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Unweaving amyloid fibers to solve prion puzzles

Amyloid fibers are best known as the plaque that gunks up neurons in people with neurodegenerative illnesses such as Alzheimer's and Creutzfeldt-Jacob disease--the human analog of mad cow disease. But even though amyloids are common and implicated in a host of conditions, researchers haven't been able to identify their precise molecular structures. Conventional techniques used to image proteins, such as X-ray crystallography and nuclear magnetic resonance imaging, don't work with fibrous structures such as amyloids. And scientists depend on these high resolution images of molecules in order to study their function.

Now, researchers have found a way to work around these limitations, illuminating the configuration of these sometimes pernicious molecules. And even though this work was done in yeast, the results provide hints as to why mad-cow type diseases tend to have a difficult time jumping species.

"These findings give us some fundamental insights in how amyloid fibers form," says Whitehead Member Susan Lindquist, lead scientist in the research team whose results will be published in the June 9 issue of the journal Nature. "They solve the important problem of identifying the intermolecular contacts that hold the amyloid fiber together."

Amyloid fibers are often composed of prions--proteins that misfold and recruit neighboring proteins to misfold as well, a process that Lindquist calls a "conformational cascade." When such a cascade occurs, the prions join and form amyloid fibers. (While not all amyloids are composed of prions, all known prions, in their transmissible states, form amyloid fibers.) But still, many scientists have been frustrated by their inability to gain anything more than a limited understanding of an amyloid's architecture.

Rajaraman Krishnan, a postdoctoral researcher in Lindquist's lab, found a way around that problem using strains of yeast. Rather than develop a single high-tech method for solving the amyloi
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Contact: David Cameron
newsroom@wi.mit.edu
617-258-5183
Whitehead Institute for Biomedical Research
8-Jun-2005


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