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This Thesis Has Been Submitted in Fulfilment of the Requirements for a Postgraduate Degree (E.G This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. A Functional Analysis of RP2 and ARL3 in X- Linked Retinitis Pigmentosa Abigail Little Thesis submitted for the degree of Doctor of Philosophy The University of Edinburgh 2018 Declaration The work presented in this thesis is my own work except when explicitly stated. This work has not been submitted for any other degree or professional qualification. Abigail Little, September 2018 ii Acknowledgements For the past four years, I have undertaken my PhD studies at the Institute of Genetic and Molecular Medicine, Human Genetics Unit and I feel very lucky to have completed my PhD studies in an institute with such a friendly and collaborative atmosphere. Special thanks has to be given to my PhD supervisor Toby Hurd who for the last four years has spent countless hours teaching me lab techniques and advising on project ideas. Thank you for always listening to my suggestions, however unfeasible and providing advice and support throughout my studies, without which I wouldn’t be here today with a completed thesis. I would also like to thank the other lab members who have come and gone in my time as a PhD student Rodanthi Lyraki, Matthieu Vermeren, Jilly Hope and other members of W2 for providing a fun lab environment and always being happy to provide the odd protocol or reagent. I am also grateful to Ian Jackson, Pleasantine Mill, Roly Megaw and their lab members whose suggestions and criticisms in lab meetings have helped shape this project. During my four years as a PhD student, I have had the pleasure of making wonderful friends in fellow students Gabi Olley, Zoe Crane-Smith, Jane Fraser and Luke Williamson. I credit these friends for keeping me sane throughout my PhD, always providing a person to vent to and a story to laugh at. Thanks for being my lunch buddies, drinking partners, travel buddies, flat mates and best friends for the last four years, a friendship that I’m sure will last for many more years to come as we take our next steps into the future. I am forever grateful to all my family and friends for their endless support, encouragement and belief in me. Thank you to my parents, Peter and Yvonne, and my sisters Kerry, Holly and Eilidh for listening to my stories of PhD life despite never understanding my project or what my work involves. No matter what the ups and downs I knew I could always rely on my Mum’s encouragement from her favourite moto “What’s meant for you won’t go by you” an attitude which proved invaluable during my PhD studies and one which I’m sure will serve me well in my next steps in life. iii Abstract Retinitis Pigmentosa (RP) is a disease of the retina, which causes progressive retinal degeneration. X-linked RP is one of the most severe subtypes with an estimated 15% of cases caused by mutations in RP2. RP2 functions as a GTPase Activating Protein (GAP) for the small G protein ARL3, which is proposed to regulate the traffic of lipid- modified proteins within photoreceptors. It is hypothesised that mutations in RP2 result in dysregulation of ARL3 and therefore protein mis-trafficking. In order to elucidate the contribution of ARL3 dysregulation to the pathogenesis of RP, I have established new mouse models by CRISPR-mediated genome editing. These include an Rp2h knockout line and a line, which harbours a human pathogenic missense mutation, E135G, which abolishes interaction with ARL3. Furthermore, I have generated mice carrying a Q71L missense mutation in Arl3. This mutation locks ARL3 in the active GTP-bound state, and hence is predicted to phenocopy Rp2h knockout. Histological examination has revealed that Rp2h knockout, Rp2h E135G and Arl3 Q71L/+ mutant animals display progressive retinal degeneration evident from age 6 months. Arl3 Q71L/Q71L animals display retinal degeneration at age 3 months demonstrating that elevated levels of ARL3-GTP is a driver of retinal degeneration in mice. Immunofluorescence analysis has shown ARL3 Q71L mice, Rp2h knockout mice and Rp2h E135G/Y mice show mislocalisation of lipid modified proteins likely driving retinal degeneration, however further analysis has shown that these mice do not completely phenocopy each other suggesting that levels of ARL3-GTP may not be the only mechanism contributing to retinal degeneration in Rp2h mutant mice. The mechanisms of RP2 regulation are not well understood; therefore to identify potential interactors of RP2 a BIO-ID proximity labelling assay in RPE-1 cells was performed. A top hit from this assay was palmitoyltransferase ZDHHC5. I confirmed this interaction in cells and using a click chemistry based approach demonstrated that it is unlikely that this enzyme functions to palmitoylate RP2. Using immunofluorescence in HeLa cells I have shown that overexpression of ZDHHC5 can rescue the localisation of human pathogenic RP2 mutants C3S and G2A, which are normally mislocalised in vivo, independent of its catalytic activity. SiRNA knockdown of ZDHHC5 in cells leads to mislocalisation of RP2 demonstrating ZDHHC5 has a role in trafficking RP2. Results from these studies have provided new knowledge iv regarding the mechanisms that cause retinal degeneration and new insights into the potential mechanisms that regulate the trafficking of lipid-modified proteins in photoreceptors. v Lay Summary The retina is the part of the eye that is responsible for detecting light and sending signals to the brain. Within the retina, the specialised cells which detect light, are called photoreceptors. Inherited Retinal Degenerations are a group of diseases that lead to death of these photoreceptor cells and cause blindness in humans. One specific disease called Retinitis Pigmentosa can be caused by a defect in a molecule called RP2. It is not understood why defects in RP2 cause death of photoreceptors, therefore research into the function of RP2 is essential for the development of treatments for patients. Previous research has suggested that RP2 controls the localisation of other molecules in the photoreceptors by working with another molecule called ARL3. RP2 acts as a switch to inactivate ARL3 in cells, therefore defects in RP2 are thought to lead to photoreceptors which have too much active ARL3. It is thought that this active ARL3 disrupts photoreceptor function eventually leading to cell death. In order to determine if high levels of active ARL3 is the only issue in photoreceptors with defective RP2 I used mouse models that had been designed to have no RP2, defective RP2 or only active ARL3. If having high levels of active ARL3 is the only issue in photoreceptors with defective RP2 all of these mice should become progressively blind at the same rate. Analysis of visual function and photoreceptor health in these animals revealed that they do not all become blind at the same time and that the issues in the photoreceptors leading to blindness are not identical, suggesting RP2 may have other roles in photoreceptors, which when missing also contribute to photoreceptor cell death. The mechanisms which control RP2 in photoreceptors are not understood, therefore an experiment which identifies new molecules which regulate RP2 was performed. This revealed a new molecule, which controls where RP2 is located in cells and provides new insights into the ways the localisation of molecules in photoreceptors are controlled. Overall, the research described in this thesis provides new knowledge into the causes of photoreceptor death when RP2 is defective in patients with Retinitis Pigmentosa. vi Abbreviations 17- ODYA: 17- Octadecynoic Acid 8-oxoG: 8-Oxoguanine A2: Annexin 2 AD: Activating domain ADRP: Autosomal Dominant Retinitis Pigmentosa AIF: Apoptosis Inducing Factor Aipl1: Aryl Hydrocarbon Receptor Interacting Protein Like 1 Akt: Cellular Homolog of Murine Thymoma virus akt8 Oncogene AP-1: Activator Protein- 1 AP2: Adaptor Complex 2 ARF: ADP Ribosylation Factor ARL13B: Arf- like Protein 13B ARL2: Arf-like Protein 2 ARL3: Arf-like Protein 3 ARL6: Arf-like Protein 6 ARPE19: Adherent Retinal Pigment Epithelium 19 Arr: Arrestin ARRP: Autosomal Recessive Retinitis Pigmentosa ATF6: Activating Transcription Factor 6 ATP: Adenosine Triphosphate BCL2: B-cell lymphoma 2 BD: DNA binding domain BIO-ID: Proximity Based Biotinylation BRF: Biomedical Research Facility BSA: Bovine Serum Albumin C3: Cysteine 3 cAMP: Cyclic Adenosine Monophosphate CC: Connecting Cilium CD36: Cluster of Differentiation 36 cGMP: Cyclic Guanosine Monophosphate CNG: Cyclic Nucleotide Gated CNGA1: Cyclic Nucleotide Gated Alpha 1 CNGB1: Cyclic Nucleotide Gated Beta 1 CNTF: Ciliary Neurotrophic Factor CO-IP: Co-Immunoprecipitation COS: Cone Outer Segment CREB: cAMP response element binding protein CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats
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