JUN 14, 2017 7:12 PM PDT

Visualizing the Molecular Interactions of an Under-diagnosed Disorder

WRITTEN BY: Carmen Leitch

Myasthenia gravis is a disorder that is seldom diagnosed; it is estimated that many people have the disease and do not know it. The symptoms can vary and there are few therapeutic options for those affected but new work may help change that. Researchers have completed a three-dimensional structure of the molecular interactions at the heart of the disease, which is likely to eventually aid patients; it was published in eLife.

To solve the structure of myasthenia gravis, scientists mixed proteins from the nAChR a1 and myasthenia gravis auto-antibody, to create crystals of the nicotinic acetylcholine receptors, a neuromuscular receptor responsible for movement, as it is disrupted by the autoimmune disease, myasthenia gravis. The crystals were shot with an X-ray (synchrotron, Advanced Photon Source in Chicago) to solve the structure. / Credit: USC Chen lab and Advanced Photon Source in Chicago

"Patients are just waiting for breakthroughs in research and better treatment," explained Kaori  Noridomi, a  a doctoral candidate with Professor Lin Chen's Molecular and Computational Biology lab at the USC Dornsife College of Letters, Arts and Sciences. "They may also, because the disease attacks their immune system, end up with other diseases. I met one patient who had myasthenia gravis and had also dealt with four different types of cancer.”

Noridomi and a research team that included Chen were able to view a neural receptor that is the usual target of the disease on the molecular level for the first time. It provides insight into the mechanism of the disease; illustrating how it disrupts signals from muscle to brain. Lin Chen, the study's corresponding author and a USC Dornsife College Professor of Biological Sciences and Chemistry, is hopeful this work will lead to new therapies for the disease.

"Because of this finding, we may also find a better quantitative way to identify patients," Chen said.

While it’s considered under diagnosed by the Myasthenia Gravis Foundation of America, between 36,000 and 60,000 Americans are impacted by myasthenia gravis annually.

The treatment usually only confronts some of the symptoms of the disorder, while not addressing the causes, said Noridomi. Symptoms might include weakness in facial muscles and eyes, or arms, slurred speech or difficulty swallowing.

Myasthenia gravis has a well-defined autoimmune target, nicotinic acetylcholine receptors. In the disease, antibodies run amok attack those receptors. Those antibodies are also the ones that respond to nicotine and other drugs like it. In the muscles however, they act to transmit the signals sent by the brain to the muscle that control movement.

In the disease, the antibodies disrupt this process, interrupting the natural binding that normally occurs between the receptors in the muscles and the acetylcholine molecules.The antibodies are trying to destroy a protein within the receptors. The disease is usually diagnosed by confirming the presence of those antibodies. Learn more about the disorder from the following video.

For this work, the investigators were able to visualize the cross-linking between the rogue antibodies and the targeted proteins in the receptors in the muscles. The study indicated that it could be possible to use drugs to stop the antibodies from getting to the receptor. The wide range of disease seen in patients remains a mystery, however.

"It's a little bit of disease and a little bit of heredity that cause this," Noridomi said. "In some people, the level of symptoms may be so slight and varied that they may not even go to the trouble of finding out if they have a disease. By that, I mean, maybe they just don't feel good one day, like they don't feel like going to work. They don't know that ultimately they are suffering an attack.”

 

Sources: AAAS/Eurekalert! via USC, NINDS, eLife

About the Author
  • Experienced research scientist and technical expert with authorships on over 30 peer-reviewed publications, traveler to over 70 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
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