The failure of mammalian CNS neurons to regenerate their axons derives from a combination of intrinsic deficits and extrinsic factors. Following injury, chondroitin sulfate proteoglycans (CSPGs) within the glial scar inhibit axonal regeneration, an action mediated by the sulfated glycosaminoglycan (GAG) chains of CSPGs, especially those with 4-sulfated (4S) sugars. Arylsulfatase B (ARSB) selectively cleaves 4S groups from the non-reducing ends of GAG chains without disrupting other, growth-permissive motifs. We demonstrate that ARSB is effective in reducing the inhibitory actions of CSPGs both in in vitro models of the glial scar and after optic nerve crush (ONC) in adult mice. ARSB is clinically approved for replacement therapy in patients with mucopolysaccharidosis VI and therefore represents an attractive candidate for translation to the human CNS.

Proteoglycans (PGs) in the extracellular matrix (ECM) play vital roles in axon growth and navigation, plasticity, and regeneration of injured neurons. Different classes of PGs may support or inhibit cell growth, and their functions are determined in part by highly specific structural features. Among these, the pattern of sulfation on the PG sugar chains is a paramount determinant of a diverse and flexible set of outcomes. Recent studies of PG sulfation illustrate the challenges of attributing biological actions to specific sulfation patterns, and suggest ways in which highly similar molecules may exert opposing effects on neurons. The receptors for PGs, which have yet to be fully characterized, display a similarly nuanced spectrum of effects. Different classes of PG function via overlapping families of receptors and signaling pathways. This enables them to control axon growth and guidance with remarkable specificity, but it poses challenges for determining the precise binding interactions and downstream effects of different PGs and their assorted sulfated epitopes. This review examines existing and emerging evidence for the roles of PG sulfation and receptor interactions in determining how these complex molecules influence neuronal development, growth, and function.