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bioRxiv · 10.1101/2024.05.09.593410

O-GalNAc glycans enrich in white matter tracts and regulate nodes of Ranvier

Noel, M.·Suttapitugsakul, S.·Cummings, R. D.·Mealer, R. G.
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Abstract

Protein O-glycosylation is a critical modification in the brain, as genetic variants in the pathway are associated with both common and severe neuropsychiatric phenotypes. However, little is known about the most abundant type of O-glycan in the mammalian brain, which are O-GalNAc linked. Here, we determined the spatial localization, protein carriers, and cellular function of O-GalNAc glycans in mouse brain. We observed striking spatial enrichment of O-GalNAc glycans in white matter tracts and at nodes of Ranvier. Glycoproteomic analysis revealed that more than half of the identified O-GalNAc glycans were present on chondroitin sulfate proteoglycans termed lecticans, and display both domain enrichment and site-specific heterogeneity. Though genetic ablation in a single cell type failed to replicate the severe phenotypes seen in congenital disorders, inhibition of O-GalNAc synthesis in neurons reduced binding of Siglec-4, a known regulator neurite growth, and shortened the length of nodes of Ranvier. This work highlights a new function of O-GalNAc glycans in the brain and will inform future studies on their role in development and disease.

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Noel, M., Suttapitugsakul, S., Cummings, R. D., Mealer, R. G.. 2024-05-09. O-GalNAc glycans enrich in white matter tracts and regulate nodes of Ranvier. https://doi.org/10.1101/2024.05.09.593410

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