Identification of a critical sulfation in chondroitin that inhibits axonal regeneration

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Abstract

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.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Craig S Pearson

Laboratory of Developmental Neurobiology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1906-6347
Caitlin P Mencio

Laboratory of Developmental Neurobiology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Amanda C Barber

Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Keith R Martin

Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

For correspondence
krgm2@cam.ac.uk

Competing interests
The authors declare that no competing interests exist.
Herbert M Geller

Laboratory of Developmental Neurobiology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States

For correspondence
gellerh@nhlbi.nih.gov

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7048-6144

Funding

National Institutes of Health (1ZIAHL006135)

Craig S Pearson
Caitlin P Mencio
Herbert M Geller

Cambridge Eye Trust

Amanda C Barber
Keith R Martin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#H-0186R3) of the National Heart, Lung, and Blood Institute, NIH. Mice were anesthetized using 1-2% isoflurane, and every effort was made to minimize suffering.

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.