Phosphorylation of N-glycans in the brain: The case for a non-canonical pathway?

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.