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.
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.”