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Identifying and rectifying aberrant RNA metabolism in amyotrophic lateral sclerosis

Wilkins, Oscar G; (2023) Identifying and rectifying aberrant RNA metabolism in amyotrophic lateral sclerosis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Amyotrophic lateral sclerosis is a devastating and incurable disease. Despite decades of work, its cause is yet to be fully understood, and we lack effective treatments. There is therefore a great need for further research on the mechanisms which drive disease to help guide new drug development. In this thesis, I describe work spanning from the development of new techniques and software to aid the fundamental study of RNA biology, to the identification of a novel disease mechanism in ALS that should be straightforward to target therapeutically, and the development of a new precision medicine approach that could enable safer and more efficacious gene therapy for this disease. In the first chapter, I outline three short projects: 1. The development of software for the processing of fastq files with inline barcodes and UMIs; 2. A streamlined computational and experimental method for the removal of rRNA sequences from sequencing libraries, and 3. Several related protocols for the production of various RNA sequencing library types, all of which involve template-switching. In the second chapter, I describe how I helped characterise and validate a novel cryptic exon in UNC13A using a variety of wet- and dry-lab-based approaches. Furthermore, I describe how I designed and tested candidate therapeutic antisense oligonucleotides to rescue this splicing abnormality, and how I developed a protocol for detecting large numbers of cryptic exons in parallel. Finally, in the third chapter, I describe the development of software to design expression vectors which are activated by the depletion of TDP-43, potentially paving the way towards safer and more efficacious gene therapy for ALS and related diseases.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Identifying and rectifying aberrant RNA metabolism in amyotrophic lateral sclerosis
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2023. 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
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/10167175
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