Proteoglycans and Injury of the Central Nervous System

Blackwell Science, LtdOxford, UKCGACongenital Anomalies0914-3505The Japanese Teratology Society, 2004XX 2004444181188Review ArticleProteoglycans and CNS injuryF. Matsui and A. Oohira Congenital Anomalies 2004; 44, 181–188 181 REVIEW ARTICLE Proteoglycans and injury of the central nervous system Fumiko Matsui and Atsuhiko Oohira Department of Perinatology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan ABSTRACT Proteoglycan is a family of glycopro- INTRODUCTION teins which carry covalently-linked glycosaminoglycan It is well known that axonal regeneration is unsuccessful in chains, such as chondroitin sulfate and heparan sulfate. the injured adult mammalian central nervous system (CNS). Proteoglycans are believed to play important roles in Histochemical studies have shown that a glial scar is formed morphogenesis and maintenance of various tissues at the injury site and prevents axonal regeneration. Many including the central nervous system (CNS) through inhibitory molecules, such as myelin-associated glycopro- interactions with cell adhesion molecules and growth fac- tein, Nogo, Semaphorin, and chondroitin sulfate proteogly- tors. In the CNS, a significant amount of evidence has cans (CSPG), have been found in the glial scar (for reviews, been accumulated to show that proteoglycans function as see Fawcett & Asher 1999; Morgenstern et al. 2002; Prop- modulators in various cellular events not only in the erzi et al. 2003; Rhodes & Fawcett 2004). Of these mole- development, but also in the pathogenesis of neuronal cules, CSPG recently have come into the limelight in terms diseases and lesions. When the CNS is injured, several of injury repair of the CNS. chondroitin sulfate proteoglycans (CSPG) are up-regu- Proteoglycan consists of a core protein and glycosami- lated in glial scars formed around the lesion site. The glial noglycan chains, such as chondroitin sulfate and heparan scar also contains some molecules inhibitory to axonal sulfate (Bandtlow & Zimmermann 2000; Oohira et al. growth, such as myelin-associated glycoprotein, Nogo, 2000). The core protein also attaches N-linked and O-linked and Semaphorin. In vitro studies revealed that CSPG oligosaccharides. Some proteoglycans exist in the extracel- largely exert a repulsive effect on axonal regeneration, lular matrix as secretory molecules, and others exist at the and a signal from CSPG modulates the actin cytoskeleton cell surface as transmembrane or glycosylphosphatidylinos- of outgrowing neurites through the Rho/ROCK pathway. itol (GPI) -anchored molecules (Fig. 1). Their expressions These findings suggest that CSPG are responsible for are developmentally regulated (Bandtlow & Zimmermann unsuccessful axonal regeneration in glial scars. Various 2000), and the structure of their carbohydrate moieties, attempts to overcome the inhibitory effect of CSPG have namely both glycosaminoglycans and oligosaccharides, also been pursued in vivo. Digestion of chondroitin sulfate changes in a development-related manner (Shuo et al. 2004). chains by chondroitinase ABC, suppression of CSPG In many cases, both core proteins and carbohydrate moieties core protein synthesis by decorin, suppression of gly- are necessary for proteoglycans to interact with extracellular cosaminoglycan chain synthesis by a DNA enzyme, and matrix molecules, cell adhesion molecules, and growth fac- inhibition of the Rho/ROCK pathway with specific inhib- tors (Oohira et al. 2000). Since those interactions are sup- itors were all successful for increasing axonal regenera- posed to be important for morphogenesis of various tissues, tion. For a clinical application, the most effective proteoglycan seems to modulate its function through the combination of these treatments needs to be examined in structural changes of protein and carbohydrate moieties in the future. the process of development. In the CNS, proteoglycans are considered to play pivotal Key Words: central nervous system, neurocan, phosphacan, roles in cell-cell and cell-substratum interactions in the proteoglycans, regeneration development, maintenance, and aging of normal tissues (Bandtlow & Zimmermann 2000; Oohira et al. 2000). Addi- tionally, since expressions of some CSPG drastically change Correspondence: Fumiko Matsui, PhD, Department of Perinatology, Insti- in response to CNS injuries, they are believed to be involved tute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi 480-0392, Japan. Email: [email protected] in the pathogenesis and/or repair processes of neuronal dam- Received August 12, 2004; revised and accepted August 23, 2004. ages (Fawcett & Asher 1999; Morgenstern et al. 2002; 182 F. Matsui and A. Oohira NEUROCAN proteoglycans are predominantly present in the CNS, and (Secretory type) others are in non-neuronal tissues as well as neuronal tissues. chondroitin sulfate A few, such as a small chondroitin/dermatan sulfate pro- core protein teoglycan decorin, are distributed ubiquitously in animal NEUROGLYCAN C bodies (Iozzo 1999). (Transmembrane type) The CNS consists of two different cell types; neuronal GLYPICAN (GPI-anchored type) cells and glial cells. Both cell types can be divided further Extracellular into many subclasses with a particular morphology and func- Intracellular chondroitin tion. Some proteoglycans are exclusively expressed by one sulfate heparan GPI cell type, but others are expressed by both. A typical glial sulfate proteoglycan is NG2, a large transmembrane CSPG, which Cell is expressed by oligodendrocyte progenitor cells in the CNS Nucleus (Levine & Nishiyama 1996). Neurocan is reported to be synthesized and secreted mainly by neuronal cells in the Fig. 1 Schematic representation of three types of proteoglycan. normal CNS, although it becomes actively synthesized by Neurocan (Rauch et al. 1992), glypican (Stipp et al. astroglial cells in response to injuries of the CNS (for details, 1994), and neuroglycan C (Watanabe et al. 1995) are depicted representing a secretory proteoglycan, a glyco- see below). In contrast, phosphacan and receptor-type pro- sylphosphatidylinositol (GPI) -anchored proteoglycan, and tein tyrosine phosphatase z/b (RPTPz/b) are produced by a membrane-spanning proteoglycan, respectively. both glial and neuronal cells (Shintani et al. 1998). Each individual proteoglycan shows a particular spa- tiotemporal expression pattern in the CNS, and in many Properzi et al. 2003; Rhodes & Fawcett 2004). Very inter- cases interacts with other extracellular and/or intracellular estingly, depletion of chondroitin sulfate chains or core pro- molecules (Oohira et al. 2000). This suggests that it would teins of CSPG from the lesion site promotes axonal function as a ligand and/or receptor in particular phases in regeneration in the mature CNS. For example, chondroitin CNS development. In fact, it has recently become clearer sulfate degrading enzyme improved axonal regeneration and that neural proteoglycans are involved in various develop- brought about a functional recovery of spinal cord axons mental events of the CNS including cell proliferation, migra- when the enzyme was applied to a rat with a spinal cord tion, cellular differentiation, neurite elongation, pathfinding injury (Bradbury et al. 2002). of axons, and synaptogenesis through molecular interactions In this paper, we first reviewed the research related to with growth factors, extracellular matrix molecules, cell nervous tissue proteoglycans, and then dealt with the recent adhesion molecules, and cytoskeletal components (Bandtlow reports on the expression of proteoglycans, especially & Zimmermann 2000; Oohira et al. 2000; Yoneda & CSPG, in the injured CNS. We also described the inhibitory Couchman 2003). In addition, neural proteoglycans have mechanism of CSPG for axonal regeneration and various been shown to regulate the neuronal plasticity by forming attempts to promote neuronal regeneration by depleting perineuronal nets around synapses (Matsui et al. 1998; Piz- CSPG of the injured sites. zorusso et al. 2002). As a result, more clues are available for understanding how to recover neuronal plasticity even in the Overview of proteoglycans in the central nervous system mature CNS. Early studies on proteoglycans were mainly pursued using connective tissues as sources, especially the cartilage which Expression changes of chondroitin sulfate proteoglycans has a massive amount of extracellular matrix. Although the after central nervous system injury CNS does not have as much the amount of extracellular Many proteoglycan species have been shown to change their matrix compared to the cartilage, it contains multiple species expression levels around lesion sites in response to CNS of proteoglycan in the extracellular matrix and at the cell injuries. Typical examples of those proteoglycans are sum- surfaces of neural cells (Oohira et al. 1994a; Bandtlow & marized in Table 1 and are reviewed below. Zimmermann 2000). They can be classified into two groups: Moon et al. (2002) reported that, following axotomy of proteoglycans bearing chondroitin sulfate chains (CSPG) the nigrostriatal tract in adult rats, HSPG were predomi- and proteoglycans bearing heparan sulfate chins (HSPG). In nantly found within the lesion core, whereas CSPG and addition, there are a few proteoglycans bearing keratan sul- KSPG were predominantly found in the lesion surrounding fate chains (KSPG). Many CSPG, such as neurocan, versican it. Axons sprouted within the lesion core, but rarely grew and aggrecan, exist in the extracellular

Load more