Delafosse, Juliette Julka Antoinette;
(2022)
Role of Apg-2 in retinal pigment epithelium homeostasis and age-related macular degeneration.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world, but its causes are still unclear. This project aims to understand the role of a heat shock protein, Apg-2, in AMD and more specifically in the RPE. Apg-2 has been shown to be downregulated by around 50% in macular RPE during early AMD. Preliminary data from our lab suggested that epithelial cells enter senescence and start to dedifferentiate upon depletion of Apg-2. In my thesis, I show that in RPE cells (ARPE-19 and porcine primary RPE cells), Apg2 depletion by RNAi induces a senescent phenotype. Apg-2 depleted RPE cells show markers and traits of senescence such as increased p53 and p21 expression, increased senescence-associated B-galactosidase activity, and decreased proliferation due to cell cycle arrest. Apg-2 depletion also induces proinflammatory signalling as the NFkB pathway becomes stimulated, promotes activation of the metabolism-regulating mTOR pathway and leads to increased intracellular ROS. Morphologically, knockdown of Apg-2 increases multinucleation, which is associated with ageing in the RPE. SFK signalling is also disrupted, and the SFK regulator SHP2 is mislocalised. Finally, ZONAB, a transcription factor shown to be required for the prevention of senescence by other work in our lab, appears downregulated in Apg-2 depleted RPE. I also show that a similar phenotype is observed in endothelial cells, suggesting Apg-2 could be important in other cell types. The observed cellular consequences of loss of Apg-2 are in agreement with the hypothesis that its downregulation contributes to the pathophysiology of AMD. Hence, Apg-2 and its pathway components may be targets for future therapeutic approaches for AMD.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Role of Apg-2 in retinal pigment epithelium homeostasis and age-related macular degeneration |
| 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 > 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 > Institute of Ophthalmology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10152202 |
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