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Dissecting the molecular mechanisms by which oligodendrocytes contribute to synucleinopathies

Evans, James R.; (2025) Dissecting the molecular mechanisms by which oligodendrocytes contribute to synucleinopathies. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Neurodegenerative diseases are a group of heterogenous disorders characterised by the progressive and targeted loss of neurons, in which the clinical manifestation of each condition reflects the specific neuronal population affected. Parkinson’s disease (PD), the fastest growing of these conditions, occurs due to the degeneration, and ultimately loss, of midbrain dopaminergic neurons. However, research suggests that across these diseases, despite neurons displaying the primary characteristic pathology, non-neuronal ‘helper’ cell types, known collectively as glia, play a causative role, and at least in part, drive disease pathology. Genetic data and single-cell approaches highlight a significant role for oligodendrocytes in the pathogenesis of PD, with oligodendrocytes enriched for PD-associated genes and oligodendrocyte-specific transcriptomic alterations found early in the disease process. Aggregation of the protein alpha-synuclein (αSyn), the key driver of cellular dysfunction in PD, is present within oligodendrocytes in multiple synucleinopathies, further implicating their involvement in PD. Despite this, the role oligodendrocytes play in initiating or propagating αSyn aggregation, and in contributing to wider glial dysfunction and neuronal loss, is unknown. Here, to understand the oligodendrocyte-specific process, and downstream cellular consequences, of αSyn aggregation in vitro, I optimised two cell models to generate cultures of enriched oligodendrocytes derived from human induced pluripotent stem cells (hiPSCs) and isolated primary oligodendrocyte progenitor cells. Using these models, I explored the effects of αSyn aggregation using (i) exogenous fluorescently labelled monomeric αSyn and (ii) PD patient-derived hiPSCs with SNCA mutation (the gene that encodes αSyn).Through these two experimental paradigms, I revealed that αSyn aggregation within oligodendrocytes, whether triggered through exogenous uptake or endogenous mutation, results in significant organelle dysfunction characterised by mitochondrial dysfunction and the emergence of lipid droplets. I further demonstrated that αSyn aggregation within oligodendrocytes is localised on the surface of αSyn-induced lipid droplets, in addition to the mitochondria, which leads to a loss of membrane integrity of both organelles. In addition to this, I also showed that both triggers of aggregation (exogenous and endogenous) induce an inflammatory cascade, mediated by pattern recognition receptors. Cytoplasmic aggregates compromise organellar membrane integrity, which may lead to nucleic acid release, whilst endogenous nuclear-localised aggregates activate IFI16-mediated detection of DNA double-strand breaks. Furthermore, I generated an hiPSC-derived microglial cell model to demonstrate that this αSyn induced oligodendrocyte inflammatory signature promotes activation of other glial cell types. Together, the data reveals αSyn-induced mechanisms by which oligodendrocytes contribute to cellular dysfunction and a broader glial inflammatory response in PD.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Dissecting the molecular mechanisms by which oligodendrocytes contribute to synucleinopathies
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 > Clinical and Movement Neurosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10202922
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