The fragility factor
|
|
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.
