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Cited by 154Nerve injury and regenerationProteoglycans and glycosaminoglycans researchNeurogenesis and neuroplasticity mechanisms

A sulfated carbohydrate epitope inhibits axon regeneration after injury

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Brown, Joshua M., Xia, Jiang, Zhuang, BinQuan, Cho, Kin-Sang, Rogers, Claude J., Gama, Cristal I., Rawat, Manish, Tully, Sarah E. +7 more·2012·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1121318109PMC PMC3323996
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Abstract

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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  • The relative abundance of CS isomers incorporated into CS-GAG chains has been linked to key biological functions within the brain, including charged molecule diffusion (0S-CS), neurocircuit plasticity (4S-CS and 6S-CS), glial scarring (4S6S-CS), and neurite outgrowth (2S6S-CS).

    “The relative abundance of CS isomers incorporated into the CS-GAG chains has been linked to key biological functions within the brain including charged molecule diffusion (0S-CS (Nicholson & Hrabětová 2017)), neurocircuit plasticity (4S-CS and 6S-CS (Miyata et al. 2012; Yang et al. 2021)), glial scarring (4S6S-CS (Brown et al. 2012)), and neurite outgrowth (2S6S-CS (Shida et al. 2019; Clement et a”

    From Perineuronal net deglycosylation associates with tauopathy‐induced gliosis and neurodegeneration (2024) · cites this paper as Brown et al. 2012

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Authors
Brown, J. M., Xia, J., Zhuang, B., Cho, K.-S., Rogers, C. J., Gama, C. I., Rawat, M., Tully, S. E., Uetani, N., Mason, D. E., Tremblay, M. L., Peters, E. C., Habuchi, O., Chen, D. F., & Hsieh-Wilson, L. C.
Affiliations
  • California Institute of Technology (US)
  • Massachusetts Eye and Ear Infirmary (US)
  • McGill University (CA)
  • Genomics Institute of the Novartis Research Foundation (US)
  • Aichi University of Education (JP)
  • Division of Chemistry and Chemical Engineering and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125;
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2012-03-12
Volume
109
Issue
13
Pages
4768-4773
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1121318109
PMC
PMC3323996
OpenAlex
W2086360927
Cited by
154
References
4
Citations by year
2026: 7 · 2025: 4 · 2024: 7 · 2023: 6 · 2022: 9 · 2021: 13 · 2020: 17 · 2019: 13 · 2018: 14 · 2017: 15 · 2016: 5 · 2015: 8 · 2014: 15 · 2013: 17 · 2012: 4
FWCI
5.80
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • Christopher and Dana Reeve Foundation
  • California Institute of Technology
  • National Institutes of Health
  • Japan Society for the Promotion of Science (23570175)
  • National Institute of General Medical Sciences (T32GM007616, 5T32 GM07616-30S1, R01GM093627)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
chondroitin sulfate proteoglycans, chondroitin sulfate E, axon regeneration, axon growth inhibition, central nervous system injury, PTPσ, protein tyrosine phosphatase, oligosaccharide synthesis, structure-activity relationship
MeSH terms
Animals, Antibodies, Monoclonal, Epitopes, Axons, Carbohydrate Conformation, Chickens, Chondroitin Sulfates, Ganglia, Spinal, Nerve Regeneration, Chondroitin Sulfate Proteoglycans, Signal Transduction, Neurites, Antibodies, Blocking, Growth Cones, Mice, Receptor-Like Protein Tyrosine Phosphatases, Class 2, Antibodies, Neutralizing

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