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Genetic Analysis of Multiple System Atrophy and Related Movement Disorders

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Genetic analysis of multiple system atrophy and related movement disorders Thesis submitted for the degree of Doctor of Philosophy (PhD) by Lucia Valentina Schottlaender Supervisors Prof Henry Houlden, Prof Andrew Lees and Dr Conceição Bettencourt UCL, Institute of Neurology 2018 1 DECLARATION OF AUTHORSHIP I, Lucia Valentina Schottlaender, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, or others have contributed, I confirm this has been indicated in the thesis. 2 ABSTRACT The understanding of the pathophysiology of most neurodegenerative movement disorders has been elusive. Such is the case of multiple system atrophy (MSA) and primary familial brain calcification (PFBC). In this thesis I used a range of genetic techonologies and functional strategies to unravel the genetic basis of MSA and PFBC. First, I describe the work performed in MSA and related atypical movement disorders initially by investigating candidate genes. My key findings were: i) begative results when attempting to replicate the association between COQ2 and the risk of MSA, by Sanger sequencing the largest pathologically confirmed MSA cohort the largest pathologically confirmed MSA cohort; ii) reduced levels of Coenzyme Q10 (CoQ10) in the cerebellum of MSA patients with a cerebellar or mixed MSA subtypes when compared to normal controls and other neurodegenerative movement disorders, when I measured the levels in post- mortem brain tissue of MSA and other patients and controls by high performance liquid chromatography (HPLC); iii) identification of three C9orf72 repeat expansions and one intermediate expansion in patients presenting with a corticobasal and progressive supranuclear palsy syndrome, and confirmation of the absence of the expansion in pathologically proven MSA, corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP); iv) identification of a LRRK2 protective variant in MSA by case control analysis of genotyping of LRRK2 candidate variants. Second, I detail my work applying next generation sequencing techonologies (i.e. whole exome sequencing (WES)) to the study of genetic risk factors in MSA: i) Initially I analysed a definite MSA family and ii) later I performed the largest WES study so far in sporadic MSA. This study included 450 cases out of which 298 were 3 pathologically confirmed. These data were first investigated for candidate genes linked to MSA, other synucleinopathies and related neurodegenerative disorders, and later by peforming a case control association study for common and rare variants. The results of this work where not able to replicate previous findings that linked MSA to COQ2 or SNCA, notwidstanding it revealed interesting candidates that require follow up. Third, I studied genetically patients with PFBC. My key findings were: i) a pathogenic SLC20A2 mutation segregating with the disease in an interesting family, found by investigating recently discovered candidate genes I identified by Sanger sequencing; ii) I detail how I studied two independent primary brain calcification consanguineous families by means of homozygosity mapping and WES. I was able to identify a homozygous nonsense mutation segregating with the disease in both families in JAM2, a gene encoding the Junction adhesion molecule 2, a tight junction protein. This is a novel gene previously unreported as a cause of human disease. Through collaborations with other scientists, I showed the absence of the expression of the JAM2 protein in a fibroblast cell line of a homozygous patient compared to a heterozygous carrier and 2 independent controls. Aditionally we studied a knock out JAM-b (ortolog of human JAM2) mouse model and showed gait abnormalities and abnormal brain histopathology. In conclusion, by applying genetic technologies and related methods, I generated important insights into the CoQ10 pathway in MSA, I generated the largest dataset of WES in MSA and I discovered a new gene for PFBC. My findings are discussed inlight of the recent literature and future directions of research into each subject. 4 ACKNOWLEDGEMENTS I am extremely thankful to my primary supervisor, Prof Henry Houlden, for having given me the opportunity of working in the neurogenetics lab at such an exciting time for this field. Prof Henry Houlden patiently supported me during all these years and has always been an excellent mentor encouraging my work with new ideas. I am grateful to my secondary supervisor Prof Andrew Lees for giving me the opportunity of coming to London in the first place and being a great teacher in clinic. I am also very grateful to my third supervisor and friend, Dr Conceição Bettencourt, for her constant teaching, support and advice in the lab. I would also like to thank Prof John Hardy and Prof Nicholas Wood, the heads of the department of molecular neuroscience, for accepting me to work in the department and for both always being inspirational scientists giving me important advice and support on my projects. I want to specially thank Dr Ricardo Reisin for his collaborative efforts and especially for his permanent understanding and support. I would like to thank Dr Marcelo Merello for introducing me to Professor Lees several years ago. I would also like to thank Dr Chris Turner for his advice before I started my PhD. I would also like to mention my fellow colleagues in the lab: Dr Anna Sailer, Dr Niccolo Mencacci, Dr Josh Hersheson, Dr Sarah Wiethoff, Miss Debbie Hughes, Dr Alan Pittman, Mr Mark Gaskins, Mr Hallgeir Jonvick, Dr Lee Stanyer, Dr Jana Vandrovcova, Dr Sarah Morgan, Dr Viorica Chelban, Miss Stephanie Efthymiou, Dr Iain Hargreaves, Dr David Lynch, Dr Arianna Tucci, Dr Boniface Mok, Dr Rosella Abeti, Dr Paola Giunti, Dr Zane Jaunmuktane. I would also like to thank my colleagues from the queen square brain bank: Dr Aoife Kiely, Dr Sandrine Wauters and Prof Janice Holton. And also, Prof Lees team of fellows: Dr Laura Silveira Moriyama, Dr Helen Ling, Dr Atbin Djamshidian-Tehrani, Dr Karen Doherty. I am also grateful to the colleagues in the NIH that received me in their lab and collaborated during these years: Dr Andy Singleton, Dr Monia Ben-Hamad Hammer, Dr Celeste Sassi, Dr Monica Federoff, Dr Dena Hernandez, Dr Raphael Gibbs, Dr Bryan Traynor, Dr Sonja Scholz. 5 I would also like to thank my supervisors Prof Muntoni and Dr Mariacristina Scoto and the team at the Dubowitz neuromuscular centre for their support while I was writing up my thesis. This thesis is dedicated to my children Fermin and Paz who were both born during my PhD years. They are a permanent source of happiness and joy. I would like to specially thank my husband Cristian who has walked with me through this journey. Cristian gave be boundless support at all times. I would like to thank my parents for teaching me that education is and should always be a top priority. No matter what I choose or what I do, I will always work responsibly and gratefully for the opportunity that I have been given. And last but not least, I would like to acknowledge and thank all patients and their families for participating in research and being so collaborative and generous. I hope that my small contribution to the field will help in the understanding of the diseases studied and this eventually improves the treatments offered to patients. 6 TABLE OF CONTENTS DECLARATION OF AUTHORSHIP ....................................................................................... 2 ABSTRACT ........................................................................................................................ 3 ACKNOWLEDGEMENTS .................................................................................................... 5 TABLE OF CONTENTS ........................................................................................................ 7 LIST OF FIGURES ............................................................................................................. 15 LIST OF TABLES ............................................................................................................... 21 LIST OF ABBREVIATIONS ................................................................................................ 23 LIST OF PUBLICATIONS ................................................................................................... 29 1 CHAPTER 1: GENERAL INTRODUCTION ..................................................................... 31 1.1 INTRODUCTION TO NEUROLOGICAL DISORDERS ................................................................. 31 1.2 INTRODUCTION TO GENETICS AND GENOMICS ................................................................... 31 1.3 PRECISION MEDICINE .................................................................................................. 32 1.4 GENETICS OF MENDELIAN AND COMPLEX DISEASE .............................................................. 33 1.5 RECENT ADVANCES IN NEUROGENETICS ........................................................................... 35 1.6 THE GENETIC BASIS OF NEUROLOGICAL DISEASE ................................................................. 40 1.7 THESIS AIMS AND OUTLINE ........................................................................................... 41 2 CHAPTER 2: INTRODUCTION TO MSA AND RELATED MOVEMENT DISORDERS ......... 43 2.1 PARKINSON’S DISEASE AND ATYPICAL PARKINSONISM ......................................................... 43 2.2 MULTIPLE SYSTEM ATROPHY ........................................................................................
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