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Some degenerative diseases prove similar at the molecular level

07.05.2007
Alzheimer’s disease, Parkinson’s disease, type 2 diabetes, the human version of mad cow disease (Creutzfeldt-Jakob disease), and other degenerative diseases are more closely related at the molecular level than many scientists realized, an international team of researchers, including an ESRF researcher, report in the journal Nature.

The brains of patients with these diseases contain harmful rope-like structures known as amyloid fibrils, which are protein molecules linked by water-tight “molecular zippers”.

“We have shown that the fibrils have a common atomic-level structure,” said David Eisenberg, a UCLA-DOE professor of chemistry and biology and a member of the research team. “All of these diseases are similar at the molecular level; all of them have a dry steric zipper. With each disease, a different protein transforms into amyloid fibrils, but the proteins are very similar at the atomic level.”

The UCLA team, together with scientists from the University of Copenhagen and the ESRF, carried out part of their research at the microfocus beamline at the ESRF, where they used a very small beam of X-rays to study micro-crystals. “It has been a great international collaboration,” Eisenberg said.

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The research, while still preliminary, could help scientists develop tools for diagnosing these diseases, and potentially for treating them through “structure-based drug design,” said Eisenberg.

The researchers report 11 new three-dimensional structures of fibril forming segments, including those for both of the main proteins that form amyloid fibrils in Alzheimer’s disease.

“It has been a joy to see so many new structures,” said Michael Sawaya, member of the team. “We see many similarities, but some details are different. As we study more structures, we expect to determine the common features among them”.

“It is clear from the positions of the atoms where the zipper is,” Sawaya added. “Like pieces in a jigsaw puzzle, they have to fit together just right. We are finding out how they fit together. We don’t yet know all the ways of forming the zippers; we are working to fill in the missing pieces and are hopeful of doing so.”

The research shows that very short segments of proteins are involved in forming amyloid fibrils; Eisenberg and his colleagues know some of the segments. Knowing the segments makes it easier to design tests to detect whether a new drug is effective, Eisenberg noted. Several of the disease-related proteins contain more than one amyloid fibril-forming segment.

If the molecular zipper is universal in amyloid fibrils, as Eisenberg believes, is it possible to pry open the zipper or prevent its formation? The team can now produce fibrils and has developed a test to determine whether the fibrils break up, using a wide variety of chemical compounds. This strategy could be potentially used to break up the fibrils.

A mystery on which the new Nature paper sheds light is what causes different strains of prions (infectious proteins) in which the protein sequence is identical. Scientists present a strong hypothesis that the origin of prion strains is encoded in the packing of the molecules in the fibrils.

In an earlier Nature paper (9 June 2005), Eisenberg and his colleagues presented the three-dimensional structure of an amyloid-like protein from yeast that revealed the surprising molecular zipper.“In 2005, we were like prospectors who found flakes of gold in a stream,” Eisenberg said. “Now we see the real nuggets. In this paper, we present atomic-level structures for crystals related to fibrils from proteins associated with numerous human diseases.”

Montserrat Capellas | alfa
Further information:
http://www.esrf.fr/news/pressreleases/disease/

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