Molecules in focus
Chondroitin sulfate: A key molecule in the brain matrix

https://doi.org/10.1016/j.biocel.2012.01.004Get rights and content

Abstract

Chondroitin sulfate is a glycosaminoglycan composed of N-acetylgalactosamine and glucuronic acid. It attaches to a core protein to form chondroitin sulfate proteoglycan (CSPG). Being a major component of the brain extracellular matrix, CSPGs are involved in neural development, axon pathfinding and guidance, plasticity and also regeneration after injury in the nervous system. In this review, we shall discuss the structure, the biosynthetic pathway, its functions in the nervous system and how we can improve regeneration in the nervous system by modulating its structure and binding properties.

Introduction

Chondroitin sulfate (CS), together with heparan sulfate (HS), dermatan sulfate (DS), keratan sulfate and hyaluronan (HA), belongs to the glycosaminoglycan (GAG) family - unbranched polysaccharide chains consisting of repeating disaccharide units. The basic structure of the CS disaccharide unit was first reported in 1913 in which glucuronic acid (GlcA) was identified and within the course of the following 2 years, the structure of the other subunit N-acetylgalactosamine (GalNAc) was also reported (Levene and La Forge, 1914). Apart from HA, all GAGs are attached to a protein core, forming proteoglycans (PGs; Fig. 1). To date, there are at least 16 chondroitin sulfate proteoglycans (CSPGs) identified in the nervous system, with aggrecan, neurocan, versican, brevican and phosphacan being the most common members (Herndon and Lander, 1990).

Section snippets

Structure

The basic unit of CS is a disaccharide composed of GalNAc and GlcA. They are linked together by glycosidic linkage GlcA β(1  3) GalNAc β(1  4) to form unbranched GAG chains (Fig. 1; Iozzo and Murdoch, 1996). One single GAG chain can consist of up to 50 disaccharide subunits. Sulfation is one of the most common modifications on GAGs and it is mainly found at C-4 or C-6 of the GalNAc, C-2 in the IdoA and occasionally in C-3 of GlcA (Fig. 1). The CS disaccharides are classified according to the

Expression, activation and turnover

The synthesis of CS-GAG chain starts in the endoplasmic reticulum (ER) while the core protein is being synthesized and continues in the Golgi apparatus. Many steps and enzymes are involved in the process of CS synthesis and they are depicted in Fig. 2.

Biological functions

In general, CSPGs act to organize the brain ECM, control neuronal growth and plasticity (Yamaguchi, 2000). CSPGs are also significantly up-regulated in glial scar and are believed to be the principle cause of regeneration failure after nervous system injury.

Clinical significance

The removal of CSPGs and modulations of PNN formation with ChABC have been successfully demonstrated in improving regeneration and plasticity in various injury models (see review Kwok et al., 2011). However, there remains a challenge in translating this success into clinical applications. ChABC is a bacterial enzyme which requires repeated injections or continuous application (e.g. intrathecal or intracerebroventricular delivery) over a period of time into the injury sites for sustained

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