Amyloid fibers sprout one step...( y. In this technique an immobilized fi...)

y. In this technique, an immobilized fiber is first tagged with one fluorescent molecule. When shorter amyloid segments or monomers are tagged with a fluorescent molecule of a different color and added to the immobilized fiber, researchers can watch the growth of the fiber.

The analytical approaches revealed that the yeast amyloid fibers grow by the addition, one by one, of individual monomers -- rather than assembly of amorphous, globular oligomers. Thus, said Weissman, if the oligomeric globules are, indeed, the toxic molecules, they form in competition with the structured fibers, rather than being key intermediates in fiber formation. Such a possibility could have implications for treating amyloid diseases such as Alzheimer's and Parkinson's, he said.

"Investigators are now screening for drugs that would prevent amyloid from forming, to treat these disorders," said Weissman. "While it is quite speculative at this point, if such drugs favored the production of more oligomers, which are toxic, then those drugs could actually have the opposite effect than was intended. Conversely, drugs that encourage the rapid formation of a relatively inert and stable amyloid might deplete the toxic oligomers and therefore be beneficial," he said.

Weissman emphasized that basic studies of amyloid formation must be extended beyond the yeast prion model before the monomer-addition mechanism can be considered a general one. Thus, he and his colleagues are now studying the mechanism of formation of other amyloid proteins, including the molecular details of how individual monomers bind to a growing fibril.

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

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