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LRRK2 GENETICS and EXPRESSION in the PARKINSONIAN BRAIN Thesis Submitted in Fulfilment of the Degree of Doctor of Philosophy

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LRRK2 GENETICS and EXPRESSION in the PARKINSONIAN BRAIN Thesis Submitted in Fulfilment of the Degree of Doctor of Philosophy LRRK2 GENETICS AND EXPRESSION IN THE PARKINSONIAN BRAIN Thesis submitted in fulfilment of the degree of Doctor of Philosophy 2010 Queen Square Brain Bank, Department of Molecular Neuroscience, Institute of Neurology & Institute of Human Genetics and Health, University College London Simone Sharma Declaration I hereby declare that the work described in this thesis is solely that of the author, unless stated otherwise in the text. None of the work has been submitted for any other qualification at this or any other university. Simone Sharma Abstract Mutations in LRRK2 have been established as a common genetic cause of Parkinson’s disease (PD). Variation in gene expression of PARK loci has previously been demonstrated in PD pathogenesis, although it has not been described in detail for LRRK2 expression in the human brain. This study further elucidates the role of LRRK2 in development of PD by describing an investigation into the role of LRRK2 genetics and expression in the human brain. The G2019S mutation is a common LRRK2 mutation that exhibits a clinical and pathological phenotype indistinguishable from idiopathic PD. Thus, the study of G2019S mutation is a recurrent theme. The frequency of G2019S was estimated in unaffected subjects that lived or shared a cultural heritage to the predicted founding populations of the mutation, and was found not to be common in these populations. Morphological analysis revealed a ubiquitous expression for LRRK2 mRNA and protein in the human brain. In-situ hybridisation data suggests that LRRK2 mRNA is present as a low copy number mRNA in the human brain. A semi-quantitative analysis of LRRK2 immunohistochemistry revealed extensive regional variation in the LRRK2 protein levels, although the weakest immunoreactivity was consistently identified in the nigrostriatal dopamine region. No difference was observed in the morphological localisation of LRRK2 mRNA and protein in unaffected, IPD or G2019S positive PD subjects. Dysregulation of LRRK2 mRNA expression and the effects of cis- acting genetic variation on these levels were demonstrated. A widespread decrease of LRRK2 mRNA was observed in IPD and G2019S positive PD subjects in comparison to unaffected controls. Furthermore, non-coding genetic variation was also demonstrated to have an effect on the LRRK2 transcriptional activity in PD subjects. Collectively, these findings suggest that LRRK2 has an important physiological role, and a dysregulation in its levels could affect auxiliary mechanisms that contribute to PD pathogenesis. This data also supports the possibility of a shared mechanism contributing to the identical phenotype of IPD and G2019S linked PD. Acknowledgements Firstly, I would like to thank the Institute of Human Genetics and Health (IHGH) and my principal supervisor Prof. Nick Wood for giving me the opportunity and support to undertake this project. I am extremely grateful and owe a special thanks to my secondary supervisors, Dr. Janice Holton and Dr. Rina Bandopadhyay for their guidance, constant encouragement, an infinite amount of patience and the much needed strictness that really helped bring this project together. Thanks are given to all the lab colleagues at the Department of Molecular Neuroscience, Queen Square Brain Bank and Reta Lila Weston Institute for their guidance and assistance. I would especially like to thank Drs. Ann Kingsbury and Tammaryn Lashley for teaching me the many joys of the histochemical work. Profs. Tamas Revesz and John Hardy, and Dr. Rohan de Silva have given me some very useful advice over the years and I thank them for that. I am also grateful to Dr. Costas Kallis for advising me on the statistics, and to Drs. Carles Vilarino Guell and Alan Pittman for all their help with the genetics in the early days. I would also like to thank Dr. Patrick Lewis for his critical reading and insightful comments on the final section of this thesis. I am grateful to all the patients and their families, without whom none of this research would have been possible. I would like to thank the IHGH team, especially Prof. Steve Humphries and Dr. Neil Bradman for their support and guidance in the project. The interdisciplinary training gained through IHGH was very helpful in making me appreciate the point view of other disciplines. A special thanks goes to my friends and fellow IHGH PhD students: Alan Renton and Alex Calladine for all the giggles and the debates- be it about housekeeping genes, genetic reductionism or just general existential crisis! I am thankful to Jutta Palmen and Dr. Andrew Smith (Rayne Institute, UCL) for all their assistance, and also to my current colleagues for their patience during the writing procedure. A huge thank you to my mum and dad, and the rest of the family and friends for their understanding, support and for dealing with my whingeing all these years! Lastly, this thesis is dedicated with love to all my grandparents who continue to be a source of great love and inspiration. [2] Table of contents Abstract ........................................................................................................................ 1 Acknowledgements ...................................................................................................... 2 Abbreviations ............................................................................................................ 12 Gene abbreviations ................................................................................................... 16 1 Introduction ....................................................................................................... 18 1.1 Parkinson’s Disease ...................................................................................... 18 1.2 Clinical phenotype ........................................................................................ 18 1.3 Pathological phenotype ................................................................................ 20 1.3.1 Nigral cell loss....................................................................................... 20 1.3.2 Lewy body inclusions ........................................................................... 21 1.3.3 Extra-nigral pathology .......................................................................... 22 1.3.4 Neuropathological stages associated with PD progression ................... 24 1.3.5 PD pathology and autonomic symptoms............................................... 27 1.3.6 Glial cell loss ......................................................................................... 27 1.4 Basal ganglia circuitry .................................................................................. 28 1.5 Disease Aetiology ......................................................................................... 31 1.5.1 Environmental factors ........................................................................... 31 1.5.2 Genetics of PD ...................................................................................... 33 1.6 LRRK2 – a link between familial and idiopathic PD .................................... 51 1.6.1 LRRK2 gene structure and function ...................................................... 52 1.6.2 LRRK2 and neurodegeneration............................................................. 56 1.6.3 LRRK2 G2019S mutation in PD ........................................................... 57 1.7 Objectives and Principal questions addressed in the thesis .......................... 63 2 Methods and Materials ..................................................................................... 66 2.1 QSBB Tissue ................................................................................................ 66 [3] 2.1.1 Paraffin embedded tissue ...................................................................... 66 2.1.2 Frozen tissue ......................................................................................... 67 2.2 Nucleic acid extraction ................................................................................. 67 2.2.1 DNA extraction ..................................................................................... 67 2.2.2 RNA isolation and extraction ................................................................ 68 2.3 Genotyping ................................................................................................... 69 2.3.1 Polymerase chain reaction (PCR) ......................................................... 69 2.3.2 PCR components ................................................................................... 69 2.3.3 Restriction Fragment length polymorphisms ........................................ 70 2.3.4 Agarose gel Electrophoresis .................................................................. 70 2.3.5 Taqman assays ...................................................................................... 71 2.4 PCR based mRNA expression studies .......................................................... 71 2.4.1 Reverse-Transcriptase (RT-PCR) ......................................................... 71 2.4.2 Quantitative real Time PCR (qPCR) ..................................................... 72 2.5 Histochemical techniques ............................................................................. 77 2.5.1 In situ hybridisation protocol ................................................................ 77 2.5.2 Immunohistochemistry .......................................................................... 82 2.6 Western blot and immunoabsorption assay
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