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Growth factor signalling axes impact retrograde axonal transport of signalling endosomes in healthy and diseased motor neurons

Rhymes, Elena Ruth; (2022) Growth factor signalling axes impact retrograde axonal transport of signalling endosomes in healthy and diseased motor neurons. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Axonal transport between the soma and axonal terminal is fundamental for neuronal survival. The long axons of motor neurons make this cell type especially vulnerable to changes in axonal transport, and accordingly, in vivo and in vitro axonal transport deficits are one of the earliest reported pathologies in the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS). A screen of protein kinase inhibitors previously conducted in the Schiavo lab identified several compounds capable of rescuing transport deficits in SOD1G93A mice, including inhibitors of p38 mitogen-activated protein kinases (p38 MAPK), and insulin-like growth factor receptor 1 (IGF1R). Another target identified in the screen was the RET proto- oncogene, a component of the receptor for glial cell-line derived neurotrophic factor (GDNF), a neurotrophin fundamental for motor neuron development and survival. In this thesis, I show that RET inhibition accelerates wildtype retrograde transport speeds, with inhibitor specificity confirmed using genetic knockdown of the growth factor receptor. This effect has been replicated in vivo, where RET inhibition is able to enhance transport speeds in SOD1G93A mice. Furthermore, direct inhibition of AKT, a kinase activated downstream of IGF1R and RET signalling also enhances signalling endosome transport speeds. It is possible, therefore, that inhibition of IGF1R and RET accelerates transport through indirect inhibition of AKT. Interestingly, I have also shown that the in vitro SOD1G93A axonal transport deficits are not present under basal conditions, however, in response to treatment with 50 ng/ml brain derived neurotrophic factor (BDNF), signalling endosome transport speeds are significantly reduced. These findings highlight a key interaction between axonal transport speeds and growth factor signalling, validate RET inhibitors as transport enhancers, and promote axonal transport deficits as a therapeutic target in the treatment of ALS.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Growth factor signalling axes impact retrograde axonal transport of signalling endosomes in healthy and diseased motor neurons
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/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 > 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 > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
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/10150250
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