Axonal Regeneration by Glycosaminoglycan

Abstract

Like other biomolecules including nucleic acid and protein, glycan plays pivotal roles in various cellular processes. For instance, it modulates protein folding and stability, organizes extracellular matrix and tissue elasticity, and regulates membrane trafficking. In addition, cell-surface glycans are often utilized as entry receptors for viruses, including SARS-CoV-2. Nevertheless, its roles as ligands to specific surface receptors have not been well understood with a few exceptions such as selectins and siglecs. Recent reports have demonstrated that chondroitin sulfate and heparan sulfate, both of which are glycosaminoglycans, work as physiological ligands on their shared receptor, protein tyrosine phosphatase sigma (PTPσ). These two glycans differentially determine the fates of neuronal axons after injury in our central nervous system. That is, heparan sulfate promotes axonal regeneration while chondroitin sulfate inhibits it, inducing dystrophic endbulbs at the axon tips. In our recent study, we demonstrated that the chondroitin sulfate (CS)-PTPσ axis disrupted autophagy flux at the axon tips by dephosphorylating cortactin. In this minireview, we introduce how glycans work as physiological ligands and regulate their intracellular signaling, especially focusing on chondroitin sulfate.

Keywords: PTPσ; autophagy; axonal regeneration; chondroitin sulfate; dystrophic endbulb; heparan sulfate.

FIGURE 1

Mechanistic insight into the formation of dystrophic endbulb by CS. The severed axons run into the gradient of CS originated from the perineuronal net and the reactive astrocyte in the lesion. The CS-E tetrasaccharide segment, which rarely appears on a CS chain, preferentially monomerizes and activates its axonal receptor PTPσ/LAR. Contrary, HS protects the formation of dystrophic endball by inducing clustering of the receptors. RPTP dephosphorylates cortactin, which is localized onto the lysosome surface and stabilizes actin fibers to facilitate autolysosome formation. As a consequence, the CS-RPTP axis disrupts autophagy flux, inducing the failure of fusion between autophagosomes and lysosomes, and thus abnormal accumulation of autophagosomes. That leadsto transforms of axon tips to dystrophic endbulb. Xyl, xylose; Gal, galactose; GlcA, glucuronic acid; GalNAc, N-acetylgalactosamine; P, tyrosine phosphorylation.