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 > School of Infection & Immunity
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