Heparanase attenuates axon degeneration following sciatic nerve transection

Whitehead, M. J., McGonigal, R., Willison, H. J. and Barnett, S. C. (2018) Heparanase attenuates axon degeneration following sciatic nerve transection. Scientific Reports, 8, 5219. (doi: 10.1038/s41598-018-23070-6) (PMID:29581478) (PMCID:PMC5980233)

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Axon degeneration underlies many nervous system diseases; therefore understanding the regulatory signalling pathways is fundamental to identifying potential therapeutics. Previously, we demonstrated heparan sulphates (HS) as a potentially new target for promoting CNS repair. HS modulate cell signalling by both acting as cofactors in the formation of ligand-receptor complexes and in sequestering ligands in the extracellular matrix. The enzyme heparanase (Hpse) negatively regulates these processes by cleaving HS and releasing the attached proteins, thereby attenuating their ligand-receptor interaction. To explore a comparative role for HS in PNS axon injury/repair we data mined published microarrays from distal sciatic nerve injury. We identified Hpse as a previously unexplored candidate, being up-regulated following injury. We confirmed these results and demonstrated inhibition of Hpse led to an acceleration of axonal degeneration, accompanied by an increase in β-catenin. Inhibition of β-catenin and the addition of Heparinase I both attenuated axonal degeneration. Furthermore the inhibition of Hpse positively regulates transcription of genes associated with peripheral neuropathies and Schwann cell de-differentiation. Thus, we propose Hpse participates in the regulation of the Schwann cell injury response and axo-glia support, in part via the regulation of Schwann cell de-differentiation and is a potential therapeutic that warrants further investigation.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Willison, Professor Hugh and Barnett, Professor Susan and McGonigal, Dr Rhona and Whitehead, Mr Michael
Authors: Whitehead, M. J., McGonigal, R., Willison, H. J., and Barnett, S. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN (Online):2045-2322
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Scientific Reports 8:5219
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
632341MRC Doctoral Training Grant 2013/14, 2014/15 and 2015/16George BaillieMedical Research Council (MRC)MR/K501335/1MVLS GRADUATE SCHOOL
5887510BBSRC Doctoral Training Partnership 2012George BaillieBiotechnology and Biological Sciences Research Council (BBSRC)BB/J013854/1MVLS COLLEGE SENIOR MANAGEMENT
722551Pathophysiological factors in the diagnosis and treatment of the Guillain-Barre syndromesHugh WillisonWellcome Trust (WELLCOTR)202789/Z/16/ZIII -IMMUNOLOGY