Receptors of Chondroitin Sulfate Proteoglycans and CNS Repair

Review Article

Austin J Neurol Disord Epilepsy. 2015; 2(1): 1010.

Receptors of Chondroitin Sulfate Proteoglycans and CNS Repair

Yosuke Ohtake and Shuxin Li*

Department of Anatomy and Cell Biology, Temple University School of Medicine, USA

*Corresponding author: Shuxin Li, M.D. PhD., Department of Anatomy and Cell Biology, Shriners Hospital’s Pediatric Research Center, Temple University School of Medicine, 3500 N. Broad Street, Philadelphia, PA, 19140, USA

Received: March 15, 2015; Accepted: June 02, 2015; Published: June 08, 2015

Abstract

Axon disconnections in the CNS usually cause persistent dysfunction with a very limited recovery and the medical treatments to enhance recovery from neurological deficits due to signal conduction failure are largely restricted. Among numerous factors that contribute to regenerative failure of CNS axons, the extracellular matrix molecules Chondroitin Sulfate Proteoglycans (CSPGs) generated by scar tissues are critical for blocking axon elongation following CNS injuries. Overcoming inhibition by CSPG axon growth inhibitors is very important for promoting successful axon regeneration and functional recovery after CNS injuries. Recent progress in understanding of molecular mechanisms underlying CSPG suppression of neuronal growth may facilitate development of new treatments to surmount scar- mediated inhibition. Particularly, a number of studies demonstrate that CSPG inhibitors convey their suppression of axon growth by interacting with several neuronal transmembrane receptors. Two members of the Leukocyte Common Antigen Related (LAR) phosphatase subfamily, protein tyrosine phosphatase σ and LAR, bind CSPGs with high affinity and mediate CSPG inhibition as functional receptors. CSPGs appear also to bind two receptors for myelin-associated growth inhibitors, Nogo receptors 1 and 3. Transgenic or pharmacological blockade of these receptors significantly surmounts CSPG function and promotes CNS axon regeneration. Identification of the CSPG receptors is likely to facilitate developing novel and selective therapies to promote axon sprouting/regeneration and functional recovery after CNS injuries.

Keywords: Axon regeneration; CNS injury; Reactive glial scar; CSPG receptor; LAR; PTPσ; Nogo receptor

Introduction

Following CNS injuries, astrogliosis is a defense response to minimize and repair primary damage, including isolating intact tissue from secondary lesions, maintaining a favorable environment for surviving neurons, preserving the blood brain barrier (BBB), generating permissive substrates for neurite extension and other protective effects (Karimi-Abdolrezaee and Billakanti, 2012; Sofroniew, 2009). Ablation of reactive astrocytes or interfering with their activation could exacerbate tissue damage after Spinal Cord Injury (SCI) by increasing tissue degeneration and failing to reconstruct BBB (Faulkner et al., 2004; Sofroniew, 2009). However, the reactive glial scars ultimately generate detrimental effects due to forming both physical and chemical barriers to axon regeneration, including producing high levels of inhibitory molecules to suppress neuronal regeneration. Proliferation and migration of a large number of reactive astrocytes into and around the lesion areas and formation of glial scar tissues constitute physical barrier of axon regeneration. Upregulation of suppressing substances strongly hinders axon regeneration and neural repair and the inhibitory properties of reactive astrocytes develop with time after CNS injuries.

The integrations between growth-promoting Extracellular Matrix (ECM) molecules (such as laminin, fibronectin and integrins) and growth-suppressing molecules are essential for determining elongation or termination of lesioned CNS axons. Glial scar is a major detriment to regeneration of severed axons by upregulating a great number of molecules around the lesion and preventing regrowth of injured axons at the lesion area, including Chondroitin Sulfate Proteoglycans (CSPGs), tenascin, semaphorin 3A, Keratan Sulfate Proteoglycans (KSPGs), myelin-associated inhibitors and Ephrins/ Eph receptors. Among them, CSPGs are an extremely important class of growth inhibitors highly upregulated by scar tissues. CSPGs are a family of molecules characterized by a core protein to which the large and highly sulfated Glycosaminoglycan (GAG) chains are attached. The major CSPGs found in the CNS include lecticans (neurocan, versican, aggrecan and brevican), phosphacan (6B4 proteoglycan) and NG2. CSPGs are concentrated into perineuronal nets (PNNs), which are mainly composed of hyaluronan, CSPGs, tenascin R and link proteins. Evidence for the inhibitory nature of CSPGs on axon regeneration came largely from studies on digestion of GAG side chains of CSPGs with the bacterial enzyme Chondroitinase ABC (ChABC). Although CSPG core proteins are inhibitory by themselves (Oohira et al., 1991; Tan et al., 2006), removal of GAG side chains with ChABC makes the ECM environment much more permissive to axon elongation (Crespo et al., 2007) and promotes axon sprouting or regeneration after CNS injury. CSPGs have been found to be inhibitory for over 25 years (McKeon et al., 1991; Snow et al., 1990; Snow et al., 1991), but molecular mechanisms for them to suppress neuronal growth are not well known. One of the major advances in the scar-mediated inhibition on neuronal growth is identification of several functional receptors for CSPGs, especially two members in the Leukocyte Common Antigen Related (LAR) subfamily of Receptor Protein Tyrosine Phosphatases (RPTPs) (Fisher et al., 2011; Shen et al., 2009). In this review, we will focus on recent progress in the receptors of scar-sourced axonal growth inhibitors and the therapeutic potential for blocking CSPGs and their receptors.

Previous view of axon growth inhibition by CSPGs

A few mechanisms had previously been thought to attribute to CSPG inhibition of neuronal growth. CSPGs are the large sizes of molecules and are concentrated into PNNs with several other ECM molecules. Interactions between the PNN molecules produce a stable pericellular complex around synapses and play a vital role in controlling reduced plasticity of developed neurons (Kwok et al., 2011). CSPGs had been proposed to hinder the growth-promoting adhesion ECM molecules sterically, which are important regulators of neuronal adhesion and growth. As the transmembrane receptors for ECM molecules such as laminin, integrins function as cell surface adhesion molecules and link them to actin cytoskeleton. The highly charged GAG moieties of CSPGs can interact with these ECM molecules and suppress neurite growth by attenuating integrin activation (Afshari et al., 2010; Tan et al., 2011). Over- expression of integrins could overcome CSPG inhibition of axon growth (Condic et al., 1999). Thus, CSPGs reduce activity of integrin signaling pathway and activation of integrin signaling overcomes inhibition by CSPGs.

The lectican CSPG aggrecan suppresses laminin-mediated growth of cultured rat sensory neurons without altering surface integrin levels by reducing levels of phosphorylated focal adhesion kinase and Src (Tan et al., 2011). Activation of integrin signaling by applying manganese or an activating antibody surmounts aggrecan inhibition on elongation of cultured neurons. Over-expression of kindlin-1, a phosphoprotein involved in attachment of actin cytoskeleton to plasma membrane and integrin-mediated function, activates integrin signaling and enhances growth of sensory neurons cultured on aggrecan and regeneration of injured sensory axons across the dorsal root entry zone and into the spinal cord (Tan et al., 2012). Over-expression of growth-associated protein-43 and/or β1 integrin could partly stimulate regeneration of serotonergic axons on high levels of CSPG and blockade of β1 integrin reduced serotonergic and cortical outgrowth on laminin (Hawthorne et al., 2011). Notably, the functional link between laminin/integrins and CSPGs is not specific because integrin activation also inverted neuronal growth suppression by myelin associated inhibitors (Tan et al., 2011).

CSPGs could contribute to inhibition of neuronal growth by certain chemo-repulsive proteins. The thrombospondin repeats of Sema5A, an axon guidance cue, bind the GAG chains of both CSPGs and Heparan Sulfate Proteoglycans (HSPGs) and these interactions could convert Sema5A from an attractive to an inhibitory guidance cue (Kantor et al., 2004). Sema3A, another repulsive guidance molecule, could interact with chondroitin sulfate-4,6 enriched in the PNNs and this interaction appear to regulate the repulsive function of Sema3A (De Wit et al., 2005; Deepa et al., 2006; Kwok et al., 2011). Moreover, CSPGs may modulate neuronal growth by binding extracellular calcium or its channels and affecting calcium availability and entry into neurons (Hrabetova et al., 2009). Therefore, neuronal growth is partially mediated by the ratio between growth-promoting (such as laminin) and growth-inhibiting (such as CSPGs) molecules present in the environment (Snow et al., 2002).

Important function of CSPG receptors on neuronal growth

The molecular mechanisms for CSPG suppression of neuronal growth are not well understood although CSPGs have been known to hinder neuronal regeneration and plasticity for over two decades (McKeon et al., 1991; Snow et al., 1990; Snow et al., 1991). So far, a number of mechanisms for CSPG functions have been supported, including binding to functional receptors on the neuronal membrane, establishing a non-permissive PNNs that causes steric hindrance of growth-promoting adhesion molecules (such as laminin and integrins) and facilitating function of some chemorepulsive molecules. Because preventing GAG sulfation of CSPGs removes much of their inhibitory activity on axon growth in vitro (Gilbert et al., 2005; Sherman and Back, 2008; Wang et al., 2008), the GAG sulfation patterns are important for CSPG function. CSPGs might non-specifically impede binding of some ECM molecules to their cell surface receptors through steric interactions, but recent reports demonstrate that two transmembrane proteins of the LAR phosphatase subfamily, Protein Tyrosine Phosphatase σ (PTPσ) and LAR, function as the receptors by binding CSPGs with high affinity and mediating CSPG inhibitory effects (Figure 1). (Fisher et al., 2011; Shen et al., 2009; Xu et al., 2015). Furthermore, CSPGs may act by binding to Nogo Receptor 1 (NgR1) and NgR3, two receptors known for myelin-associated inhibitors (Dickendesher et al., 2012). Thus, CSPGs block axon regeneration likely by multiple molecular mechanisms, making them especially potent and difficult therapeutic targets.

Citation: Ohtake Y and Li S. Receptors of Chondroitin Sulfate Proteoglycans and CNS Repair. Austin J Neurol Disord Epilepsy. 2015; 2(1): 1010. ISSN:2472-3711