Chondroitinase ABC I as a novel candidate for reducing damage in spinal cord injury

Glycosaminoglycans and proteoglycans

Extracellular matrices (ECMs) and cell surfaces of the mammalian tissues contain repeating disaccharide units known as glycosaminoglycans (GAGs). These linear polysaccharides can be sulfated in various positions to obtain a negatively charged nature that is essential for molecular recognition and binding. The corresponding reactions are catalyzed by the enzymes of the sulfotransferase family. Based on the type of disaccharide units, GAGs are categorized into several groups, including hyaluronic acid (HA), chondroitin sulfate/dermatan sulfate (CS/DS), heparin/heparin sulfate (Hep/HS), and keratan sulfate (KS) ( ).

A typical chondroitin sulfate disaccharide unit in human, chondroitin-6-sulfate (C6S) with the primary configuration containing a uronic acid (Glucuronic acid) and amino sugar (Galactosamine) is shown in Fig. 1 A . As shown in Fig. 1 B; GAG chains can covalently bind at their reducing ends to a serine or asparagine residue of a target protein, forming a proteoglycan ( ). On a higher level, a biopolymer such as hyaluronic acid acts as a backbone structure to assemble similar or various types of proteoglycans ( Fig. 1 C).

These macromolecules are synthesized in all mammalian cells and based on the type and function; they may be secreted into the ECM, localized into the plasma membrane, or stored in secretory vesicles ( ; ; ; ). Due to the wide variety of functions, any defects in the synthesis and processing of proteoglycans have important clinical manifestations ( ). Regarding the protein binding affinity and biocompatibility of GAGs, they are proposed as a tool for localized drug-delivery, using enzymes as drug ( ).

Distribution and functions of GAGs and proteoglycans

The GAGs play essential roles in fundamental biological processes, and wide distribution of these biopolymers in animals demonstrates that they have conserved functions in organisms ( ). In the normal state, individual tissues of the human body contain a defined combination of GAGs, some of which are tissue-specific, and others may be temporally observe during growth, development, and pathogenic conditions.

The ability to absorb water molecules and their spatial structure enables GAGs and proteoglycans to provide a suitable scaffold that is essential to maintain the shape, cohesive properties, and mechanical features of tissues ( ). Accordingly, in tissue-based diseases, damage to the structure of proteoglycan is a central event ( ). Some of the GAGs can bind into several specific proteins such as cytokines, chemokines, growth factors, morphogens, etc., to form biologically effective types of macromolecules ( ). These interactions are crucial in regulating of some critical biological processes, including cell migration ( ), regulation of blood coagulation and homeostasis ( ; ), growth factor control ( ), cell adhesion, and signaling ( ), inflammation ( ), and pathogens attachment ( ). They are involved in multicellular processes and have critical roles in development.

The GAGs are also involved in the inhibition of smooth muscle cell proliferation ( ). It has been reported that proteoglycans may have essential roles in normal glomerular cell function and progressive renal disease ( ). They are considered as the first defensive line at the bladder’s luminal surface against urinary tract infections, that created by pathogenic Escherichia coli among postmenopausal women ( ). It has postulated that the accumulation of specific GAGs may form a physical barrier to the passage of immunocompetent cells from the mother to the fetus ( ). The changes in the composition and molecular structure of placental GAGs during pregnancy could alter the molecular transport rate through placental connective tissue and affect the rate of fetal growth ( ). It has been reported that GAGs are involved in tumor development, angiogenesis and metastasis in certain types of cancers ( ).

CSPGs in the nervous system

It has revealed that CSPGs and DSPGs are dominant proteoglycans in CNS-ECM ( ). Chondroitin sulfate proteoglycans (CSPGs) are those CS-GAGs that are covalently linked to a core protein ( ). The GAG side chains in CSPGs are of different lengths, and the disaccharide units of CSPGs have either N -acetylglucosamine or N -acetylgalactosamine as well as uronic acid (see Fig. 1 ). Hence, depending on the length and the type of disaccharide unit and the position of sulfate moiety (positions 4 or 6), different types of CSPGs have identified, some of them have important tasks in CNS ( ). In CNS-ECM, various types of CSPGs bind to linear non-sulfated polysaccharides such as hyaluronan to produce a specific combination of proteoglycans, which is collectively known as lectican family proteoglycans. They include Neurocan, Brevican, Aggrecan, Perlecan, Testican, Versican, and Biglycan ( ; ). Some of the GAGs are attached to the transmembrane proteins and form the transmembrane family of proteoglycans. A schematic representation of various proteoglycans in the cell surface and ECM of nervous tissues is provided in Fig. 2 ( ). Structurally, the CNS-ECM proteoglycans provide the viscoelastic properties, maintain ions and water content and normal osmotic pressure, and dictate proper tissue organization. It has shown that the development of the nervous system in mammals involves coordinated cellular interactions, such as patterning and routing of migrating neural cells, axon pathfinding, and synapse formation, that is due to the proper organization of the nervous ECM ( ; ). Hence, the time-dependent concentration of CSPGs relative to other adhesive matrix molecules at the various developmental stage, define the normal state of the CNS-ECM ( ).