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Analyzing the Function of TRAP1 in Models of Parkinson's Disease

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Analyzing the Function of TRAP1 in Models of Parkinson's Disease Analyzing the function of TRAP1 in models of Parkinson’s disease Von der Fakultät für Mathematik, Informatik und Naturwissenschaften der RWTH Aachen University zur Erlangung des akademischen Grades einer Doktorin der Naturwissenschaften genehmigte Dissertation vorgelegt von Li Zhang aus Changchun, Jilin (China) Berichter: Universitätsprofessor Dr. med. Jörg B. Schulz Universitätsprofessor Dr. rer. nat. Marc Spehr Tag der mündlichen Prüfung: 29.01.2016 Diese Dissertation ist auf den Internetseiten der Universitätsbibliothek online verfügbar. Eidesstattliche Versicherung ___________________________Zhang, Li ___________________________ Name, Vorname Matrikelnummer (freiwillige Angabe) Ich versichere hiermit an Eides Statt, dass ich die vorliegende Arbeit/Bachelorarbeit/ Masterarbeit* mit dem Titel __________________________________________________________________________Analyzing the function of TRAP1 in models of Parkinson’s disease __________________________________________________________________________Uebersetzung: Analyse der TRAP1-Funktion in Modellen fuer Morbus Parkinson __________________________________________________________________________ selbständig und ohne unzulässige fremde Hilfe erbracht habe. Ich habe keine anderen als die angegebenen Quellen und Hilfsmittel benutzt. Für den Fall, dass die Arbeit zusätzlich auf einem Datenträger eingereicht wird, erkläre ich, dass die schriftliche und die elektronische Form vollständig übereinstimmen. Die Arbeit hat in gleicher oder ähnlicher Form noch keiner Prüfungsbehörde vorgelegen. ___________________________Aachen, 17.12.2015 ___________________________ Ort, Datum Unterschrift *Nichtzutreffendes bitte streichen Belehrung: § 156 StGB: Falsche Versicherung an Eides Statt Wer vor einer zur Abnahme einer Versicherung an Eides Statt zuständigen Behörde eine solche Versicherung falsch abgibt oder unter Berufung auf eine solche Versicherung falsch aussagt, wird mit Freiheitsstrafe bis zu drei Jahren oder mit Geldstrafe bestraft. § 161 StGB: Fahrlässiger Falscheid; fahrlässige falsche Versicherung an Eides Statt (1) Wenn eine der in den §§ 154 bis 156 bezeichneten Handlungen aus Fahrlässigkeit begangen worden ist, so tritt Freiheitsstrafe bis zu einem Jahr oder Geldstrafe ein. (2) Straflosigkeit tritt ein, wenn der Täter die falsche Angabe rechtzeitig berichtigt. Die Vorschriften des § 158 Abs. 2 und 3 gelten entsprechend. Die vorstehende Belehrung habe ich zur Kenntnis genommen: ___________________________Aachen, 17.12.2015 ___________________________ Ort, Datum Unterschrift Members of the Thesis Committee Supervisor Univ.-Prof. Dr. med. Jörg B. Schulz Department of Neurology University Medical Center, RWTH Aachen University Pauwelsstrasse 30 52074 Aachen Second member of the Thesis Committee Univ.-Prof. Dr. rer. nat. Marc Spehr Institut für Biologie II, Zoologie Department of Biology, RWTH Aachen University Worringerweg 3 52074 Aachen Third member of the Thesis Committee Univ.-Prof. Dr. rer. nat. Bernhard Lüscher Institut für Biochemie und Molekularbiologie, Medizinische Fakultät University Medical Center, RWTH Aachen University Pauwelsstrasse 30 52074 Aachen Date of Disputation: i List of Publications Parts of this work have already been published with authorisation of Prof. Jörg B. Schulz, Head of the Department of Neurology, University Medical Centre of the RWTH Aachen University, on behalf of the thesis committee. Oral presentation. Trap1, a new player in Parkinson’s disease. Regional Drosophila Meeting 2014 Heidelberg, Germany (05. 2014) Zhang L, Karsten P, Hamm S, Pogson JH, Müller-Rischart AK, Exner N, Haass C, Whitworth AJ, Winklhofer KF, Schulz JB, Voigt A. TRAP1 rescues PINK1 loss-of-function phenotypes. Hum Mol Genet. 2013 Jul 15;22(14):2829-2841. DOI: 10.1093/hmg/ddt132 Poster Presentation. Trap1 rescues Pink1 loss-of-function phenotypes. ISN-ASN Meeting 2013 Cancun, Mexico (04. 2013) Oral presentation. A chaperone protein TRAP1 rescues Pink1 loss-of-function phenotypes and mitochondrial dysfunction in vivo. Regional Drosophila Meeting 2012 Osnabrück, Germany (10. 2012) Poster Presentation. Trap1 mitigates α-Synuclein-induced toxicity and rescues Pink1 loss- of-function phenotypes in vivo. 8th FENS Forum of Neuroscience Barcelona, Spain (07. 2012) ii Acknowledgements Hereby I would like to express my sincere and deepest gratitude, To Prof. Jörg B. Schulz, for offering me the position at the first place, for giving me great opportunities in scientific domain and broadening my mind as an international researcher, for always providing critical suggestions for the direction of the projects, and last but not least, being an excellent role model himself. To Prof. Marc Spehr and Prof. Bernhard Lüscher, for being members in my doctoral thesis committee, for the splendid suggestions from their professional point of views which expands the horizons of my projects, for their patience and precious time. To Dr. Aaron Voigt, for being a great advisor as well as a very supportive friend, for being so generous and unreserved to spread his knowledge and exchange his valuable ideas, for his kindness to care about not only the scientific projects but also my personal career blueprint, for inspiring me for the scientific questions and offering me a friendly working and studying atmosphere. To Prof. Björn Falkenburg, Dr. Peter Karsten, Dr. Hannes Voßfeldt, Dr. Malte Butzlaff, Dr. Katja Pr in , Jane Patricia Tögel, Kavita Kaur, Dr. Theodora Saridaki and Dr. Barbara Stopschinski for showing me the experiments patiently, for sharing their scientific opinions. To Sabine Hamm and Anne Lankes, for technique supporting and their kindness. To Natalie Alexandra Burdiek-Reinhard, for always being so nice, for her considerable thoughts, and her help. To Antje Hofmeister, Xia Pan, Sarah Lenz, Stefan Esser, Daniel Komnig, Anna Hilverling, Athanasios Tarampanis, Maria Ingenerf, Simon Stilling, Larissa Kaltenhäuser, Elisabeth Dinter, Markus Nippold, Julie Schmidt-Tiedemann, and other students, for being such wonderful companion, for being so amazing and caring friends, and for the lovely times spending together. To Alexander J. Withworth and Konstanze F. Winklhofer for the cooperation, and Bundesministerium für Bildung und Forschung (Nationales Genomforschungsnetz (NGFN+) and the Kompetenznetz Degenerative Demenzen (KNDD) for financial support. Finally, to the ones who love me, only with their unconditional love, I live. iii Table of contents LIST OF PUBLICATIONS ................................................................................................................................................... II ACKNOWLEDGEMENTS ................................................................................................................................................. III LIST OF FIGURES ............................................................................................................................................................... VI LIST OF TABLES .............................................................................................................................................................. VII LIST OF ABBREVIATIONS ........................................................................................................................................... VIII ABSTRACT ............................................................................................................................................................................ X 1 INTRODUCTION .............................................................................................................................................................. 1 1.1 OVERVIEW OF PARKINSON S DISEASE .......................................................................................................................................... 1 1.2 PATHOLOGICAL HALLMARKS ......................................................................................................................................................... 1 1.3 GENETICS OF PD .............................................................................................................................................................................’ 3 1.3.1 Autosomal dominant PD-causal gene, SNCA .......................................................................................................... 4 1.3.2 Autosomal recessive PD-causal gene, parkin ......................................................................................................... 5 1.3.3 Autosomal recessive PD-causal gene, Pink1 ........................................................................................................... 5 1.4 MITOCHONDRIAL DYSFUNCTION THEORY ................................................................................................................................... 8 1.5 A MODIFIER OF -SYN-INDUCED TOXICITY, TRAP1 ................................................................................................................... 9 1.6 AIM OF STUDY ............................................................................................................................................................................... 10 Α 2 MATERIAL AND METHODS ....................................................................................................................................... 12 2.1 ORGANISM ....................................................................................................................................................................................
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