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Title: Analysis of axonal transport deficits in multiple sclerosis
Author: Hares, Kelly Marie
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2013
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Multiple sclerosis (MS) is a complex disease combining both inflammatory and neurodegenerative mechanisms. Current treatments available to MS sufferers all focus on immunosuppression. However, emerging evidence reveals axonal loss taking place alongside inflammation, suggesting protection of axons and subsequent prevention of neuronal loss is a necessary tool for future MS treatments. Mechanisms of axonal injury remain unknown, but dysregulation of axonal transport mechanisms may be important. The aim of this project was to further elucidate the role of axonal transport, including both motor proteins and associated cargoes, in axonal structure and function and to assess the effects of any changes in axonal transport mechanisms in relevance to MS disease pathology. Results from experiments performed in this thesis have shown dose dependent reductions in neurofilament (NF) phosphorylation in axons exposed to inflammatory-mediated reactive oxygen species, nitric oxide (NO). Furthermore, in MS tissue, we have seen reductions in mRNA and protein of kinesin superfamily proteins (KIFs), which are important in maintaining anterograde axonal transport. Lastly, in vitro studies using rat cortical neurons have shown reduced KIFSA and KIF21B gene expression significantly reduces neuronal viability. Phosphorylated neurofilaments (pNFs) are vital in maintaining axonal integrity and function. ,Dysregulation of anterograde axonal motor proteins including, KIFSA, KIF21B and KIF1B is likely to result in reduced transport of structural cytoskeletal components such as p-NFs, compromising axonal structure and integrity, as seen in many neurodegenerative diseases. Therefore, preservation of axonal transport mechanisms and neurofilament phosphorylation may be a potential therapeutic avenue to explore to protect against on-going neurodegeneration in MS and other neurological diseases. Overall, the results presented here offer more insight into the neurodegenerative processes occurring in MS. However, further studies are required to ascertain the direct functional consequences of reduced KIF gene/protein expression on axonal transport and funct ion in the disease course.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available