Prions replicate by recruiting their normally folded counterparts into large aggregate fibers, which then break up to form new prion particles, capable of recruiting and converting further normal forms. A shortened version of the yeast protein Sup35, called SupNM, can misfold into various prion forms. These forms seed aggregates that result in phenotypes of reproducibly different strengths.
To investigate the basis for this difference, Weisman's team looked at how fast the SupNM-derived aggregate fibers elongated. Contrary to expectations, they found that the most potent form, Sc4, had the slowest growth. However, this slow growth was accompanied by increased amyloid fragility—the fibers fell apart more often.
The potency of the Sc4 form was thus explained not by aggregate size or growth rate but instead by its propensity to break into new infectious prion particles. If the same physical basis of infectivity holds true for mammalian prions, then designing therapies that stabilize prion aggregates might slow or even stop disease progression.
It would be of interest to determine whether the specific structure of the Sc4 form could explain its increased aggregate fragility. Indeed, such experiments are “high on our list,” says Weissman.