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Upon agitation, aggregates of the potent Sc4 prion form break apart (left), but a less potent form remains intact (right). WEISSMAN/MACMILLAN

Prion proteins with the same amino acid sequence but different biophysical and biochemical structures show different pathological severities. A study of a yeast prion model, by Motomasa Tanaka, Jonathan Weissman, and colleagues (University of California, San Francisco, CA) reveals that a prion's power is determined by aggregate stability—or, rather, lack of it.

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.

Reference:

Tanaka, M., et al. 2006. Nature. doi:10.1038/nature04922.

Ruth Williams

ruth.williams{at}rockefeller.edu

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This Article PDF (Full Text) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Williams, R. Search for Related Content PubMed Articles by Williams, R. Social Bookmarking                      What's this?