Menozzi, Elisa;
(2024)
Evolution of Clinical, Biochemical and Microbiome
Biomarkers of Conversion to Parkinson Disease in Glucocerebrosidase Mutation Carriers: Insights into Aetiology, Pathogenesis and Future Therapies.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The penetrance of heterozygous variants in GBA1, the commonest genetic risk factor for Parkinson disease (PD), is incomplete (10%-30%), but the reasons underlying this phenomenon are unknown. Accumulation of abnormal α-synuclein in the gastrointestinal tract with subsequent spread to the brain has been proposed as a model of pathogenesis in certain individuals with PD. Which factors trigger these pathophysiological changes in the gut, and the relevance of this model in GBA1-associated PD, remain open questions. The aim of this PhD was to investigate the potential role of the gut microbiome as a factor triggering PD pathology in the gut and contributing to PD development in carriers of GBA1 variants. I created an in-vitro model of PD pathogenesis using intestinal enteroendocrine cells, specialised in sensing bacterial factors through Toll-like receptors (TLRs). I showed that upon short-term exposure to the bacterial membrane components lipopolysaccharide (TLR4 agonist) and lipopeptides (TLR2 agonist), intracellular levels of α-synuclein protein were increased in mouse enteroendocrine cells, especially upon LPS exposure. Use of a TLR4 antagonist effectively reduced the lipopolysaccharide-mediated effect. Prior to evaluating the gut microbiome in GBA1 variant carriers, I sought to determine the effect of host GBA1 genetic status on gut microbiome composition by analysing it in mice carrying heterozygous variants in GBA1 and littermate controls. I showed that the ‘cage effect’ remarkably homogenised the gut microbiome of animals with different genotypes that were mixed in the same cage. I then examined the clinical and microbiome aspects of a cohort of carriers of GBA1 variants, with and without PD, and compared them to non-carriers. The main outcome was that PD patients carrying GBA1 variants showed worse olfactory function compared to non-carriers. Microbial richness was similar across groups, whereas some differences in gut microbiome composition emerged between healthy individuals and asymptomatic carriers, as well as between PD patients with and without GBA1 variants.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Evolution of Clinical, Biochemical and Microbiome Biomarkers of Conversion to Parkinson Disease in Glucocerebrosidase Mutation Carriers: Insights into Aetiology, Pathogenesis and Future Therapies |
| 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 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/10184682 |
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