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Characterization of Ataxin-2 and Its Interaction Partners

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Characterization of Ataxin-2 and Its Interaction Partners CHARACTERIZATION OF ATAXIN-2 AND ITS INTERACTION PARTNERS DISSERTATION ZUR ERLANGUNG DES DOKTORGRADES DER NATURWISSENSCHAFTEN VORGELEGT BEIM FACHBEREICH BIOWISSENSCHAFTEN DER JOHANN WOLFGANG GOETHE -UNIVERSITÄT IN FRANKFURT AM MAIN VON MELANIE VANESSA HALBACH (GEB. HECK) AUS KARLSRUHE FRANKFURT AM MAIN, 2015 (D30) Vom Fachbereich Biowissenschaften (15) der Johann Wolfgang Goethe - Universität als Dissertation angenommen. Dekanin: Prof. Dr. rer. nat. Meike Piepenbring Gutachter: Prof. Dr. rer. nat. Anna Starzinski-Powitz Prof. Dr. med. Georg Auburger Datum der Disputation: Table of contents 1 Introduction .................................................................................................... 1 1.1 Cerebellum: the movement coordination system .................................................. 1 1.2 Structure and connectivity of the cerebellum ........................................................ 1 1.3 Cerebellar ataxias and their classification ............................................................. 3 1.3.1 Autosomal dominant cerebellar ataxias ..................................................................... 5 1.3.2 Spinocerebellar ataxias .............................................................................................. 6 1.3.3 Trinucleotide repeat expansion disorders .................................................................. 8 1.3.4 Pathomechanism of polyglutamine disorders ............................................................ 9 1.3.4.1 The question of gain- or loss-of-function ....................................................................... 10 1.3.4.2 Involvement of the ubiquitin-proteasome system and autophagy .................................. 11 1.3.4.3 Disturbances in calcium homeostasis ............................................................................ 13 1.3.4.4 Altered RNA metabolism ............................................................................................... 14 1.3.4.5 Other mechanisms implicated in polyQ pathology ......................................................... 14 1.3.5 Spinocerebellar ataxia type 2 ................................................................................... 15 1.3.6 Therapy of Spinocerebellar ataxia type 2 ................................................................. 16 1.4 Ataxin-2 ............................................................................................................... 17 1.4.1 The Ataxin-2 gene and its protein ATXN2 ................................................................ 17 1.4.2 The function of ATXN2 ............................................................................................. 19 1.4.2.1 ATXN2 function in mRNA translation and splicing ......................................................... 19 1.4.2.2 ATXN2 participation in stress response ......................................................................... 21 1.4.2.3 Other functions of ATXN2 .............................................................................................. 22 1.4.3 Involvement of ATXN2 in other neurodegenerative diseases .................................. 23 1.4.3.1 Role of ATXN2 in ALS ................................................................................................... 23 1.4.3.2 Involvement of ATXN2 in SCA1 and SCA3 ................................................................... 26 1.5 Mouse models ..................................................................................................... 27 1.5.1 ATXN2 mouse models .............................................................................................. 28 1.5.2 ATXN1 mouse models .............................................................................................. 29 1.5.3 TDP43 mouse models .............................................................................................. 29 1.6 Aim of the thesis ................................................................................................. 31 2 Material and Methods .................................................................................. 33 2.1 Material ............................................................................................................... 33 2.1.1 General equipment and chemicals ........................................................................... 33 2.1.2 Mouse models .......................................................................................................... 36 2.1.3 Equipment used for behavioral studies, perfusion, and dissection .......................... 36 2.1.4 Blood samples .......................................................................................................... 37 2.1.5 Cell lines ................................................................................................................... 38 2.1.6 Equipment and reagents used in cell culture ........................................................... 38 2.1.7 Vector constructs and competent cells ..................................................................... 39 2.1.8 Equipment and reagents used for cloning ................................................................ 40 2.1.9 Equipment and reagents used for DNA isolation, PCR, and agarose gel electrophoresis ........................................................................................................ 41 2.1.10 Oligonucleotide primer.............................................................................................. 42 2.1.11 Equipment and Reagents used for RNA isolation, cDNA synthesis, and RT- qPCR ....................................................................................................................... 42 2.1.12 TaqMan® assays...................................................................................................... 43 2.1.13 Equipment and reagents used for protein isolation, Western Blot and co- immunoprecipitation ................................................................................................ 44 2.1.14 Equipment and reagents used for immunocyto- and immunohistochemistry .......... 45 2.1.15 Antibodies ................................................................................................................. 46 2.1.15.1 Primary antibodies ......................................................................................................... 46 2.1.15.2 Secondary antibodies .................................................................................................... 47 2.1.16 Buffers and Solutions ............................................................................................... 47 2.1.16.1 Perfusion ....................................................................................................................... 47 2.1.16.2 Transformation .............................................................................................................. 48 2.1.16.3 DNA extraction .............................................................................................................. 48 2.1.16.4 Genotyping .................................................................................................................... 49 2.1.16.5 Agarose gel electrophoresis .......................................................................................... 49 2.1.16.6 Protein isolation ............................................................................................................. 49 2.1.16.7 Co-immunoprecipitation ................................................................................................. 50 2.1.16.8 SDS-PAGE .................................................................................................................... 50 2.1.16.9 Western Blot .................................................................................................................. 51 2.1.16.10 Immunohistochemistry ................................................................................................... 52 2.1.17 Software and online databases ................................................................................ 52 2.2 Methods .............................................................................................................. 53 2.2.1 Mouse models .......................................................................................................... 53 2.2.1.1 Generation of Atxn2-CAG42-KIN / hTDP43-A315T-KIN double mutants ...................... 53 2.2.1.2 Generation of Atxn2-CAG100-KIN mice ........................................................................ 53 2.2.1.3 Animal housing and breeding ........................................................................................ 57 2.2.2 Phenotype analyses ................................................................................................. 58 2.2.2.1 Body and brain weight ................................................................................................... 58 2.2.2.2 Survival curve ................................................................................................................ 58 2.2.2.3 Rotarod .......................................................................................................................... 58 2.2.2.4 Open field ...................................................................................................................... 59 2.2.2.5 Clasping .......................................................................................................................
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