Molecular glue that binds cells in the nervous system shows up in advanced imaging
Research may provide new leads on developing treatments for multiple sclerosis
Proteins that are crucial for a properly functioning nervous system appear to work as a molecular glue, binding cells together with high precision. Researchers from Utrecht University watched the proteins in action, using advanced imaging techniques. Their results may lead to new clues for developing therapies against multiple sclerosis and certain types of cancer.
Our ability to move and feel depends on a precisely orchestrated interaction between nerve cells and the fatty substance myelin. Myelin wraps around nerve cells called axons, which increases the speed of electrical impulses traveling through nerve cells. It also helps the nervous system to learn new abilities. Although research has long recognized the crucial role of myelin, until now it was unclear how the substance binds onto cells.
Keeping cell in the nervous system separated
New results, published in the scientific journal Nature Communications, show how proteins interact intimately to glue the myelin onto neurons, and to keep them a tiny bit apart at very well calibrated distances. This discovery is important because the glue could have a role in multiple sclerosis and the small gap creates just the right condition for fast conduction through the myelinated neuron.
It is remarkable how these proteins keep the two cells at this tiny, fixed distance
Mind the gap
“It is remarkable how these proteins keep the two cells at this tiny, fixed distance, because they are rather large and flexible molecules”, says structural biologist Bert Janssen, lead author of the Nature Communications study. “We show that one side of the protein acts as the calibrated spacer and the other side contains the flexibility that allows the molecules to reach out over larger distances if they need to.”
The working mechanisms of the molecular glue was revealed by Janssen’s research team using imaging techniques based on intense X-rays. PhD student Lucas Chataigner, first author of the publication, used X-ray diffraction and small-angle X-ray scattering to visualize the proteins and their interactions in exquisite detail. This revealed which parts of the proteins are important, and showed that glycans, modifications on the protein surface, influence the interaction. The equipment used was set up at the Diamond Light Source, a British X-ray research facility.
The discovery by Janssen's team may lead to new clues for developing therapies to treat neurological disorders such as multiple sclerosis. In some people suffering from multiple sclerosis, the interaction between the ‘glue proteins’ is obstructed, probably due to an autoimmune response of the body.
“Now we have revealed how these proteins must bind to allow myelin to function properly, we may be able to paint a clearer picture of how to reinforce this interaction”, says Janssen. “At least we’re seeing clues as to which part of the proteins to target when combatting multiple sclerosis.”
This could be the starting point for developing therapies to remove these antibodies from the blood of MS patients
In addition, the autoimmune response may also cause immune cells to break down the myelin. Janssen: “Our data and tools could be used to pinpoint where these antibodies bind to the proteins. This could be the starting point for developing therapies to remove these antibodies from the blood of MS patients.”
The research work was part of an ERC Starting Grant from the European Research Council, awarded to Janssen in 2015.
Nature Communications, November 2022. DOI: 10.1038/s41467-022-34302-9
Lucas M.P. Chataigner, Christos Gogou, Maurits A. den Boer, Cátia P. Frias, Dominique M.E. Thies-Weesie, Joke C. M. Granneman, Albert J.R. Heck, Dimphna H. Meijer, Bert J.C. Janssen