Beyond the sugar coating: mucin-type O-Glycosylation as an underappreciated player in brain function and disease

Mucin-type O-glycosylation (O-GalNAcylation) is a structurally diverse post-translational modification (PTM) that serves as a critical molecular interface at the cell surface. Unlike well-characterized PTMs such as phosphorylation or N-glycosylation, the specific roles of O-GalNAcylation in the mammalian brain have long remained poorly understood. Recent studies have begun to reposition this modification as an important regulator of brain architecture and homeostasis. Emerging evidence suggests that it contributes to neuronal organization, neurovascular integrity, synaptic function, and stress-related behavioral phenotypes, and that its dysregulation may be associated with neurological and psychiatric phenotypes. This perspective synthesizes recent advances to highlight the potential importance of a "brain O-glycan code" in brain health and disease. We discuss how remodeling of this glycan landscape may intersect with aging, neuroinflammation, and synaptic plasticity, and propose that glyco-neurobiology provides an additional conceptual layer for understanding brain vulnerability and resilience. Finally, we consider how targeting O-glycosylation pathways may open new avenues for diagnostic and therapeutic strategies in neurodegenerative and psychiatric disease.