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Integrated multi-omic analysis of amyotrophic lateral sclerosis

Ziff, Oliver; (2023) Integrated multi-omic analysis of amyotrophic lateral sclerosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Amyotrophic Lateral Sclerosis (ALS) is a relentlessly progressive disease that causes paralysis from motor neuron degeneration and death on average within 4 years. The pathological hallmark is TDP-43 proteinopathy, which is observed in 97% of cases. Although there is a strong genetic component, with over 20 genes known to cause ALS, in 75% of cases no causative mutation is found. Clinical presentation is heterogeneous, in both the site of onset and the rate of progression. There are no effective disease-modifying therapies, and this remains the greatest unmet need in ALS. A key reason for the failure of ALS drug trials is the poor understanding of pathogenesis and the lack of reliable biomarkers. This is in part due to the inaccessibility of degenerating spinal cord motor neurons from patients, and so we have over-relied on unsatisfactory models, particularly mouse transgenic models that are largely not reflective of ALS. Additionally, the clinical, genetic, and pathological heterogeneity makes identifying common changes across the spectrum of ALS challenging. This thesis deals with these issues head-on. Firstly, I utilise human models wherever possible, making use of induced pluripotent stem cell-derived motor neurons (iPSMNs) and astrocytes, as well as postmortem tissue. Secondly, I address the issue of heterogeneity by increasing the sample size through next-generation sequencing dataset integration, increasing the power to detect changes across ALS subtypes. This approach confirms previously recognised pathogenic processes, such as RNA misprocessing, RNA binding protein (RBP) mislocalisation, and DNA damage, but also exposes novel disease mechanisms, including TDP-43 associated genome instability (Chapter 3), widespread mRNA nucleocytoplasmic redistribution (Chapter 4), neurotoxic astrocyte reactivity (Chapter 5) and intron splicing induced astrocyte reactivity (Chapter 6). In summary, I present an integrated bioinformatic approach of human models to understand the pathomechanisms of ALS; exposing potential biomarkers and therapeutic targets.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Integrated multi-omic analysis of amyotrophic lateral sclerosis
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 Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10166375
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