Identification of a critical sulfation in chondroitin that inhibits axonal regeneration
Open accessAbstract
The failure of mammalian CNS neurons to regenerate their axons derives from a combination of intrinsic deficits and extrinsic factors. Following injury, chondroitin sulfate proteoglycans (CSPGs) within the glial scar inhibit axonal regeneration, an action mediated by the sulfated glycosaminoglycan (GAG) chains of CSPGs, especially those with 4-sulfated (4S) sugars. Arylsulfatase B (ARSB) selectively cleaves 4S groups from the non-reducing ends of GAG chains without disrupting other, growth-permissive motifs. We demonstrate that ARSB is effective in reducing the inhibitory actions of CSPGs both in in vitro models of the glial scar and after optic nerve crush (ONC) in adult mice. ARSB is clinically approved for replacement therapy in patients with mucopolysaccharidosis VI and therefore represents an attractive candidate for translation to the human CNS.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
CS-56 analysis revealed significant increases in total extracellular CSPG in the subiculum but not visual cortex of 5xFAD mice at early stages of PNN loss.
“Analysis of total extracellular CSPG with CS-56 at early stages of PNN loss, which generally labels CSPGs excluded from PNNs e.g. those found in glial scars [54, 55], revealed significant increases in the subiculum but not visual cortex (p<0.05, p = 0.0818) of 5xFAD mice (Fig. S2A-C).”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [54]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Chondroitinase ABC promotes functional recovery after spinal cord injury
Bradbury, E. J., Moon, L. D. F., Popat, R. J., King, V. R., Bennett, G. S., Patel, P. N., Fawcett, J. W., & McMahon, S. B. (2002) · Nature · doi:10.1038/416636a · Cited by 2,357 · see citing works
Astrocyte scar formation aids central nervous system axon regeneration
Anderson, M. A., Burda, J. E., Ren, Y., Ao, Y., O’Shea, T. M., Kawaguchi, R., Coppola, G., Khakh, B. S., Deming, T. J., & Sofroniew, M. V. (2016) · Nature · doi:10.1038/nature17623 · Cited by 1,851 · see citing works
Promoting Axon Regeneration in the Adult CNS by Modulation of the PTEN/mTOR Pathway
Park, K. K., Liu, K., Hu, Y., Smith, P. D., Wang, C., Cai, B., Xu, B., Connolly, L., Kramvis, I., Sahin, M., et al. (2008) · Science · doi:10.1126/science.1161566 · Cited by 1,686 · see citing works
Reactivation of Ocular Dominance Plasticity in the Adult Visual Cortex
Pizzorusso, T., Medini, P., Berardi, N., Chierzi, S., Fawcett, J. W., & Maffei, L. (2002) · Science · doi:10.1126/science.1072699 · Cited by 1,679 · see citing works
Shechter, R., London, A., Varol, C., Raposo, C., Cusimano, M., Yovel, G., Rolls, A., Mack, M., Pluchino, S., Martino, G., et al. (2009) · PLoS Medicine · doi:10.1371/journal.pmed.1000113 · Cited by 770 · see citing works
Lens Injury Stimulates Axon Regeneration in the Mature Rat Optic Nerve
Leon, S. P., Yin, Y., Nguyen, J. T., Irwin, N., & Benowitz, L. I. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-12-04615.2000 · Cited by 606 · see citing works
Sieving, P. A., Caruso, R. C., Tao, W., Coleman, H. R., Thompson, D. J. S., Fullmer, K. R., & Bush, R. A. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600236103 · Cited by 591 · see citing works
Galtrey, C. M., & Fawcett, J. W. (2007) · Brain Research Reviews · doi:10.1016/j.brainresrev.2006.09.006 · Cited by 575 · see citing works
Hara, M., Kobayakawa, K., Ohkawa, Y., Kumamaru, H., Yokota, K., Saito, T., Kijima, K., Yoshizaki, S., Harimaya, K., Nakashima, Y., et al. (2017) · Nature Medicine · doi:10.1038/nm.4354 · Cited by 539 · see citing works
Macrophage-Derived Factors Stimulate Optic Nerve Regeneration
Yin, Y., Cui, Q., Li, Y., Irwin, N., Fischer, D., Harvey, A. R., & Benowitz, L. I. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-06-02284.2003 · Cited by 529 · see citing works
Anatomical distribution of the growth-associated protein GAP-43/B-50 in the adult rat brain
Benowitz, L. I., Apostolides, P., Perrone‐Bizzozero, N. I., Finklestein, S. P., & Zwiers, H. (1988) · Journal of Neuroscience · doi:10.1523/jneurosci.08-01-00339.1988 · Cited by 386 · see citing works
Persistent cortical plasticity by upregulation of chondroitin 6-sulfation
Miyata, S., Komatsu, Y., Yoshimura, Y., Taya, C., & Kitagawa, H. (2012) · Nature Neuroscience · doi:10.1038/nn.3023 · Cited by 365 · see citing works
de Lima, S., Koriyama, Y., Kurimoto, T., Oliveira, J. T., Yin, Y., Li, Y., Gilbert, H.-Y., Fagiolini, M., Martinez, A. M. B., & Benowitz, L. I. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1119449109 · Cited by 361 · see citing works
Suzuki, S., Saito, H., Yamagata, T., Anno, K., Seno, N., Kawai, Y., & Furuhashi, T. (1968) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)93576-3 · Cited by 314 · see citing works
Manipulating the glial scar: Chondroitinase ABC as a therapy for spinal cord injury
Bradbury, E. J., & Carter, L. M. (2010) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2010.06.015 · Cited by 314 · see citing works
Neural activity promotes long-distance, target-specific regeneration of adult retinal axons
Lim, J.-H. A., Stafford, B. K., Nguyen, P. L., Lien, B. V., Wang, C., Zukor, K., He, Z., & Huberman, A. D. (2016) · Nature Neuroscience · doi:10.1038/nn.4340 · Cited by 299 · see citing works
Rolls, A., Shechter, R., London, A., Segev, Y., Jacob–Hirsch, J., Amariglio, N., Rechavi, G., & Schwartz, M. (2008) · PLoS Medicine · doi:10.1371/journal.pmed.0050171 · Cited by 272 · see citing works
Enzyme replacement therapy in mucopolysaccharidosis VI (Maroteaux-Lamy syndrome)
Harmatz, P., Whitley, C. B., Waber, L. J., Pais, R. C., Steiner, R. D., Plecko, B., Kaplan, P. B., Simon, J., Butensky, E., & Hopwood, J. J. (2004) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2004.03.018 · Cited by 270 · see citing works
Leaver, S. G., Cui, Q., Plant, G. W., Arulpragasam, A., Hisheh, S., Verhaagen, J., & Harvey, A. R. (2006) · Gene Therapy · doi:10.1038/sj.gt.3302791 · Cited by 270 · see citing works
Restoration of Visual Function by Enhancing Conduction in Regenerated Axons
Bei, F., Lee, H. H. C., Liu, X., Gunner, G., Jin, H., Ma, L., Wang, C., Hou, L., Hensch, T. K., Frank, E., et al. (2016) · Cell · doi:10.1016/j.cell.2015.11.036 · Cited by 269 · see citing works
Rauch, U., Gao, P., Janetzko, A., Flaccus, A., Hilgenberg, L., Tekotte, H., Margolis, R. K., & Margolis, R. U. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)98755-7 · Cited by 267 · see citing works
Avnur, Z., & Geiger, B. (1984) · Cell · doi:10.1016/0092-8674(84)90276-9 · Cited by 265 · see citing works
Taxol Facilitates Axon Regeneration in the Mature CNS
Sengottuvel, V., Leibinger, M., Pfreimer, M., Andreadaki, A., & Fischer, D. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.4885-10.2011 · Cited by 254 · see citing works
Chondroitin-4-sulfation negatively regulates axonal guidance and growth
Wang, H., Katagiri, Y., McCann, T. E., Unsworth, E., Goldsmith, P., Yu, Z.-X., Tan, F., Santiago, L., Mills, E. M., Wang, Y., et al. (2008) · Journal of Cell Science · doi:10.1242/jcs.032649 · Cited by 243 · see citing works
Self-citationHarmatz, P., Ketteridge, D., Giugliani, R., Guffon, N., Teles, E. L., Sá-Miranda, C., Yu, Z., Swiedler, S. J., Hopwood, J. J., & for the MPS VI Study Group (2005) · PEDIATRICS · doi:10.1542/peds.2004-1023 · Cited by 215 · see citing works
Chau, C., Shum, D. K., Li, H., Pei, J., Lui, Y., Wirthlin, L., Chan, Y., & Xu, X. (2003) · The FASEB Journal · doi:10.1096/fj.03-0196fje · Cited by 198 · see citing works
Li, Y., Andereggen, L., Yuki, K., Omura, K., Yin, Y., Gilbert, H.-Y., Erdoğan, B., Asdourian, M. S., Shrock, C. L., de Lima, S., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1616811114 · Cited by 163 · see citing works
Luo, X., Salgueiro, Y., Beckerman, S. R., Lemmon, V., Tsoulfas, P., & Park, K. K. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2013.03.001 · Cited by 156 · see citing works
A sulfated carbohydrate epitope inhibits axon regeneration after injury
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., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1121318109 · Cited by 154 · see citing works
Burnside, E. R., & Bradbury, E. J. (2013) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12114 · Cited by 153 · see citing works
Increased axon regeneration in astrocytes grown in the presence of proteoglycan synthesis inhibitors
Smith‐Thomas, L. C., Stevens, J., Fok‐Seang, J., Faissner, A., ROGERS, J. H., & Fawcett, J. W. (1995) · Journal of Cell Science · doi:10.1242/jcs.108.3.1307 · Cited by 149 · see citing works
Brain ageing changes proteoglycan sulfation, rendering perineuronal nets more inhibitory
Foscarin, S., Raha-Chowdhury, R., Fawcett, J. W., & Kwok, J. C. F. (2017) · Aging · doi:10.18632/aging.101256 · Cited by 139 · see citing works
Retinal Ganglion Cell and Nonneuronal Cell Responses to a Microcrush Lesion of Adult Rat Optic Nerve
Sellés-Navarro, I., Ellezam, B., Fajardo, R., Latour, M., & McKerracher, L. J. (2001) · Experimental Neurology · doi:10.1006/exnr.2000.7573 · Cited by 130 · see citing works
AAV-mediated gene therapy for retinal disorders: from mouse to man
Buch, P. K., Bainbridge, J. W., & Ali, R. R. (2008) · Gene Therapy · doi:10.1038/gt.2008.66 · Cited by 122 · see citing works
6-Sulphated Chondroitins Have a Positive Influence on Axonal Regeneration
Lin, R., Rosahl, T. W., Whiting, P. J., Fawcett, J. W., & Kwok, J. C. F. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021499 · Cited by 121 · see citing works
The Time Course of Gene Expression during Reactive Gliosis in the Optic Nerve
Qu, J., & Jakobs, T. (2013) · PLoS ONE · doi:10.1371/journal.pone.0067094 · Cited by 116 · see citing works
Lin, R., Kwok, J. C. F., Crespo, D., & Fawcett, J. W. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05066.x · Cited by 116 · see citing works
The Glial Scar-Monocyte Interplay: A Pivotal Resolution Phase in Spinal Cord Repair
Shechter, R., Rapôso, C., London, A., Sagi, I., & Schwartz, M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027969 · Cited by 112 · see citing works
METACHROMATIC LEUKODYSTROPHY: ARYLSULFATASE-A DEFICIENCY IN SKIN FIBROBLAST CULTURES
Porter, M. T., Fluharty, A. L., & Kihara, H. (1969) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.62.3.887 · Cited by 107 · see citing works
The glial scar is more than just astrocytes
Silver, J. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.06.018 · Cited by 102 · see citing works
Combination treatment with chondroitinase ABC in spinal cord injury—breaking the barrier
Zhao, R., & Fawcett, J. W. (2013) · Neuroscience Bulletin · doi:10.1007/s12264-013-1359-2 · Cited by 100 · see citing works
Yi, J., Katagiri, Y., Susarla, B., Figge, D., Symes, A. J., & Geller, H. M. (2012) · Journal of Comparative Neurology · doi:10.1002/cne.23156 · Cited by 93 · see citing works
Self-citationLitjens, T., & Hopwood, J. J. (2001) · Human Mutation · doi:10.1002/humu.1190 · Cited by 92 · see citing works
Hyatt, A. J. T., Wang, D., Kwok, J. C. F., Fawcett, J. W., & Martin, K. R. G. (2010) · Journal of Controlled Release · doi:10.1016/j.jconrel.2010.06.026 · Cited by 90 · see citing works
Self-citationHirvonen, J., Wibral, M., Palva, J. M., Singer, W., Uhlhaas, P. J., & Palva, S. (2017) · eNeuro · doi:10.1523/eneuro.0338-17.2017 · Cited by 67 · see citing works
Residues Critical for Formylglycine Formation and/or Catalytic Activity of Arylsulfatase A
Knaust, A., Schmidt, B., Dierks, T., et al. (1998) · Biochemistry · doi:10.1021/bi9810205 · Cited by 66 · see citing works
Muñoz‐Rojas, M. V., Horovitz, D. D. G., Jardim, L. B., et al. (2009) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2009.11.008 · Cited by 62 · see citing works
Sugiura, N., Shioiri, T., Chiba, M., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.412676 · Cited by 60 · see citing works
Bray, E. R., Noga, M., Thakor, K., Wang, Y., Lemmon, V., Park, K. K., & Tsoulfas, P. (2017) · eNeuro · doi:10.1523/eneuro.0093-17.2017 · Cited by 52 · see citing works
Arylsulfatase B Improves Locomotor Function after Mouse Spinal Cord Injury
Yoo, M., Khaled, M., Gibbs, K. M., Kim, J., Kowalewski, B., Dierks, T., & Schachner, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057415 · Cited by 45 · see citing works
Optic nerve regeneration in mammals: Regenerated or spared axons?
Fischer, D., Harvey, A. R., Pernet, V., Lemmon, V., & Park, K. K. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.07.008 · Cited by 38 · see citing works
Retinal regeneration mechanisms linked to multiple cancer molecules: A therapeutic conundrum
Barber, A. C., Farmer, K., Martin, K. R. G., & Smith, P. D. (2016) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2016.08.003 · Cited by 16 · see citing works
Self-citationImmunohistochemical localization of chondroitin sulfate in the forestomach of the sheep.
Yamamoto, Y., Atoji, Y., Oohira, A., et al. (1995) · PubMed · Cited by 14 · see citing works
Synthesis of chondroitin sulfate CC and DD tetrasaccharides and interactions with 2H6 and LY111
Matsushita, K., Nakata, T., Takeda‐Okuda, N., et al. (2018) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2018.01.011 · Cited by 11 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain
Crapser, J. D., Spangenberg, E. E., Barahona, R. A., Arreola, M. A., Hohsfield, L. A., & Green, K. N. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2020.102919 · Cited by 280 · see citing works
Crapser, J. D., Ochaba, J., Soni, N., Reidling, J. C., Thompson, L. M., & Green, K. N. (2020) · Brain · doi:10.1093/brain/awz363 · Cited by 157 · see citing works
Wong, K. A., & Benowitz, L. I. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231710179 · Cited by 66 · see citing works
- Authors
- Pearson, C. S., Mencio, C. P., Barber, A. C., Martin, K. R., & Geller, H. M.
- Affiliations
- National Institutes of Health (US)
- University of Cambridge (GB)
- Corresponding author
- Martin, Keith R
- Geller, Herbert M
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2018-05-15
- Volume
- 7
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5976435
- OpenAlex
- W2803597233
- Cited by
- 75
- References
- 54
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 13 · 2023: 12 · 2022: 13 · 2021: 5 · 2020: 11 · 2019: 9 · 2018: 2
- FWCI
- 3.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Minerva Access (University of Melbourne) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, public-domain)
- Apollo
- Funders
- National Institutes of Health (1ZIAHL006135)
- Cambridge Eye Trust
- 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
- Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Keywords
- chondroitin sulfate proteoglycans, axon regeneration, glial scar, arylsulfatase B, optic nerve crush, central nervous system injury, mucopolysaccharidosis type VI, sulfation, neuroprotection
- MeSH terms
- Animals, Axons, Cells, Cultured, Disease Models, Animal, Humans, Chondroitin Sulfate Proteoglycans, Regeneration, Sulfates, Treatment Outcome, N-Acetylgalactosamine-4-Sulfatase, Optic Nerve Injuries, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
