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Title: Investigating stress responses in models of Amyotrophic Lateral Sclerosis
Author: Clarke, Benjamin
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available