Wernick, Anna Irene;
(2024)
An Examination of the Effect of Neuronal Beta-Glucocerebrosidase Dysfunction, and the Search for Endogenous Regulators.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder, pathologically defined by aberrant aggregation of alpha-synuclein and widespread neuronal loss. There are currently no disease-modifying therapies available. One of the greatest genetic risk factors for PD are heterozygous mutations in GBA, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase). Homozygous GBA mutations are causative of the lysosomal storage disorder, Gaucher’s disease (GD). GCase dysfunction is characteristic of both sporadic- and GBA-PD. Our understanding of the myriad ways in which GCase dysfunction induces cellular toxicity, and of the endogenous regulators of GCase, is incomplete. In this study, two human neuronal models of GCase dysfunction were generated from PD and GD patients with heterozygous and homozygous p.N370S GBA mutations, respectively. The main aims of this project were (i) to characterise the downstream consequences of GCase dysfunction and (ii) identify regulators of GCase activity. The predominant early phenotype in these cell lines were morphological changes to the lysosome, namely swelling and increased numbers per cell. GBA mutant neurons exhibited dysfunction of the lysosomal protease and PD-associated gene, cathepsin B (CatB), independent of its protein expression. Moreover, CatB was identified as a negative regulator of GCase activity. In both neuroblastoma cells and wild-type iPSC-derived neurons, but not GBA mutant cells, inhibition of CatB significantly increased live-cell GCase activity. This may be an indirect result of an up-regulation of autophagic flux. CatB inhibition increased both autophagosomal content (LC3-II levels) and autolysosome formation. CatB inhibition also increased nuclear translocation of the lysosomal transcription factor EB (TFEB) and the pool of functional lysosomes, suggesting an increase in lysosomal biogenesis. These results suggest a bidirectional relationship between GCase and CatB that should be further investigated in the pathogenesis of PD.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | An Examination of the Effect of Neuronal Beta-Glucocerebrosidase Dysfunction, and the Search for Endogenous Regulators |
| 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 |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10187055 |
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