Sugar molecules help keep the brain’s electrical signals on track

Sugarcoating isn’t just for making things taste or sound sweeter. In the brain, complex sugar molecules decorate key proteins and help them function.

Researchers from Gifu University have now discovered that one long-overlooked class of these sugars is essential for maintaining the tiny structures, called nodes of Ranvier, that keep electrical impulses racing through the brain quickly and reliably.

The study was published in Communications Biology on July 13.

Glycans are sugar molecules, attached to proteins, that influence how those proteins behave inside and outside cells. One type, O-mannose glycans, is known as essential for muscle health, but the functions of most O-mannose glycans have remained elusive. Since these glycans are especially abundant in the brain, scientists have long suspected they play important roles in the nervous system.

“Defects in O-mannose glycans have previously been associated with neurological disorders, but exactly what these sugar structures do under normal conditions has yet to be fully understood,” said Yasuhiko Kizuka, professor at Gifu University’s Institute for Glyco-core Research (iGCORE) and corresponding author of the study.

To investigate, researchers deleted in laboratory mice the gene encoding MGAT5B, a brain-specific enzyme that produces branched O-mannose glycans. The team then combined biochemical analyses with electrophysiological measurements and behavioral studies to determine how the loss of these sugar branches affects the nervous system.

“We found that mice lacking MGAT5B developed abnormally widened nodes of Ranvier in the brain’s white matter,” Kizuka said.

Nodes of Ranvier are tiny gaps in the insulating myelin sheath surrounding nerve fibers. These microscopic relay stations allow electrical impulses to “jump” rapidly along axons, enabling fast and reliable communication throughout the nervous system. The structural changes in the nodes impaired nerve signaling, causing electrical impulses to travel more slowly and with greater variability than in healthy mice. The knockout mice also performed worse on a test of motor coordination.

The team traced these effects to neurofascin 186 (NF186), a protein that helps organize nodes of Ranvier. MGAT5B adds branched O-mannose glycans to NF186, and the researchers found that these sugar modifications regulate NF186’s interaction with Contactin 1, another protein involved in organizing the node. By fine-tuning these molecular interactions, the glycans help preserve the narrow architecture required for efficient nerve conduction.

“Branching of glycans is critically involved in formation of nodes of Ranvier, which in turn is required for fast and less variable speed of nerve conductivity,” Kizuka said.

It’s worth noting that restoring MGAT5B specifically in neurons corrected the nodal defects in the knockout mice, demonstrating that the enzyme acts directly within neurons to maintain node structure.

The findings establish branched O-mannose glycans as critical regulators of node of Ranvier formation and function, providing a long-sought understanding of the physiological role for these brain-specific sugar structures.

The team noted that important questions remain. The precise molecular mechanism by which O-mannose glycan branching controls node width is still unclear, and the detailed glycan structures attached to NF186 have yet to be characterized.

“We hope to determine whether defects in these sugar modifications contribute to diseases involving myelin or impaired nerve conduction,” Kizuka said.

Funding 

• FOREST program nos. JPMJFR2145 and JPMJFR215Z from the Japan Science and Technology Agency (JST),
• Grant-in-Aid for Scientific Research (B) no. 24K02222, Grants-in-Aid for Scientific Research (C) no. JP23K06302, Core-to-Core Program no. JPJSCCA202000007 and J-PEAKS program no. JPJS00420230009 from the Japan Society for the Promotion of Science (JSPS),
• AMED-CREST grant no. JP23gm1410011 from the Japan Agency for Medical Research and Development (AMED),
• Human Glycome Atlas Project (HGA) from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT).