Map of the Neuronal Tissue O-glycoproteome Reveal Specific Traits in the Secretogranin Family

Impairments in protein glycosylation cause severe developmental disorders and most with prominent neurological involvement. This includes the most abundant GalNAc-type O-glycosylation, but unravelling underlying disease etiologies caused by deficiencies in this glycosylation pathway is hampered by limited knowledge of neuronal O-glycoproteins. Here we report a comprehensive map of GalNAc-type O-glycoproteins (>800) and O-glycosites (>4,000) from neuronal tissues and cell lines that are compiled in a web-based resource. We identified abundant O-glycosites within major classes of proteins involved in neuroplasticity, including perineuronal nets, synapse formation, axon guidance, membrane remodeling and dense core granulogenesis. We demonstrate that Chromogranin A, a key player in neurotransmitter signaling, is abundantly decorated with O-glycans and glycosaminoglycans, and that glycosylation is important for proper multimerization. We further demonstrate that neuronal cell lines deficient in O-glycosylation exhibit higher capacity for storing the neurotransmitter noradrenaline and enlarged neurotransmitter-containing dense core granules