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Unravelling the cellular pathology leading to neurodegeneration in motor neuron disease

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King, Anna Elizabeth (2008) Unravelling the cellular pathology leading to neurodegeneration in motor neuron disease. PhD thesis, University of Tasmania.

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Abstract

Despite advances in amyotrophic lateral sclerosis (ALS) research, important questions remain to be answered. Many degenerative processes have been attributed to the disease, but how these result in the selective degeneration of motor neurons and their links to observed pathological changes is not yet known. The subject of this thesis has been to investigate the relationship between the pathogenic factors in ALS, the neuroaxonal alterations to the motor neuron cytoskeleton and their selective degeneration.
There is substantial evidence to implicate the cell selective vulnerability of motor neurons to excitotoxocity in the pathogenesis of ALS. However, the role of the different glutamate receptor subunits is still unknown. This thesis has used immunocytochemical techniques to investigate the cell type specific changes in glutamate receptor localisation and expression in relation to susceptibility to excitotoxicity in a cortical cell culture model. Vulnerability to N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity occurred prior to their localisation in apposition to pre-synaptic terminals, indicating that excitotoxicity can be mediated by extrasynaptic receptor puncta. However, vulnerability to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated excitotoxicity was related to localisation ofreceptors at synapses and in spines. Additionally, a subclass of neurons was identified with a specific compliment of receptor subunits, indicating the presence of calcium permeable AMP A receptors and suggesting vulnerability to excitotoxicity.
Mouse models of neurofilament disruption have demonstrated the importance of neurofilament pathology in ALS. However, the sequence of cytoskeletal changes in ALS is yet to be determined. This thesis has used an immunohistochemical approach to investigate the time course of cytoskeletal alterations in the G93A mouse model of ALS. Accumulations of neurofilament proteins occurred in the spinal cord prior to the development of symptoms, and this pathology was followed by neurofilament changes in the descending white matter tracts, indicative of upper motor neuron involvement.
To investigate the causes of cytoskeletal disruption in ALS, this thesis has used a novel cell culture model of spinal motor and cortical neurons grown on an astrocyte feeder layer. Spinal motor neurons, but not cortical neurons, exposed to excitotoxins developed accumulations of neurofilament proteins in the distal portions of their axons, which showed a strong resemblance to the spinal neurofilament disruption seen in ALS. Additionally, a proximal axonopathy was induced in spinal motor neurons grown on mixed glial feeder layers, and ageing the feeder layer prior to plating the neurons exacerbated this pathology. These culture models are the first to replicate the neurofilament axonopathy of ALS and are likely to serve as useful tools for further investigations into the mechanisms of motor neuron degeneration and for the screening of potential therapeutic agents.

Item Type: Thesis (PhD)
Keywords: Amyotrophic lateral sclerosis, Motor neurons
Copyright Holders: The Author
Copyright Information:

Copyright 2008 the Author - The University is continuing to endeavour to trace the copyright
owner(s) and in the meantime this item has been reproduced here in good faith. We
would be pleased to hear from the copyright owner(s).

Additional Information:

Available for library use only and copying in accordance with the Copyright Act 1968, as amended. Thesis (PhD)--University of Tasmania, 2008. Includes bibliographical references

Date Deposited: 19 Dec 2014 02:52
Last Modified: 09 May 2017 06:01
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