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Headlines Published on 25 May 2007

Title Researchers uncover molecular connection on degenerative diseases

An international research team has made an interesting discovery: several degenerative diseases, including Parkinson's, Alzheimer's and type 2 diabetes, are more closely related at the molecular level than initially thought. The researchers conducted a study on the brains of patients inflicted with these diseases. The team found that the patients' brains contain amyloid fibrils, which are protein molecules linked by water-tight “molecular zippers”. Hailing from UCLA, the European Synchrotron Radiation Facility (ESRF) and the University of Copenhagen, the researchers reported their findings in the journal Nature.

A montage of 100 micro-crystals used to determine the X-ray structures of amyloid fibril cross-beta spines.  © Michael Sawaya, David Eisenberg/UCLA
A montage of 100 micro-crystals used to determine the X-ray structures of amyloid fibril cross-beta spines.
© Michael Sawaya, David Eisenberg/UCLA
From a visual perspective, amyloid fibrils are rope-like structures. According to David Eisenberg, research team member and director of the UCLA-DOE Institute for Genomics and Proteomics, the team was able to prove that the fibrils have a common atomic-level structure. ‘All of these diseases are similar at the molecular level,’ explained Dr Eisenberg. ‘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.’

On a global scale, the study has proven significant. Dr Eisenberg said, ‘It has been a great international collaboration.’ The team carried out part of its research at the microfocus beamline at the ESRF. They used a very small beam of X-rays to study micro-crystals.

Dr Eisenberg said that despite the fact that research is still in its early stages, scientists can now use the findings to develop tools for diagnosing these diseases. They may also be applied for the treatment through ‘structure-based drug design’, he noted.

The team reported 11 new three-dimensional structures of fibril forming segments, including those for main proteins that form amyloid fibrils in Alzheimer's disease.

Researcher and team member Michael Sawaya is likewise pleased with the results. ‘We see many similarities, but some details are different,’ he explained. ‘As we study more structures, we expect to determine the common features among them.’

Dr Sawaya commented that the team was able to determine the location of the zipper because of the positions of the atoms. ‘Like pieces in a jigsaw puzzle, they have to fit together just right,’ he said. ‘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 researchers found that the very short segments of proteins play a key role in the formation of amyloid fibrils. Dr Eisenberg said because the team already knows some of the segments, designing tests to find out whether a new drug is effective becomes less challenging. More than one amyloid fibril-forming segment can be found in a number of disease-related proteins.

Besides being able to produce fibrils and develop a test to establish whether the fibrils break up, the researchers also hypothesise that the origin of prion strains is encoded in the packing of the molecules in the fibrils. The team's report in Nature offers some interesting answers to experts and laypeople alike.

More information:

  • ESRF
  • Nature

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