Fodder, Katherine Elizabeth;
(2025)
The role of DNA methylation and oligodendrocytes in neurodegeneration.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Neurodegenerative diseases form a heterogeneous group of conditions characterised by the progressive degeneration of the structure and function of the central or peripheral nervous systems. The pathogenic mechanisms underlying these diseases are not fully understood. Various pathogenic mechanisms are thought to contribute to disease, and an increasing number of studies implicate dysfunction of oligodendrocytes (the myelin producing cells of the central nervous system) and myelin loss. Aberrant DNA methylation, the most widely studied epigenetic modification, has been associated with many neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson's disease (PD), Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). Recent research highlights aberrant DNA methylation in oligodendrocyte (OLG)/myelin-related genes. In this thesis, we describe the results of investigations into the role of dysregulated DNA methylation within oligodendrocyte lineage genes across neurodegenerative diseases. Through complementary computational approaches, we identify key genes which have not previously been linked to altered DNA methylation as important in neurodegeneration. We also utilise gene expression datasets to follow up on findings, in order to uncover functional consequences of dysregulated DNA methylation. We find that several crucial myelin/OLG lineage genes such as MBP are differentially methylated and expressed across dementias. We also investigate DNA methylation changes during oligodendrocyte differentiation using DNA methylation profiles from iPSC derived cells across differentiation stages, and identify genes that we had found to be differentially methylated in disease as also being top differentially methylated genes during differentiation. This implicates aberrant DNA methylation as a mechanism that could be contributing to dysfunction of OLG lineage progression. Finally, we investigate the oligodendrocyte-specific gene MOBP, which has been associated with multiple neurodegenerative diseases at the genetic level. MOBP has also been previously identified as aberrantly differentially methylated in multiple MSA. In this work, we highlight a shared genetic loci between ALS and PSP within MOBP that appears to be associated with changes in DNA methylation and gene expression in disease. Through this work, we have demonstrated dysregulation of DNA methylation affecting OLG lineage cells in neurodegeneration.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The role of DNA methylation and oligodendrocytes in neurodegeneration |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2025. 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 > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10207737 |
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