discoveries of prion strains and CJD molecular subtypes pose …