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Pathogenic Mutation of Lrrk2 – a Mouse Model for Pre-Motor Parkinson’S Disease

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Pathogenic Mutation of Lrrk2 – a Mouse Model for Pre-Motor Parkinson’S Disease Technische Universität München Lehrstuhl für Entwicklungsgenetik Pathogenic Mutation of Lrrk2 – a mouse model for pre-motor Parkinson’s disease Florian H. H. Giesert Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. K. Schneitz Prüfer der Dissertation: 1. Univ.-Prof. Dr. W. Wurst 2. Univ.-Prof. Dr. A. Kapurniotu Die Dissertation wurde am 24.10.2011 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 27.02.2012 angenommen. _____________________________________________ Table of contents 1 Table of contents 1 TABLE OF CONTENTS ............................................................................ I 2 ABSTRACT / ZUSAMMENFASSUNG ..................................................... 1 3 INTRODUCTION ...................................................................................... 4 3.1 Parkinson’s Disease ................................................................................................... 4 3.1.1 The characteristics of Parkinson’s Disease ............................................................. 4 3.1.2 The basal ganglia circuit .......................................................................................... 5 3.2 The genetic aspects of Parkinson’s Disease ........................................................... 9 3.3 Common pathways in Parkinson’s disease ........................................................... 11 3.4 PARK8: Lrrk2 – the Leucine-rich repeat kinase 2 ................................................. 12 3.4.1 The structure of the Lrrk2 gene and its protein ...................................................... 13 3.4.2 The genetic basis of Lrrk2-linked PD ..................................................................... 17 3.4.3 What is known about the function of LRRK2? ....................................................... 20 3.5 Mouse models for Parkinson’s Disease ................................................................. 22 3.5.1 Genetic rodent models of PD ................................................................................. 23 3.5.2 Mouse models of LRRK2-linked PD....................................................................... 24 4 AIM OF THE STUDY .............................................................................. 27 5 RESULTS ............................................................................................... 28 5.1 Comparative Expression Analysis of Lrrk1 and Lrrk2 ......................................... 28 5.1.1 Expression during embryonic development ........................................................... 28 5.1.2 Expression in the postnatal and adult brain ........................................................... 33 5.1.3 LRRK2 protein expression in the adult CNS .......................................................... 37 5.1.4 Lrrk2-expressing neuronal subtypes in the striatum .............................................. 40 5.2 Generation of the Lrrk2 R1441C knock-in mouse line .......................................... 41 5.2.1 The Lrrk2 R1441C knock-in targeting strategy ...................................................... 42 5.2.2 Generation of Lrrk2 R1441C transgenic ES cells .................................................. 43 5.2.3 Generation of the Lrrk2 R1441C knock-in mouse line ........................................... 45 5.3 The Lrrk2 knockdown mouse line .......................................................................... 46 5.4 Functional analysis of the Leucine-rich repeat kinase 2 ...................................... 48 5.4.1 Analysis of Lrrk2 R1441C mouse embryonic fibroblasts ....................................... 48 5.4.2 The cytoskeleton in Lrrk2 R1441C cells................................................................. 50 5.4.2.1 Basal stability of the cytoskeleton network .................................................... 51 5.4.2.2 Neurite outgrowth in R1441C neurons .......................................................... 52 5.4.2.3 Tubulin hyperacetylation in R1441C neurons can be further enhanced by HDAC-6 inhibition .......................................................................................... 60 5.4.2.4 LRRK2 and the cold-stability of the microtubular network ............................ 62 I _____________________________________________ Table of contents 5.4.3 LRRK2 function at the synapse .............................................................................. 64 5.4.3.1 LRRK2 protein colocalizes with NSF in synaptosomes ................................ 64 5.4.3.2 Synaptic function: Exocytosis and endocytosis cycles in R1441C neurons . 66 5.5 The morphological analysis of the Lrrk2 R1441C line .......................................... 69 5.5.1 The development of the CNS in Lrrk2 R1441C mice ............................................. 69 5.5.2 Pathology of mid-aged Lrrk2 R1441C mice ........................................................... 71 5.5.3 Pathology of fully aged Lrrk2 R1441C mice ........................................................... 73 5.6 Behavioural analysis ................................................................................................ 76 5.6.1 Analysis of young Lrrk2 R1441C and Lrrk2 knockdown mice ............................... 76 5.6.1.1 Motor behaviour of the Lrrk2 mouse lines ..................................................... 77 5.6.1.2 Cognition and memory in the Lrrk2 mouse lines ........................................... 79 5.6.1.3 Depression- and anxiety-like behaviour ........................................................ 81 5.6.2 Odour discrimination in aged Lrrk2 R1441C and Lrrk2 knockdown mice .............. 84 5.6.3 Gait analysis of aged Lrrk2 R1441C and Lrrk2 knockdown mice .......................... 87 6 DISCUSSION ......................................................................................... 91 6.1 Analysis of Lrrk1 and Lrrk2 expression ................................................................. 91 6.1.1 Expression during embryogenesis ......................................................................... 91 6.1.2 Lrrk2 mRNA expression in the adult CNS .............................................................. 93 6.1.3 LRRK2 protein expression in the adult CNS .......................................................... 96 6.1.4 Lrrk2 expression in the adult striatum .................................................................... 98 6.2 Generation of the Lrrk2 R1441C knock-in mouse model ................................... 101 6.3 Functional analysis ................................................................................................ 102 6.4 Dopaminergic system, histological analysis ....................................................... 112 6.5 Behavioural analysis .............................................................................................. 115 6.6 Concluding remarks ............................................................................................... 122 7 MATERIALS AND METHODS ............................................................. 125 7.1 Materials .................................................................................................................. 125 7.1.1 Chemicals ............................................................................................................. 125 7.1.2 Enzymes ............................................................................................................... 128 7.1.3 Commercial kits .................................................................................................... 128 7.1.4 Solutions ............................................................................................................... 129 7.1.5 Instrumentation ..................................................................................................... 133 7.1.6 Antibodies ............................................................................................................. 135 7.2 Methods ................................................................................................................... 136 7.2.1 Methods in Molecular biology ............................................................................... 136 7.2.1.1 General methods working with DNA ........................................................... 136 7.2.1.2 General methods working with RNA ........................................................... 138 7.2.1.3 General methods working with bacteria ...................................................... 139 7.2.1.4 The polymerase chain reaction ................................................................... 139 7.2.1.5 Southern blot analysis ................................................................................. 142 7.2.1.6 Western blot analysis .................................................................................. 144 7.2.1.7 Protein fractionation ..................................................................................... 146 7.2.1.8 HPLC analysis ............................................................................................. 148 7.2.2 Histological methods ...........................................................................................
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