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Analysis of Dehydrogenase-Independent Functions of HSD17B10 in Humans and Animal Models

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Analysis of Dehydrogenase-Independent Functions of HSD17B10 in Humans and Animal Models Analysis of dehydrogenase-independent functions of HSD17B10 in humans and animal models presented by Dipl.-Biol. Katharina Rauschenberger Analysis of dehydrogenase-independent functions of HSD17B10 in humans and animal models Dissertation submitted to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto-Carola University of Heidelberg, Germany for the degree of Doctor of Natural Sciences presented by Dipl.-Biol. Katharina Rauschenberger born in Friedrichshafen, Germany Date of oral examination: 25 February 2011 Analysis of dehydrogenase-independent functions of HSD17B10 in humans and animal models prepared at the Institute of Human Genetics, Heidelberg Division of Developmental Genetics Referees: Prof. Dr. rer. nat. Herbert Steinbeisser Prof. Dr. Dr. med. Johannes Zschocke The following publication originated from this work: Rauschenberger K, Scholer K, Sass JO, Sauer S, Djuric Z, Rumig C, Wolf NI, Okun JG, Kolker S, Schwarz H, Fischer C, Grziwa B, Runz H, Numann A, Shafqat N, Kavanagh KL, Hammerling G, Wanders RJ, Shield JP, Wendel U, Stern D, Nawroth P, Hoffmann GF, Bartram CR, Arnold B, Bierhaus A, Oppermann U, Steinbeisser H, Zschocke J (2010) A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival. EMBO Mol Med 2(2): 51-62 Table of contents 1 SUMMARY ................................................................................................. 1 2 ZUSAMMENFASSUNG ................................................................................ 2 3 INTRODUCTION........................................................................................ 3 3.1. 17β-hydroxysteroid-dehydrogenase type 10 – an evolutionary conserved multifunctional protein ....................................................... 3 3.2. Function of HSD10 in fatty acid metabolism and isoleucine breakdown .......................................................................................... 4 3.3. HSD10 in steroid metabolism .............................................................. 6 3.4. HSD10 deficiency in humans ............................................................... 7 3.5. Implication of HSD10 in Parkinson’s, Alzheimer’s and other clinical symptoms .............................................................................. 10 3.6. HSD10 – cytoprotective or cytotoxic?................................................ 12 3.7. Intrinsic and extrinsic regulation of apoptosis .................................. 13 3.8. HSD10 function in the model organisms Drosophila and mouse................................................................................................ 15 3.9. HSD10 in the development of Xenopus laevis.................................... 17 3.10. Interaction partners of HSD10 .......................................................... 18 3.11. HSD10 as a component of human mitochondrial RNaseP................... 18 3.12. Purpose of this study......................................................................... 22 4 RESULTS ................................................................................................. 23 4.1. Localisation and amount of HSD10 in human cells under various conditions ............................................................................. 23 4.1.1. Mitochondrial localisation of HSD10 in HSD10 deficiency patient fibroblasts ............................................. 23 4.1.2. Mitochondrial and HSD10 content in HSD10 deficiency patient fibroblasts ............................................. 25 4.1.3. HSD10 translocates from the mitochondrial matrix to the membrane under oxidative stress ............................ 26 4.2. Mitochondrial morphology and function after HSD10 loss-of- function ............................................................................................. 28 4.2.1. Mutations D86G and R130C cause severe disruption of mitochondrial morphology.............................................. 28 4.2.2. Mitochondrial disintegration after conditional HSD17B10 knock-out in mice ............................................. 29 4.2.3. HSD10 knock-down in Xenopus impairs mitochondrial integrity....................................................... 32 4.3. Induction of apoptosis after HSD10 gain- and loss-of-function ......... 35 4.3.1. HSD10 gain-of-function in Xenopus induces apoptosis............................................................................ 35 4.3.2. Apoptosis induced by HSD10 gain-of-function is not due to the unfolded protein response ................................. 36 4.3.3. Analysis of the apoptotic pathway induced by HSD10 loss-of-function .................................................................. 38 4.4. HSD10 function and characterisation of mutations under cellular stress conditions................................................................... 43 4.5. Identification of interaction partners of HSD10................................. 47 4.5.1. Homology based BLAST in yeast......................................... 47 4.5.2. Functional interaction of human HSD10 and UXT in vivo .................................................................................... 50 4.5.3. Pull-down/IMAC approach to identify binding partners of HSD10 .............................................................. 52 4.6. Function of HSD10 as a component of human mitochondrial RNaseP .............................................................................................. 59 4.6.1. Accumulation of tRNA precursors after HSD10 loss- of-function.......................................................................... 59 4.6.2. Reconstitution of RNaseP activity using mutated HSD10 after HSD10 loss-of-function................................... 61 4.6.3. RNaseP activity in patient fibroblasts under physiological and oxidative stress conditions..................... 63 4.6.4. Effect of impaired RNaseP activity on mitochondrial translation.......................................................................... 66 4.6.5. RNaseP dependency of apoptosis induced by HSD10 loss-of-function .................................................................. 68 5 DISCUSSION........................................................................................... 73 5.1. A dehydrogenase-independent function of HSD10 is essential for mitochondrial integrity ................................................................ 73 5.2. HSD10 function in apoptosis, RNaseP activity and cellular stress ................................................................................................ 75 5.2.1. HSD10 function in apoptosis............................................... 75 5.2.2. HSD10 function under cellular stress.................................. 77 5.2.3. Function of HSD10 as a component of human mitochondrial RNaseP ........................................................ 79 5.3. Dehydrogenase- and RNaseP-independent function of HSD10 outside of mitochondria? ................................................................... 82 6 MATERIALS............................................................................................. 87 6.1. Chemicals .......................................................................................... 87 6.2. Buffers, solutions and cell culture media........................................... 89 6.3. Equipment ......................................................................................... 91 6.4. Kits.................................................................................................... 92 6.5. Enzymes, proteins and markers......................................................... 93 6.6. Oligonucleotides................................................................................ 94 6.7. Plasmids............................................................................................ 96 6.8. Bacteria ............................................................................................. 96 6.9. Cell lines............................................................................................ 96 6.10. Animals ............................................................................................. 97 6.11. Software............................................................................................ 97 6.12. Online databases ............................................................................... 97 7 METHODS ............................................................................................... 99 7.1. Embryological methods ..................................................................... 99 7.1.1. Embryo culture and microinjection..................................... 99 7.1.2. TUNEL assay (Terminale deoxynucleotidyl transferase-mediated dUTP digoxygenin nick end labelling) ............................................................................ 99 7.1.3. Tissue preparation from mice ........................................... 100 7.2. Molecular biology ............................................................................ 101 7.2.1. Isolation of DNA (midiprep) ............................................. 101 7.2.2. Isolation of RNA ............................................................... 101 7.2.3. Phenol-chloroform purification of nucleic acids................ 101 7.2.4. Precipitation of nucleic acids ............................................ 102 7.2.5. Concentration and quality of nucleic acids.......................
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