Insights into fibers' structure could aid studies of Alzheimer's, more


In work that will aid scientists' understanding of amyloid fibers, best known as the plaque that gunks up neurons in people with neurodegenerative illnesses such as Alzheimer's, MIT and Whitehead Institute researchers have developed a technique to probe the fibers' architecture.

Even though amyloids are common and implicated in a host of conditions that also include Creutzfeldt-Jacob disease, the human analog of mad cow disease, 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 led by MIT Professor of Biology and Whitehead Member Susan Lindquist have found a way to work around these limitations, illuminating the configuration of these sometimes pernicious molecules.

"These findings give us some fundamental insights in how amyloid fibers form," says Lindquist "They solve the important problem of identifying the intermolecular contacts that hold the amyloid fiber together." The work will be published in the June 9 issue of the journal Nature.

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 amyloid structure, he instead used a combination of low-resolution tools to analyze varieties of prion strains and piece together the puzzle of how amyloids form.

Krishnan was able to identify the precise segment at which the prions interact--something that no one had done before him with a real prion. To do this, he took a variety of yeast prion strains and modified them in such a way that if particular designated regions came into contact with each other, they would emit a fluorescent signal, allowing him to map the pattern by which the different strains of prions interacted with each other.

He found that each prion molecule had only two points at which they connected to other prion molecules. One point he called the "head," the other the "tail." The head of one prion would only interact with the head of another prion, and likewise with tails. Remarkably, the same prion from the same yeast species could sometimes fold differently, and this fold would form its own cascade of interactions. In this altered form, the prion molecules interact in slightly different places, presenting different surfaces to promote the conversion of other prion molecules.

While the results of this research are clearly of interest to scientists investigating conditions such as Alzheimer's, it's also relevant to scientists studying nanotechnology. In March of 2003, Lindquist published a paper in which she described how amyloid fibers can become the core of nanoscale electrical wires, opening the possibility of one day incorporating them into integrated circuits.

"These findings are quite relevant for the material sciences," says Lindquist. "The more we understand about how these fibers work, the more we can get them to self-assemble," a key advantage for nanoscale devices that are very difficult to manipulate directly. In addition, amyloids are unusually robust, which also makes them attractive for nano devices.

This research was supported by the DuPont-MIT Alliance and an NIH grant.


Topics: Bioengineering and biotechnology, Health sciences and technology

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