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Modifying axonal transport as a therapeutic strategy for Amyotrophic Lateral Sclerosis

Gibbs, KL; (2015) Modifying axonal transport as a therapeutic strategy for Amyotrophic Lateral Sclerosis. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Deficits in retrograde axonal transport have been described at a presymptomatic stage in the SOD1G93A mouse model of ALS. The early appearance of transport defects suggests that they may play an important role in disease pathogenesis. However, the causative role of axonal transport deficits in ALS motor neuron degeneration has not yet been demonstrated directly. The goal of my PhD project was to identify pharmacological enhancers of retrograde axonal transport that could be used to prove conclusively whether axonal transport defects play a significant role in ALS pathogenesis. To this aim, I developed and performed a microscopy-based screen for the identification of pharmacological enhancers of retrograde axonal transport in motor neurons. I was able to demonstrate that the accumulation of α-p75NTR and HCT in the cell body of mouse ES-derived motor neurons acts as a sensitive read-out of retrograde axonal transport efficiency and using this assay, I identified and validated two compounds (A1 and E4) that were able to accelerate retrograde axonal transport in motor neurons. Compound A1 was revealed to be an inhibitor of p38 MAPK. Inhibition of p38 MAPK was found to correct deficits in retrograde axonal transport in SOD1G93A motor neurons both in vitro and in vivo. Using genetic and pharmacological approaches, I was able to demonstrate that p38 MAPKα is responsible for the transport deficits observed. Compound E4 was revealed to be an inhibitor of the IGF1 receptor (IGF1R). It was found to accelerate retrograde axonal transport in both wild type and SOD1G93A motor neurons, but had no effect on anterograde transport speeds. In conclusion, this thesis work has identified inhibitors of p38 MAPK and IGF1R as novel modifiers of retrograde axonal transport and demonstrated that inhibitors of p38 MAPKα can be used to determine the role of axonal transport defects in ALS pathogenesis.

Type: Thesis (Doctoral)
Title: Modifying axonal transport as a therapeutic strategy for Amyotrophic Lateral Sclerosis
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices
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
URI: https://discovery.ucl.ac.uk/id/eprint/1472409
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