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Asparagine-linked glycosylation (N-glycosylation) is a common co- and post-translational modification that refers to the addition of complex carbohydrates, called N-linked glycans (N-glycans), to asparagine residues within defined sequons of polypeptide acceptors. Some N-glycans can be modified by the addition of phosphate moieties to their monosaccharide residues, thus forming phospho-N-glycans (PNGs). The most prominent such carbohydrate modification is mannose-6-phosphate (M6P) which plays a well-established role in trafficking of acid hydrolases to lysosomes. However, comparatively little is known about potential alternative types of glycan phosphorylation, particularly when it comes to the brain which is especially rich in phosphorylated oligosaccharides. Combining data from the literature and novel insights derived from our own analyses of published datasets, here we present what is currently known about PNGs in the brain and the glycoproteins they modify. We show that brain PNGs exhibit several distinctive features that don't completely align with our current understanding of the canonical M6P pathway. Furthermore, we demonstrate that there are numerous differences in the way that lysosomal and non-lysosomal neural glycoproteins are modified by PNGs. Based on these observations, we put forward the hypothesis that, in addition to the conventional M6P pathway, the brain employs an alternative oligosaccharide phosphorylation mechanism for the modification of a discrete set of glycoproteins. Here we examine the evidence underpinning this hypothesis and discuss the implications that it raises. Overall, our work suggests that phosphorylation of N-glycans in the brain may be more complex and more diverse than previously recognised.

Obstructive sleep apnea (OSA) is a prevalent disease associated with increased risk for cardiovascular and metabolic diseases and shortened lifespan. The aim of this study was to explore the possibility of using N-glycome as a biomarker for the severe form of OSA. Seventy subjects who underwent a whole-night polysomnography/polygraphy and had apnea–hypopnea index (AHI) over 30 were compared to 23 controls (AHI under 5). Plasma samples were used to extract 39 glycan peaks using ultra-high-performance liquid chromatography (UPLC) and 27 IgG peaks using capillary gel electrophoresis (CGE). We also measured glycan age, a molecular proxy for biological aging. Three plasma and one IgG peaks were significant in a multivariate model controlling for the effects of age, sex, and body mass index. These included decreased GP24 (disialylated triantennary glycans as major structure) and GP28 (trigalactosylated, triantennary, disialylated, and trisialylated glycans), and increased GP32 (trisialylated triantennary glycan). Only one IgG glycan peak was significantly increased (P26), which contains biantennary digalactosylated glycans with core fucose. Patients with severe OSA exhibited accelerated biological aging, with a median of 6.9 years more than their chronological age (p < 0.001). Plasma N-glycome can be used as a biomarker for severe OSA.