Researchers get first peek at amyloid's spine

Thursday, 09 June, 2005

Researchers at the Howard Hughes Medical Institute in US have provided the first detailed look at the core structure of the abnormal protein filaments found in at least 20 devastating diseases, ranging from Alzheimer's to Creutzfeldt-Jakob disease, the human version of "mad cow" disease.

The images reveal that the filaments form a short zipper that is closed and stuck. To get a more realistic picture of what the fibrils look like, however, one should picture a towering stack of zippers, each of which is tightly bonded to the one below.

"To do something about these diseases, you have to be able to see the parts at the atomic level," David Eisenberg said, a Howard Hughes Medical Institute (HHMI) investigator at the University of California, Los Angeles. "Only then can you design an intervention."

In each disease, a different protein transforms into the misfolded threads known as amyloid fibrils. Scientists believe that the various proteins share a common underlying feature that explains how they assemble into the persistent fibrils that can accumulate in the brain and other tissues.

The common trait of these different proteins was discovered more than thirty years ago. But even the most advanced technologies have been unable to capture anything more than a fuzzy image.

"We call it the spine of the amyloid," said Eisenberg, who is also director of the UCLA-Department of Energy Institute of Genomics and Proteomics. "A little bit of each protein forms the spine, and the rest of the protein is hanging out in globular domains that decorate the spine and give the fibril its thickness and bumpiness. Once these amyloid fibrils form in tissues or cells, they are very hard to get rid of."

Now, he and his colleagues report the first detailed look at one protein's version of the shared core feature. In this case, it was a yeast prion, a misfolded protein that has the additional knack of being able to infect other cells or organisms, said first author Rebecca Nelson, a graduate student. Unlike in people, the yeast prion causes a condition which may be beneficial. In people, scientists do not know the role of the fibrils in the disease process in most associated diseases, but the formation of fibrils is associated with diseases.

According to yeast prion expert Jonathan Weissman, an HHMI investigator at the University of California, San Francisco, determining this structure "is a monumental achievement that will open up a new era in the structural analysis of amyloids."

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