Modern spectroscopy 'may explain protein toxicity'

Amyloid diseases, such as Alzheimer’s disease, type 2 diabetes and cataracts all share the common trait that proteins aggregate into long fibres which then form plaques.

Unfortunately, laboratory studies have not been unable to locate the source of toxicity as neither the amylin monomer precursors nor the plaques themselves are very toxic.

In new research published via Biomedical Spectroscopy & Imaging (BSI), a group of scientists claim to have found an explanation as to why proteins aggregate into toxic plaques.

I am not encouraging us to begin engineering our DNA to match that of rats

Martin Zanni

According to a BIS report, new evidence using two-dimensional infrared spectroscopy has revealed an intermediate structure during the amylin aggregation pathway that may explain toxicity, opening a window for possible interventions.

“Figuring out how and why amyloid plaques form is exceedingly difficult, because one needs to follow the atomic shapes of the protein molecules as they assemble. Most tools in biology give either shapes or motions, but not both,” said lead investigator Martin T. Zanni, of the Department of Chemistry at the University of Wisconsin-Madison.

“We have been developing a new spectroscopic tool, called two-dimensional infrared spectroscopy, which can monitor the plaques as they form in a test tube.”

Two-dimensional infrared spectroscopy (2D IR) is a relatively modern technique used for investigating molecular structures and dynamics.

This technique is said to have several advantages over standard linear infrared spectroscopies because in 2D IR, infrared spectra are spread into a second dimension, providing information on vibrational couplings and separating the effects of homogeneous and inhomogeneous dynamics - a technology which significantly assists the study of molecular structures, researchers say.

Zanni and his team employed this technology to study the amyloid protein associated with type 2 diabetes.

Isotope labelling was used to measure the secondary structure content of individual residues.

By following many 2D IR spectra from one particular region over several hours, the researchers claim they were able to visualise the amylin as it progressed from monomers to fibres.

“We learned that, prior to making the plaques, the proteins first assemble into an unexpected and intriguing intermediate and organised structure,” said Zanni.

“The proteins undergo a transition from disordered coil [in the monomer], to ordered ?-sheet [in the oligomer] to disordered structure again [in the fibre],” he added.

The authors have suggested that differences between species in their capacity to develop type 2 diabetes may be related to the capacity to form these intermediate amylin structures.

That may be an explanation as to why humans develop the disease while dogs and rats do not, the researchers said.

“I am not encouraging us to begin engineering our DNA to match that of rats, but our findings may help to develop plaque inhibitors or hormone replacement therapies for people suffering from type 2 diabetes, because we know the structure we want to avoid,” said Zanni.