Amyloid fibers sprout one step...( e said. Initial efforts to understa...)

Initial efforts to understand amyloid formation compared the process to the formation of the cell's cytoskeleton, a better understood mechanism known as nucleation-polymerization, in which the cytoskeletal proteins (actin and tubulin) coalesce into long fibers. Experiments from a number of labs, however, revealed that this process could not explain amyloid formation.

Amyloid formation was also associated with the transient accumulation of intermediate molecules that have been implicated in causing disease. "The process of forming amyloids seems to be implicated in disease perhaps as much as the actual aggregates themselves," said Weissman. "So understanding why some proteins form amyloids and aggregate, and under what conditions that occurs, and the intermediate processes involved, is critical in determining what is toxic about amyloid and how it might be possible to affect the pathology it causes. Yet despite the importance of this process, we know little about the underlying mechanism by which amyloid forms and grows."

For example, said Weissman, evidence is accumulating that it is not the plaque itself that is toxic, but rather the smaller and more amorphous oligomers that typically accompany plaque formation. But why such oligomers form and what role they play in making amyloid plaques was unknown.

Weissman and his colleagues sought to understand the dynamics of how the amyloid puzzle pieces assemble themselves. They analyzed the timing of the yeast prion protein assembly, and how that varied with different concentrations of the fiber and of the individual units, or monomers, that add to the growing fibers. The researchers also explored a particularly puzzling feature of amyloid formation: the fact that agitation dramatically accelerates the process.

Drawing on expertise in the Vale laboratory, the scientists complemented these indirect studies with "single-molecule fluorescence technology" to observe fiber growth directl
'"/>

Contact: Jennifer Michalowski
michalow@hhmi.org
301-215-8576
Howard Hughes Medical Institute
20-Sep-2004