Chondroitin sulfate proteoglycans in the nervous system: inhibitors to repair

Abstract

Chondroitin sulfate proteoglycans (CSPGs) are widely expressed in the normal central nervous system, serving as guidance cues during development and modulating synaptic connections in the adult. With injury or disease, an increase in CSPG expression is commonly observed close to lesioned areas. However, these CSPG deposits form a substantial barrier to regeneration and are largely responsible for the inability to repair damage in the brain and spinal cord. This review discusses the role of CSPGs as inhibitors, the role of inflammation in stimulating CSPG expression near site of injury, and therapeutic strategies for overcoming the inhibitory effects of CSPGs and creating an environment conducive to nerve regeneration.

Figure 1

Schematic representation of individual proteoglycan molecules. (a) Members of the lectican family: aggrecan, brevican neurocan, and the three isotypes of versican, all share a similar homology, with a G1 domain at the N-terminus and a G3 domain at the C-terminus. The GAG side chain varies in number among the different lectican family members but is attached to the central core of the protein. (b) Phosphacan is a splice variant of the RPTP molecule, lacking the transmembrane and two intracellular domains, found in the RPTP molecule. (c) NG2 is a transmembrane proteoglycan that lacks homology to any of the other CSPGs. NG2 has two large extracellular domains separated by an extended region, where the GAGs are attached, a transmembrane domain and short cytoplasmic tail. NG2 can be cleaved by enzymes at the cell surface and released into the extracellular matrix (adapted and modified from [16, 18]).

Figure 2

Diagram of the sulfation patterns of the disaccharide unit of the GAG chain. Sulfation at different carbon atom positions in the GlcA and/or GalNAc saccharide unit is one of the major factors that influence the effects of the proteoglycan. Monosulfation can occur at position 4 of the GalNAc resulting in synthesis of CS-A GAG or position 6 of the GalNAc resulting in the synthesis of the CS-C GAG. Disulfation can also occur with sulfation of position 6 of the GalNAc and position 2 of the GlcA, resulting in synthesis of the CS-D GAG, or sulfation of positions 4 and 6 on the GalNAc saccharide unit resulting in formation of the CS-E GAG (adapted and modified from [16, 18]).

Figure 3

Damage to the central nervous system, either by trauma or disease processes, initiates an increase in proinflammatory cytokines, which stimulates the upregulation of CSPGs expression.