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'Study of the Transcriptional Regulation of Α-Synuclein' National and Kapodistrian University of Athens School of Health Sciences Faculty of Medicine Thesis for doctoral degree (Ph.D) ‘Study of the transcriptional regulation of α-synuclein’ Georgia Dermentzaki, MSc Biomedical Research Foundation Academy of Athens Center for Neuroscience September 2015 This research has been co-financed by the European Union (European Social Fund – ESF) and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program: Heracleitus II. Investing in knowledge society through the European Social Fund. ‘Transcriptional regulation of α-synuclein in primary neurons and in vivo; focus on the ZSCAN21 transcription factor’ 1 Supervisor Stefanis Leonidas, M.D., Ph.D Professor of Neurology and Neurobiology Faculty of Medicine, University of Athens Advisory Committee 1. Stefanis Leonidas, M.D., Ph.D Professor of Neurology and Neurobiology Faculty of Medicine, University of Athens 2. Thanos Dimitrios, Ph.D Professor, President of the Scientific Board Biomedical Research Foundation of the Academy of Athens 3. Stamboulis Elefterios, M.D., Ph.D Professor of Neurology Faculty of Medicine, University of Athens Examination Committee 1. Stefanis Leonidas, M.D., Ph.D Professor of Neurology and Neurobiology Faculty of Medicine, University of Athens 2. Thanos Dimitrios, Ph.D Professor, President of the Scientific Board Biomedical Research Foundation of the Academy of Athens 3. Stamboulis Elefterios, M.D., Ph.D Professor of Neurology, Faculty of Medicine, University of Athens 4. Politis Panagiotis, Ph.D Assistant Professor - Level C Biomedical Research Foundation of the Academy of Athens 5. Poul Henning Jensen, M.D., Ph.D, Professor of Medical Biochemistry Aarhus University, Denmark 6. Efthimiopoulos Spyros, Ph.D Professor of Physiology and Neurobiology Faculty of Biology, University of Athens 7. Papazafiri Panagiota, Ph.D Associate Professor of Physiology Faculty of Biology, University of Athens 2 THE HIPPOCRATIC OATH “I swear by Apollo the physician, and Asclepius, and Hygieia and Panacea and all the gods and goddesses as my witnesses, that, according to my ability and judgement, I will keep this Oath and this contract: To hold him who taught me this art equally dear to me as my parents, to be a partner in life with him, and to fulfill his needs when required; to look upon his offspring as equals to my own siblings, and to teach them this art, if they shall wish to learn it, without fee or contract; and that by the set rules, lectures, and every other mode of instruction, I will impart a knowledge of the art to my own sons, and those of my teachers, and to students bound by this contract and having sworn this Oath to the law of medicine, but to no others. I will use those dietary regimens which will benefit my patients according to my greatest ability and judgement, and I will do no harm or injustice to them. I will not give a lethal drug to anyone if I am asked, nor will I advise such a plan; and similarly I will not give a woman a pessary to cause an abortion. In purity and according to divine law will I carry out my life and my art. I will not use the knife, even upon those suffering from stones, but I will leave this to those who are trained in this craft. Into whatever homes I go, I will enter them for the benefit of the sick, avoiding any voluntary act of impropriety or corruption, including the seduction of women or men, whether they are free men or slaves. Whatever I see or hear in the lives of my patients, whether in connection with my professional practice or not, which ought not to be spoken of outside, I will keep secret, as considering all such things to be private. So long as I maintain this Oath faithfully and without corruption, may it be granted to me to partake of life fully and the practice of my art, gaining the respect of all men for all time. However, should I transgress this Oath and violate it, may the opposite be my fate.” Translation by National Library of Medicine, USA, 2002 3 ACKNOWLEDGEMENTS First and foremost I would like to express my sincerest gratitude to my supervisor, Professor Leonidas Stefanis, who has supported me throughout not only my Ph.D but also throughout my undergraduate and master study with his excellent knowledge and guidance. Literally, he is one of the most hard-working professors I know, full of enthusiasm and new ideas regarding a project. I had the opportunity close to him to be involved in many projects, publications and also to attend many outstanding conferences. I gained through him important knowledge on how to prepare successful presentations and how to write scientific articles. Importantly, I had the opportunity to learn and apply so many different techniques that I feel quite secure for my next step as a post-doctoral fellow. This dissertation, as well as all the achievements I obtained would not have been possible without his help, encouragement and of course persistence. My choice of pursuing a post-doctoral position after my Ph.D is to a great extent inspired by his passion and integrity in science. Secondly, I would like to especially thank Dr. Lee Clough, my co-supervisor during my master thesis but most important friend who taught me (his Jedi / little star) how to master molecular biology techniques. I was extremely fortunate to have his as my mentor. A side effect from this collaboration was the black humor/sarcasm (innate to English people, I guess) he managed to somehow infect in me. At this point, I must mention that my Ph.D study is a continuation of Dr. Lee Clough’s work, which unveiled the importance of the intron 1 region of SNCA in its transcriptional regulation, and identified the importance of the ZSCAN21 transcription factor, with which (ZSCAN21) I got ultimately involved in a complicated long-lasting torturous relationship. I would like to show my gratitude to my committee members: Professor Dimitris Thanos, Professor Eleftherios Stamboulis, Professor Poul Henning Jensen, Assistant- Professor Panagiotis Politis, Professor Spyros Efthimiopoulos, Associate-Professor Panagiota Papazafiri, I really appreciate the time and effort they put into reading and commenting on my work. My special thanks to Dr. Panagiotis Politis, who substantially helped me throughout my project with his expertise regarding many molecular assays as well as his extremely helpful suggestions. He was always there to answer my questions and help in troubleshooting, when I was storming in his lab without leaving him the option to say no. I would like to acknowledge other people’s substantial participation in this work. Importantly, Dr. Maria Xilouri, a stunning scientist, who took the time to explain to me all the viruses-involving protocols and trained me to perform stereotactic surgeries in vivo. However mostly, I would like to thank her for her advice, support, and being my friend all this time and especially in Ph.D-involved crises. Dr. Nikos Paschalidis for his significant contribution in the setting and application of the sorting assay. My student Dimitra Mazaraki for her involvement in constructing and producing the AV viruses as well as student Martina Kamaratou for her patience to show us the protocols. I would also like to thank for the advice, sharing ideas as well as reagents, and of course troubleshooting upon experimental assays Dr. Evangelia Emmanouilidou aka Lilian, we shared many stories regarding our mothers, Dr. Hardy Rideout for his advice in 4 molecular-based assays and importantly for helping me with my post-doc position at Columbia, Dr. Kostas Vekrellis for all the laughter, Dr. Matina Maniati thanks for all the orders and especially the cakes, Dr. Thanasis Stavropoulos, two words: molecular expert, Dr. Ioanna Galani for her help in handling small quantity RNA samples, Dr. Apostolos Klinakis for his help in the 3'RACE assay, Thanasis Stergiopoulos for his help in clonings, in stainings, for protocols and much troubleshooting, Dafni Antoniou my SOS response when we ran out of reagents in the lab and for showing me the neurosphere culture assay, Myrto Rizou for the CHIP assay and Giorgos Divolis for his guidance in the luciferase assay. Importantly, I would like to thank all the lab members present and alumni for giving an extra glitter over all these years. Certainly, will be no exaggeration to say that this lab feels like a family to me (a having many members family). And by name, first I would like to thank my beloved friend Dr. Alexia Polissidis (Queen / mother of the most adorable twins) for many reasons but mostly for being one of the most (if not the most) enthusiastic and optimistic person I have ever met that has this special gift of spreading positive energy and making you feel that everything will work out. My labmate Katerina Melachroinou for all the things we shared so many years (anxieties, delights, secrets, rooms in conferences and so many more). Mantia Karampetsou, the pay attention to detail- close to be Ph.D / friend for all the talks and troubleshooting late at night at the institute, and my companion on weekends. Maria Keramioti (code name: Titsa) for all the inspired conversations with members of the lab (especially Oystein Brekk) and also for being a good friend, the charming Giovanna Arianoglou for all the books she gave me to read and mostly for introducing me to the world of Jo Nesbo, our doctor Georgia Nikolopoulou, the quiet power of the lab and a very good friend, the mystifying Vasia Sykioti again my companion on weekends, Anna Memou the other quite power of the lab (I am sure that the virus will work in the end), the marathon runner and gaming master Oystein Brekk (refined movements with RNA), the adorable (even though she will hate me for calling her that way) Manuela Leandrou, our other doctor Nikos Papagianakis (or moving library) for his valuable help in computer-based situations, statistical analysis and of course his mother’s cakes and the intellectual / alternative (doctor again)Vasilis Papadopoulos.
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