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Investigation of Parkin Molecular Pathways

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Investigation of Parkin Molecular Pathways Investigation of molecular pathways associated with Parkin Hsiu-Chuan Wu UCL Institute of Neurology Thesis submitted in fulfilment of the degree of Doctor of Philosophy (UCL) Declaration: I, Hsiu-Chuan Wu, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 2 Abstract: Parkinson’s disease (PD) is an incurable neurodegenerative disease. Although the majority of PD cases are sporadic, 5-10% of cases are inherited. Studies of sporadic and genetic forms of PD suggest shared pathogenesis such as mitochondrial dysfunction. Mutations in the gene encoding Parkin are the most common cause of autosomal recessive, young-onset PD. Parkin has been shown to regulate mitochondrial quality control (mitophagy), however the molecular pathways that regulate Parkin activity remain poorly characterised. MEKK3/p38, MAPK/ERK, and PI3K/Akt signalling pathways have been described in association with Parkin regulation. In this thesis, I have investigated whether activation of any of these pathways could lead to Parkin phosphorylation by utilising inducible cell lines overexpressing MEKK3-ER, Raf- ER or Akt-ER genes. I found that Parkin was not phosphorylated following the activation of the p38, ERK and Akt pathways. In an attempt to depolarise mitochondria in neuroblastoma SH-SY5Y cells lines by mitochondrial uncoupler carbonyl cyanide m-chlorophenyl hydrazone (CCCP), I found that Parkin was phosphorylated at serine 101 (S101). In order to investigate the role of phosphorylation of Parkin S101 in mitochondrial quality control, I established SH-SY5Y clones stably expressing wild type (WT), non-phosphorylatable (S101A), or phosphomimetic (S101D) FLAG-Parkin. I found that this phosphorylation is associated with increased Parkin’s E3 ligase activity. S101A cells showed deficiencies in translocation of Parkin to depolarised mitochondria, ubiquitination of outer mitochondrial membrane proteins, p62 (an autophagy adaptor) recruitment, perinuclear mitochondrial clustering and mitophagy. Overall the work presented in this thesis demonstrates that Parkin is activated during mitochondrial depolarisation, and that the regulation of Parkin function via phosphorylation at S101 plays an important role in mitochondrial quality control associated with PD pathophysiology. 3 Acknowledgement: I’m deeply grateful to the many people I’ve come to know throughout these years in the lab. I would like to sincerely thank my supervisor, Hélène Plun-Favreau, for giving me this great opportunity to learn to be a scientist and offering her guidance, expertise and most important of all, endless support throughout my PhD and during the preparation of this thesis. I’m also grateful to John Hardy, who’s always be there giving me invaluable suggestions and encouragement. I want to express my gratitude to Julia Fitzgerald for patiently guiding me to learn all the techniques I need since my first day in the lab. Thanks to Vikki Burchell for providing assistance in setting up qPCR and confocal imaging acquisition. I am grateful to Claudia Manzoni and Marc Soutar for their willingness to share their expertise in all the protein work, to Fernando Bartolome and Kira Holmström for helping me in live cell imaging, to Michael Devine and Selina Wray for technical support in stem cell work, to Una-Marie Sheerin for obtaining patient’s skin biopsy, to Niccolo Mancacci and the genetic lab for the help in PCR and sequencing work, to Marta Delgado Camprubi for the contribution of data in chapter 3, and to Wolfdieter Springer for the contribution of data in chapter 5. I’d especially like to thank all the postdocs and PhD students, past and present, who made my PhD an enjoyable experience. I’m truly blessed to share the same office with Claudia Manzoni, Daniah Trabzuni, Sybille Dihanich, Marc Soutar, Fernando Bartolome, Suran Nethisinghe, Boniface Mok, and Arianna Tucci. I’ll really miss you and all those crazy talks about science, food, travel, culture, and so much more. An enormous thank you to Marc for reading this thesis many times and giving me invaluable feedbacks. I also need to thank Daniah and Boniface for helping the preparation of this thesis. Last, I’d like to thank my family and friends for their support, especially my husband who shared all the housework with me while he was also doing a PhD same time as me, my two children who draw countless pictures every day to make me smile, and my parents who always encourage me to fly and follow my dream. 4 Table of Contents Declaration: ........................................................................................................................................ 2 Abstract: ............................................................................................................................................... 2 Acknowledgement: ......................................................................................................................... 4 Table of Contents ............................................................................................................................. 5 Table of Figures ................................................................................................................................ 9 Table of Tables ............................................................................................................................... 11 Abbreviations ................................................................................................................................. 12 Mitochondrial Rho GTPase 1 ................................................................................................... 13 Publications arising from this thesis: .................................................................................. 17 Chapter 1 Introduction ........................................................................ 18 1.1 Parkinson’s disease ...................................................................................................... 18 1.2 Genetics of Parkinson’s disease .............................................................................. 22 1.2.1 Autosomal dominant PD: α-synuclein and LRRK2 ...................................................... 26 1.2.2 Autosomal recessive PD: PINK1, Parkin, DJ-1, ATP13A2, FBXO7 and HtrA2. 27 1.3 Parkin: an E3 ubiquitin ligase.................................................................................. 30 1.3.1 Gene structure and pathogenic mutations ...................................................................... 30 1.3.2 Protein structure and localisation....................................................................................... 32 1.3.2.1 Effects of protein domains on Parkin’s E3 ubiquitin ligase activity ........................ 34 1.3.2.2 Alteration of protein characteristics by pathogenic mutations .............................. 36 1.3.3 Functions of Parkin .................................................................................................................... 38 1.3.3.1 E3 ubiquitin ligase ................................................................................................. 38 1.3.3.2 Mitochondrial quality control ............................................................................... 45 1.3.3.3 Neuronal protection ............................................................................................. 48 1.3.3.4 Tumour suppression ............................................................................................. 50 1.3.4 Parkin substrates......................................................................................................................... 52 1.3.5 Models for investigating Parkin function ........................................................................ 56 1.3.5.1 Genetic animal models ......................................................................................... 56 1.3.5.2 Cell models ........................................................................................................... 56 1.3.5.3 Parkin-patient derived cell lines as potential models ............................................ 57 1.3.6 Post-translational modification (PTM) of Parkin ........................................................ 57 1.3.6.1 S-nitrosylation....................................................................................................... 57 1.3.6.2 Dopamine modification ........................................................................................ 58 1.3.6.3 SUMOylation ........................................................................................................ 59 1.3.6.4 Neddylation .......................................................................................................... 59 1.3.6.5 Phosphorylation .................................................................................................... 59 1.3.7 Signalling pathways associated with Parkin regulation ........................................... 62 1.3.7.1 Mitogen-activated protein kinase (MAPK) signalling pathways ............................. 62 1.3.7.2 PI3K/Akt signalling pathway .................................................................................. 64 1.3.7.3 NF-κB signalling pathway ...................................................................................... 64 1.4 Objectives of this thesis .............................................................................................
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