A sulfated carbohydrate epitope inhibits axon regeneration after injury

Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2012; 109(13):4768-73. DOI: 10.1073/pnas.1121318109
Source: PubMed


Chondroitin sulfate proteoglycans (CSPGs) represent a major barrier to regenerating axons in the central nervous system (CNS), but the structural diversity of their polysaccharides has hampered efforts to dissect the structure-activity relationships underlying their physiological activity. By taking advantage of our ability to chemically synthesize specific oligosaccharides, we demonstrate that a sugar epitope on CSPGs, chondroitin sulfate-E (CS-E), potently inhibits axon growth. Removal of the CS-E motif significantly attenuates the inhibitory activity of CSPGs on axon growth. Furthermore, CS-E functions as a protein recognition element to engage receptors including the transmembrane protein tyrosine phosphatase PTPσ, thereby triggering downstream pathways that inhibit axon growth. Finally, masking the CS-E motif using a CS-E-specific antibody reversed the inhibitory activity of CSPGs and stimulated axon regeneration in vivo. These results demonstrate that a specific sugar epitope within chondroitin sulfate polysaccharides can direct important physiological processes and provide new therapeutic strategies to regenerate axons after CNS injury.

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    • "Importantly, a further enhancement of axon regeneration was observed in triple NgR1, NgR3, and RPTPσ knockout mice. NgR1, NgR3 and RPTPσ all show specificity to monosulfated CS-B and disulfated CS-D and CS-E but not CS-A or CS-C (Brown et al., 2012; Dickendesher et al., 2012). "
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    ABSTRACT: Chondroitin Sulfate Proteoglycans (CSPGs) are a major component of the extracellular matrix in the central nervous system (CNS) and play critical role in the development and pathophysiology of the brain and spinal cord. Developmentally, CSPGs provide guidance cues for growth cones and contribute to the formation of neuronal boundaries in the developing CNS. Their presence in perineuronal nets plays a crucial role in the maturation of synapses and closure of critical periods by limiting synaptic plasticity. Following injury to the CNS, CSPGs are dramatically upregulated by reactive glia which form a glial scar around the lesion site. Increased level of CSPGs is a hallmark of all CNS injuries and has been shown to limit axonal plasticity, regeneration, remyelination, and conduction after injury. Additionally, CSPGs create a non-permissive milieu for cell replacement activities by limiting cell migration, survival and differentiation. Mounting evidence is currently shedding light on the potential benefits of manipulating CSPGs in combination with other therapeutic strategies to promote spinal cord repair and regeneration. Moreover, the recent discovery of multiple receptors for CSPGs provides new therapeutic targets for targeted interventions in blocking the inhibitory properties of CSPGs following injury. Here, we will provide an in depth discussion on the impact of CSPGs in normal and pathological CNS. We will also review the recent preclinical therapies that have been developed to target CSPGs in the injured CNS. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Apr 2015 · Experimental Neurology
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    • "Indeed, the complex nature of chondroitin sulfate biology—synthesis, macromolecular organization, and signaling—suggests multiple candidate targets for intervention (Brown et al., 2012; Carulli et al., 2010; Grimpe and Silver, 2004; Hur et al., 2011; Takeuchi et al., 2013; Wang et al., 2008). "
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    ABSTRACT: Astrocytes react to CNS injury by building a dense wall of filamentous processes around the lesion. Stromal cells quickly take up residence in the lesion core and synthesize connective tissue elements that contribute to fibrosis. Oligodendrocyte precursor cells proliferate within the lesion and help to entrap dystrophic axon tips. Here we review evidence that this aggregate scar acts as the major barrier to regeneration of axons after injury. We also consider several exciting new interventions that allow axons to regenerate beyond the glial scar, and discuss the implications of this work for the future of regeneration biology.
    Full-text · Article · Jan 2014 · Experimental Neurology
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    • "In contrast to the common non-sequence-specific binding of HS to many proteins, there is strong evidence that the 4,6-sulfation epitope of CS enhances growth factor binding and signaling. This has been found to play an important role in the central nervous system by regulating neurite out-growth [84]. In addition to sulfation pattern , carbohydrate conformation is a key aspect in DS for both growth factor interactions, as well as promoting anticoagulant activity. "
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    ABSTRACT: Glycosaminoglycans (GAGs) are linear, negatively charged polysaccharides that interact with a variety of positively-charged growth factors. In this review article, the effects of engineering GAG chemistry for molecular delivery applications in regenerative medicine are presented. Three major areas of focus at the structure-function-property interface are discussed: 1) macromolecular properties of GAGs, 2) effects of chemical modifications on protein binding, and 3) degradation mechanisms of GAGs. GAG-protein interactions can be based on 1) GAG sulfation pattern, 2) GAG carbohydrate conformation, and 3) GAG polyelectrolyte behavior. Chemical modifications of GAGs, which are commonly performed to engineer molecular delivery systems, affect protein binding and are highly dependent on the site of modification on the GAG molecules. The rate and mode of degradation can determine the release of molecules as well as the length of GAG fragments to which the cargo is electrostatically coupled and eventually released from the delivery system. Overall, GAG-based polymers are a versatile biomaterial platform offering novel means to engineer molecular delivery systems with a high degree of control in order to better treat a range of degenerate or injured tissues.
    Full-text · Article · Oct 2013 · Acta biomaterialia
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