Clarke, Benjamin;
(2019)
Investigating stress responses in models of Amyotrophic Lateral Sclerosis.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The ability of motor neurons and surrounding glia to respond to stressful conditions is crucial for their survival in injury or disease states. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease defined by the loss of both upper and lower motor neurons resulting in muscle paralysis. Several pathomechanisms in both motor neurons and glial cells contribute to motor neuron death in ALS. Among these, dysfunction in stress responsive pathways involved in inflammation, proteostasis and mitochondrial function are known to be important. Since ALS is defined by loss of motor neurons in specific anatomical areas, with spinal motor neurons most affected, regional differences in glial stress responses may contribute towards this specific pattern of damage. In this Thesis, a regional difference in the NO-iNOS-NF-κB inflammatory pathway was observed, with spinal cord glia displaying a stronger response than cortical glia. While this regional difference was observed, no clear differences were found in the inflammatory responses of glia from mutant SOD1 (mSOD1) models of ALS. However, mSOD1 glia were unable to activate the heat shock response (HSR), a cytoprotective response involving the upregulation of heat shock proteins (Hsps), as effectively as wildtype glia. Reduced activation of the HSR increased the inflammatory responses of mSOD1 glia. Therefore, dysregulation of the HSR may further exacerbate an inherent ability of spinal cord glia to promote inflammatory damage in ALS. Mitochondrial dysfunction is also an important pathomechanism in ALS. Several Hsps are specifically localised to mitochondria. mSOD1 spinal cord motor neurons expressed lower levels mitochondrial Hsps TRAP1 and Hsp60. In a cellular ALS model of oxidative stress, overexpression of these proteins was protective to mitochondrial functions in motor neurons, while knockdown was detrimental. Together, these data suggest that manipulating stress responses of motor neurons and glia may be a viable therapeutic target for ALS.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Investigating stress responses in models of Amyotrophic Lateral Sclerosis |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) Licence (https://creativecommons.org/licenses/by-nc-nd/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10085063 |
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