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Identification of Genetic Factors Underpinning Phenotypic Heterogeneity in Huntington’S Disease and Other Neurodegenerative Disorders

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Identification of Genetic Factors Underpinning Phenotypic Heterogeneity in Huntington’S Disease and Other Neurodegenerative Disorders Identification of genetic factors underpinning phenotypic heterogeneity in Huntington’s disease and other neurodegenerative disorders. By Dr Davina J Hensman Moss A thesis submitted to University College London for the degree of Doctor of Philosophy Department of Neurodegenerative Disease Institute of Neurology University College London (UCL) 2020 1 I, Davina Hensman Moss confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Collaborative work is also indicated in this thesis. Signature: Date: 2 Abstract Neurodegenerative diseases including Huntington’s disease (HD), the spinocerebellar ataxias and C9orf72 associated Amyotrophic Lateral Sclerosis / Frontotemporal dementia (ALS/FTD) do not present and progress in the same way in all patients. Instead there is phenotypic variability in age at onset, progression and symptoms. Understanding this variability is not only clinically valuable, but identification of the genetic factors underpinning this variability has the potential to highlight genes and pathways which may be amenable to therapeutic manipulation, hence help find drugs for these devastating and currently incurable diseases. Identification of genetic modifiers of neurodegenerative diseases is the overarching aim of this thesis. To identify genetic variants which modify disease progression it is first necessary to have a detailed characterization of the disease and its trajectory over time. In this thesis clinical data from the TRACK-HD studies, for which I collected data as a clinical fellow, was used to study disease progression over time in HD, and give subjects a progression score for subsequent analysis. In this thesis I show blood transcriptomic signatures of HD status and stage which parallel HD brain and overlap with Alzheimer’s disease brain. Using the Huntington’s disease progression score in a genome wide association study, both a locus on chromosome 5 tagging MSH3, and DNA handling pathways more broadly, are shown to modify HD progression: these results are explored. Transcriptomic signatures associated with HD progression rate are also investigated. In this thesis I show that DNA repair variants also modify age at onset in spinocerebellar ataxias (1, 2, 3, 6, 7 and 17), which are, like HD, caused by triplet repeat expansions, suggesting a common mechanism. Extending this thesis’ examination of the relationship between phenotype and genotype I show that the C9orf72 expansion, normally associated with ALS/FTD, is also the commonest cause of HD phenocopy presentations. 3 Impact Statement The work presented in this thesis has been disseminated and had an impact both within and beyond academia. Foremost among the positive impacts of this work has been the identification of MSH3 as a modifier of disease progression in Huntington’s disease, and, by extension of work presented in this thesis is likely to be a modifier of other polyglutamine repeat disorders. As a result of my work, ongoing study has been taking place about the likely mechanism of this modifier effect. It is likely that small molecule inhibitors of MSH3 may have the potential to slow progression of HD in patients, and as a consequence several pharmaceutical companies are working on this potential therapeutic avenue. The following key papers have been published in scholarly journals based on material covered in this thesis, along with various other papers in which I had a smaller role or that were beyond the scope of this thesis (listed in Appendix 2). The relevant thesis chapter is given, and the number of papers citing each paper (on 25/03/2019) is given in parenthesis. 1. Chapter 3. Hensman Moss DJ*, Pardiñas AF*, et al. Identification of genetic variants associated with Huntington’s disease progression: a genome-wide association study. The Lancet Neurology. 2017. 16(9) 701-711. *Co-first author. (43) 2. Chapter 4. Bettencourt C*, Hensman Moss D*, Flower M*, Wiethoff S* et al. DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases. Ann Neurol. 2016 Jun;79(6):983-90. doi: 10.1002/ana.24656. *Co-first author. (51) 3. Chapter 6. Hensman Moss DJ et al. C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies. Neurology. 2014 Jan 28;82(4):292-9. (140) 4. Chapter 6. Beck J*, Poulter M*, Hensman D et al. Large C9orf72 Hexanucleotide Repeat Expansions Are Seen in Multiple Neurodegenerative Syndromes and Are More Frequent Than Expected in the UK Population. Am J Hum Genet. 2013 Mar 7;92(3):345-53. (221) 5. Chapter 7. Hensman Moss DJ et al. Huntington’s disease blood and brain show a common gene expression pattern and share an immune signature with Alzheimer’s disease. Nature Scientific Reports. 2017. 7, 44849. (5) I have presented work from this thesis at various international meetings and conferences, and it has attracted the following prizes: 4 1. The Alzheimers Research UK Jean Corsan Prize which is awarded each year for the best scientific paper in neurodegeneration published by a PhD or MD/PhD student, London, March 2018. 2. Huntington Study Group ‘Insight of the Year’ award for most influential paper in Huntington’s disease in 2017. HSG Meeting, Denver, USA, November 2017. 3. Neuromics Consortium Prize for best poster presentation at the Neuromics Meeting, Berlin, May 2017. 4. European Huntington’s Disease Network Prize for best presentation at the EHDN Meeting, The Hague, September 2016. I have also taken part in several activities to disseminate my work to a broader audience, including being interviewed for profile pieces in Lancet Neurology (https://doi.org/10.1016/S1474-4422(18)30329-6) and ARUK’s Demenia blog https://www.dementiablog.org/scientist-focus-davina-hensman-moss/) along with news features on the St George’s Hospital and UCL websites and talks to patient groups. 5 Acknowledgements Firstly, I would like to thank the participants and those who support them who generously gave their time to be part of the research projects upon which this PhD Thesis is based, in particular those people who took part in the TRACK-HD and TrackOn-HD studies which were so critical to my work. I would like to thank my supervisor Prof. Sarah Tabrizi for her unending support and guidance, in the clinic, in the lab and beyond. It has been a pleasure to work for such an inspirational role model. I would like to thank Prof. Lesley Jones, my secondary supervisor at Cardiff University for her wisdom, council and sound guidance, particularly for the genetics aspects of my work. I would give thanks to the following: Prof. Simon Mead for the training in genetics, supervising the C9orf72 aspects of this thesis, and for ongoing advice; Prof. Douglas Langbehn for the extensive statistical input to my projects; Prof. Peter Holmans for his clear vision, and for statistical genetics input to my projects; Dr Antonio Pardiñas interesting discussions, and a huge amount of help with data analysis. The discussions between Sarah Tabrizi, Lesley Jones, Douglas Langbehn, Peter Holmans and myself about the nature of progression in Huntington’s disease and how best to examine it were an inspiration, and formed a valuable bedrock for the subsequent work in this thesis. My PhD has been highly collaborative and it has been a pleasure and a privilege to work with many brilliant collaborators during the course of these projects. I would like in particular to thank the following, in no particular order, for their invaluable input in various aspects of my work: Dr Kitty Lo, Dr Vincent Plagnol, Prof. Henry Houlden, Dr Conceicao Bettencourt, Dr Sarah Weithoff, Dr Michael Flower, Dr Willeke van Roon-Mom, Prof. Alexandra Durr, Dr Edward Wild, Dr Rob Goold, Dr Ralph Andre, Dr Alison Wood-Kaczmar, Dr Timothy Stone, Prof. Darren Monckton, Mark Poulter, Jon Beck, Gary Adamson, Tracy Campbell, Ruth Farmer, Dr Rachael Scahill, Dr Marina Papoutsi, Dr Peter McColgan, Nicci Robertson and all the members of the HD Research Centre. I would also like to thank CHDI for its funding of TRACK-HD, TrackOn-HD and particularly for funding me as Clinical Fellow for TrackOn-HD; the European Commission for funding Neuromics and through that much of the genetic analysis; and the Guarantors of Brain who funded me through an exit fellowship and travel bursaries. Finally I would like to thank my parents Barbara and Nigel Hensman who encouraged my curiosity and always had faith in me; my husband George Moss for his unfailing love, support and understanding, and my children Arthur, Freddie and Louisa who arrived during the course of this PhD and have made my world a richer place. 6 Table of Contents Abstract ........................................................................................................................................ 3 Impact Statement ........................................................................................................................ 4 Acknowledgements...................................................................................................................... 6 Table of Contents ......................................................................................................................... 7 List of Figures ............................................................................................................................. 13 List of Tables .............................................................................................................................
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