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Final Copy 2019 05 07 Khazi This electronic thesis or dissertation has been downloaded from Explore Bristol Research, http://research-information.bristol.ac.uk Author: Khazim, Mahmoud Title: Investigating synucleinopathies using translating ribosome affinity purification in cellular Parkinson’s disease models General rights Access to the thesis is subject to the Creative Commons Attribution - NonCommercial-No Derivatives 4.0 International Public License. A copy of this may be found at https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode This license sets out your rights and the restrictions that apply to your access to the thesis so it is important you read this before proceeding. Take down policy Some pages of this thesis may have been removed for copyright restrictions prior to having it been deposited in Explore Bristol Research. However, if you have discovered material within the thesis that you consider to be unlawful e.g. breaches of copyright (either yours or that of a third party) or any other law, including but not limited to those relating to patent, trademark, confidentiality, data protection, obscenity, defamation, libel, then please contact [email protected] and include the following information in your message: •Your contact details •Bibliographic details for the item, including a URL •An outline nature of the complaint Your claim will be investigated and, where appropriate, the item in question will be removed from public view as soon as possible. Investigating synucleinopathies using translating ribosome affinity purification in cellular Parkinson’s disease models Mahmoud Rabi Khazim Bristol Medical School January 2019 A dissertation submitted to the University of Bristol in accordance with the requirements for award of the degree of Doctorate of Philosophy in the Faculty of Translational Health Sciences Word count: 46,111 i Abstract Parkinson’s disease (PD) is a neurodegenerative disease characterised by accumulation of α- synuclein protein and loss of midbrain dopaminergic (mDA) neurons of the Substantia nigra (SN), resulting in motor dysfunction. Mutations and multiplications of the SNCA locus, which encodes α-synuclein, have been associated with familial Parkinson’s Disease. Using lentiviruses to overexpress wild-type and mutant α-synuclein in mDA neuron models, the transcriptomic and functional changes associated with increased α-synuclein burden were investigated. The SH-SY5Y cell line was employed to study gene expression, by profiling actively translated mRNAs isolated by translating ribosome affinity purification (TRAP). Differential expression analysis in α-synuclein overexpressing cells identified actin cytoskeleton, mitochondrial and oxidative stress response proteins, as well as a key protein involved in miRNA biogenesis, DGCR8, to be key pathways affected by α-synuclein overexpression. Validation using molecular biology techniques was able to partially validate some of these targets. mDA neurons derived from human induced pluripotent stem cells (iPSC) were employed to study functional phenotypes, differentiation capacity and neurite dynamics, in response to overexpression of wild-type and mutant α-synuclein. Whilst the capacity for iPSC cells to differentiate into mDA neurons expressing mature neuronal and dopaminergic markers was not affected, both neurite extension and axonal branching was seen to be reduced in α- synuclein overexpressing cultures. Furthermore, these models were used to interrogate alterations in expression of microRNAs (miRNA) associated with mDA function and PD pathogenesis. Intracellular miRNA analysis resulted in the identification of differential expression of miRs-34b, -34c, -155 and -494, known to be associated with regulation of neuroinflammation, oxidative stress response and post-transcriptional regulation of α- synuclein mRNA. The data presented implicates several pathways, genes and miRNA that are perturbed in response to α-synuclein overexpression. Further study of these pathways will contribute to our understanding of mechanisms underlying α-synuclein pathology and may represent potential therapeutic targets for PD. ii Dedication & Acknowledgements First and foremost, I would like to thank my supervisors Dr. Liang-Fong Wong and my secondary supervisor Professor James Uney for the opportunity to study for this PhD in their lab. I feel so lucky to have joined a lab with such a supportive and collaborative environment. Thanks also to Dr. Oscar Cordero Llana who became an unofficial supervisor. You all truly inspired me, and I appreciate the guidance, time and the sharing of your knowledge and expertise with me so much. Thank you to my colleagues in the Uney/Wong/Llana lab. Every single one of you has helped me in some way or another and made this such a positive experience. Thanks to Dr. Helen Scott and Dr. Jess Gaunt for their advice throughout TRAP. Dr Hadil Al-Ahdal and Dr. Jalilah Idris for teaching me were everything was in the lab. And to my mentor Dr. Liang-Fong Wong, I am so grateful for all your help in the planning and implementation of the experiments throughout. Thanks also to all the students I’ve supervised in the lab who were such a pleasure to teach. A big thanks also to the Caldwell group and stem cell lab colleagues. Thanks particularly to Dr. Paul Nistor, Dr. Petros Stathakos and Dr. Fella Hammachi for their warm advice and the collaborative atmosphere they created. Thanks to Dr. Abdelkader Essafi and his lab for all the advice and help with RNA-sequencing and making it feel simple. Thanks to Lorena Sueiro Ballesteros and Dr Andrew Herman for their help with all things flow cytometry and the Wolfson facility staff for their help with all things microscopy. I was always happy to book a session at both facilities. Thanks to all the admin and support staff for their help whenever anything needed to be fixed, purchased or prepared. Without the help of Doug, Dave, Bill and Andy, nothing could have been achieved. A massive thanks to all the CMM colleagues in B and C floor offices for making waking up and coming in everyday fun and exciting. And a special mention to my friends Dr. Alice Sherrard and Dr. Ahmed Basri for all the laughs. To my family and community who have shown me so much love and support, I am eternally grateful. To my friends Owen, Chi, Gareth, Chris, Jason, Siobhan and Khobir. Finally, this thesis is dedicated to my family. To my little sisters Tala and Lina who I am so lucky to have had supporting and cheering for me every step of the way. And to my father Dr. Rabi Khazim and my mother Riaf Fahs, all of this was possible because of you. Thanks to my mother for all her spiritual and logistical support throughout. And to my father who was the one who believed in me and encouraged me to do this PhD. I can never thank you enough for everything. iii Authors declaration The CMV-EGFP, PGK-EGFP lentiviral backbone plasmids were gifts from Dr. Liang-Fong Wong and the CMV-α-synucleinWT, CMV -α-synucleinA53T and the CMV-L10a-EGFP lentiviral backbone plasmids were gifts from Dr. Helen Scott. NAS2 iPSC line was a gift from Dr. Tilo Kunath’s lab in Edinburgh University TEM preparation and staining was performed by an undergraduate student Bryony McPherson NTA was performed by collaborator Dr. Andrew Shearn FACS sorting was performed with Dr. Andrew Herman Neurite analysis immunostaining and neurite analysis was performed by undergraduate student Maria Otero Jimenez I declare that the work in this dissertation was carried out in accordance with the requirements of the University's Regulations and Code of Practice for Research Degree Programmes and that it has not been submitted for any other academic award. Except where indicated by specific reference in the text, the work is the candidate's own work. Work done in collaboration with, or with the assistance of, others, is indicated as such. Any views expressed in the dissertation are those of the author. SIGNED: ............................................................. DATE: 14/01/2018 iv Table of contents Abstract ................................................................................................................................................... ii Dedication & Acknowledgements .......................................................................................................... iii Authors declaration ............................................................................................................................... iv Table of contents .................................................................................................................................... v List of figures .......................................................................................................................................... xi List of tables ......................................................................................................................................... xiii Chapter 1 – General Introduction ........................................................................................................... 1 1.1 Parkinson’s disease: A historical perspective ......................................................................... 1 1.1.1 Parkinson’s disease classification and disorder-anatomy associations ................................. 1 1.1.2 The discovery of dopamine .................................................................................................... 4 1.1.3 The development of the first targetted Parkinson’s disease treatment ..............................
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