First Atomic-Level Look at a Protein That Causes Brain Disease

For the first time, researchers have peered deeply at the atomic level into the protein that causes hereditary cerebral amyloid angiopathy (CAA) - a disease thought to cause stroke and dementia.

The study pinpointed a tiny portion of the protein molecule that is key to the formation of plaques in blood vessels in the brain.

Ohio State University chemist Christopher Jaroniec and his colleagues report their results this week in the online edition of the Proceedings of the National Academy of Sciences.

Researchers worldwide are working to understand how certain kinds of proteins, called prions, cause degenerative brain diseases such as CAA. More common prion diseases include bovine spongiform encephalopathy (mad cow disease), and Creutzfeldt-Jakob disease in humans. All are incurable and fatal.

Jaroniec understands that any discovery related to prions could raise people’s hopes for a cure, but he emphasized that his study is only a first step towards understanding the structure of the prion for CAA.

“This is a very basic study of the structure of the protein, and hopefully it will give other researchers the information they need to perform further studies, and improve our understanding of CAA,” he said.

His team partnered with biochemists from Case Western Reserve University, who took a fragment of the human prion protein for CAA and tagged it with chemical markers.

Jaroniec explained that, while the prion protein used in the study is associated with the development of hereditary CAA, it is not infectious.

After the researchers tagged the molecule, they created the right chemical conditions for it to fold into macromolecules called amyloid fibrils.

Researchers know that in the body, these fibrils form plaques that lodge in blood vessel walls in the brain. But nobody has been able to closely examine the molecular structure of CAA fibrils until now.

“These fibrils are very large and complex, and so traditional biochemical techniques won’t reveal their structure in detail,” Jaroniec said.

The assistant professor of chemistry at Ohio State is an expert in a technique that can reveal the structure of such large molecules: solid-state nuclear magnetic resonance (NMR) spectroscopy.

NMR works by tuning into the radio waves emitted by atoms within materials. Every atom emits radio waves at a particular frequency, depending on the types of atoms that surround it.

The NMR technique the chemists used, called “magic angle spinning,” involves spinning materials at a certain angle with respect to the NMR's magnetic field in order to remove radio interference among the atoms. It offers researchers a clear view of which atoms make up a particular molecule, and how those atoms are arranged.

So after the researchers let the prion proteins fold into amyloid fibrils, they used magic angle spinning NMR to study the fibrils’ structure.