The role of heparan sulphates in peripheral nerve injury, repair and myelination

Whitehead, Michael (2018) The role of heparan sulphates in peripheral nerve injury, repair and myelination. PhD thesis, University of Glasgow.

Abstract

Peripheral neuropathies (PN) represent a significant health burden, due to chronic and debilitating symptoms, that can be inherited or caused by everything from alcohol,chemotherapy and diabetes. PN are associated with both demyelination and axon degeneration, which play a fundamental role in their pathogenesis. The aim of this thesis is to identify novel mechanisms and/or potential therapeutics for protecting axon degeneration and promoting myelination. This is significant because there are currently no specific therapeutics, for PN, that have passed clinical trial successfully. Recent work in the Barnett lab has implicated heparan sulphate proteoglycans (HSPGs), as therapeutic targets in central nervous system (CNS) injury. HSPGs are able to bind a plethora of proteins, including chemokines and growth factors, where they facilitate binding to their corresponding receptors. We therefore hypothesised that HSPGs may have a regulatory role in PNS injury. To address this I data mined previously published microarrays for sciatic nerve (SN) injury. This principally identified the candidate heparanase (Hpse),which was up-regulated after injury in several different microarray analyses. Hpse is able to regulate HSPG signalling and is already implicated in several diseases including: cancer, diabetes and Alzheimer’s disease, making it an interesting candidate for further research. In order to question the role of Hpse in PNS injury we used two models of Wallerian degeneration:ex vivo SN injury model and an ex vivo neuromuscular junction (NMJ) injury model. Inhibiting Hpse acutely accelerated axon loss, while its exogenous treatment was protective. Furthermore we found that Hpse can regulate β-catenin protein levels and the transcription of genes, predicted to be regulated by β-catenin. This included Sox2, which led to an acceleration in Schwann cell dedifferentiation after in-jury. Recent evidence has linked Schwann cell dedifferentiation to early events in axon fragmentation. We also found that heparin sulphate mimetics significantly promote in vitro myelination, the mechanism for which requires further research. In conclusion, we have identified Hpse, an up-regulated enzyme after SN injury, in protecting axon loss during SN degeneration. Within the field, Wallerian degeneration is considered a useful model for studying the mechanisms behind axon loss in peripheral neuropathies, for which the role of Hpse warrants further investigation as a potential therapeutic target.Lastly we also identified heparin sulphate mimetics in promoting peripheral myelination, also making them potential therapeutic targets.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QH Natural history > QH301 Biology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Funder's Name: Medical Research Council (MRC), Biotechnology and Biological Sciences Research Council (BBSRC)
• Supervisor's Name: Barnett, Professor Susan
• Date of Award: 2018
• Embargo Date: 16 May 2022
• Depositing User: Mr Michael Whitehead
• Unique ID: glathesis:2018-9128
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 23 May 2018 12:50
• Last Modified: 17 May 2021 07:23
• URI: https://theses.gla.ac.uk/id/eprint/9128