New technology reveals insights into mechanisms underlying amyloid diseases

July 10, 2014
A schematic of the intermediate structure in the aggregation pathway of amylin. Credit: Zhang, Buchanan, Zanni, Biomedical Spectroscopy and Imaging

Amyloid diseases, such as Alzheimer's disease, type 2 diabetes, cataracts, and the spongiform encephalopathies, all share the common trait that proteins aggregate into long fibers which then form plaques. Yet in vitro studies have found that neither the amylin monomer precursors nor the plaques themselves are very toxic. New evidence using two-dimensional infrared (2D IR) spectroscopy has revealed an intermediate structure during the amylin aggregation pathway that may explain toxicity, opening a window for possible interventions, according to a report in the current issue of Biomedical Spectroscopy and Imaging.

"Figuring out how and why form is exceedingly difficult, because one needs to follow the atomic shapes of the molecules as they assemble. Most tools in biology give either shapes or motions, but not both. We have been developing a new spectroscopic tool, called two-dimensional , which can monitor the plaques as they form in a test tube," said lead investigator Martin T. Zanni, PhD, of the Department of Chemistry at the University of Wisconsin-Madison.

The investigators employed this new technology to study the associated with . Isotope labeling was used to measure the secondary structure content of individual residues. By following many 2D IR spectra from one particular region (known as the FGAIL region) over several hours, they were able to visualize the amylin as it progressed from monomers to fibers.

"We learned that, prior to making the plaques, the proteins first assemble into an unexpected and intriguing intermediate and organized structure," commented Dr. Zanni. The proteins undergo a transition from disordered coil (in the monomer), to ordered β-sheet (in the oligomer) to disordered structure again (in the fiber).

These results help to elucidate the physics of the aggregation process, the chemistry of amyloid inhibitors, and the biology of type 2 diabetes, as well as clarify previously contradictory data.

The authors suggest 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 why humans develop the disease while dogs and rats do not. "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," says Dr. Zanni. He adds that mutations in the FGAIL region may inhibit fiber formation by interfering with the formation of these intermediates.

Explore further: New look identifies crucial clumping of diabetes-causing proteins

More information: "Insights into amylin aggregation by 2D IR spectroscopy," by Tianqi O. Zhang, Lauren E. Buchanan, Martin T. Zanni. Biomedical Spectroscopy and Imaging, Volume 3/Issue 3. DOI: 10.3233/BSI-140078

Related Stories

New look identifies crucial clumping of diabetes-causing proteins

November 12, 2013
(Medical Xpress)—People get type 2 diabetes. So do cats. But rats don't, and neither do dogs. Subtle differences in the shape of proteins protect some and endanger others.

A wrong molecular turn leads down the path to Type 2 diabetes

December 20, 2013
Computing resources at the U.S. Department of Energy's (DOE) Argonne National Laboratory have helped researchers better grasp how proteins misfold to create the tissue-damaging structures that lead to type 2 diabetes. The ...

A second amyloid may play a role in Alzheimer's disease, researchers find

June 27, 2013
A protein secreted with insulin travels through the bloodstream and accumulates in the brains of individuals with type 2 diabetes and dementia, in the same manner as the amyloid beta Αβ plaques that are associated with ...

Monster mash: Protein folding gone wrong

November 1, 2013
Imagine a 1950s horror movie monster—a creeping, gelatinous, gluey tangle of gunk that strangles everything around it. That's what amyloid plaques are like when they form in body tissues. These gooey protein clumps are ...

Researchers find clue to stopping Alzheimer's-like diseases

June 27, 2014
(Medical Xpress)—Tiny differences in mice that make them peculiarly resistant to a family of conditions that includes Alzheimer's, Parkinson's and Creutzfeldt-Jakob Disease may provide clues for treatments in humans.

Recommended for you

Make way for hemoglobin

August 18, 2017
Every cell in the body, whether skin or muscle or brain, starts out as a generic cell that acquires its unique characteristics after undergoing a process of specialization. Nowhere is this process more dramatic than it is ...

Bio-inspired materials give boost to regenerative medicine

August 18, 2017
What if one day, we could teach our bodies to self-heal like a lizard's tail, and make severe injury or disease no more threatening than a paper cut?

Female mouse embryos actively remove male reproductive systems

August 17, 2017
A protein called COUP-TFII determines whether a mouse embryo develops a male reproductive tract, according to researchers at the National Institutes of Health and their colleagues at Baylor College of Medicine, Houston. The ...

Two-step process leads to cell immortalization and cancer

August 17, 2017
A mutation that helps make cells immortal is critical to the development of a tumor, but new research at the University of California, Berkeley suggests that becoming immortal is a more complicated process than originally ...

New Pathology Atlas maps genes in cancer to accelerate progress in personalized medicine

August 17, 2017
A new Pathology Atlas is launched today with an analysis of all human genes in all major cancers showing the consequence of their corresponding protein levels for overall patient survival. The difference in expression patterns ...

New technique overcomes genetic cause of infertility

August 17, 2017
Scientists have created healthy offspring from genetically infertile male mice, offering a potential new approach to tackling a common genetic cause of human infertility.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.