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Investigating Developmental and Functional Deficits in Neurodegenerative UNIVERSITY OF CALIFORNIA, IRVINE Investigating developmental and functional deficits in neurodegenerative disease using transcriptomic analyses DISSERTATION submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Biomedical Sciences by Ryan Gar-Lok Lim Dissertation Committee: Professor Leslie M. Thompson, Chair Assistant Professor Dritan Agalliu Professor Peter Donovan Professor Suzanne Sandmeyer 2016 Introduction, Figure 1.1 © 2014 Macmillan Publishers Limited. Appendix 1 © 2016 Elsevier Ltd. All other materials © 2016 Ryan Gar-Lok Lim DEDICATION This dissertation is dedicated to my parents, sister, and my wife. I love you all very much and could not have accomplished any of this without your love and support. Please take the time to reflect back on all of the moments we’ve shared, and know, that it is because of those moments I have been able to succeed. This accomplishment is as much yours as it is mine. ii TABLE OF CONTENTS Page LIST OF FIGURES vi LIST OF TABLES ix ACKNOWLEDGMENTS x CURRICULUM VITAE xiii ABSTRACT OF THE DISSERTATION xv Introduction Huntington’s disease, the neurovascular unit and the blood-brain barrier 1 1.1 Huntington’s Disease 1.2 HTT structure and function 1.2.1 Normal HTT function and possible loss-of-function contributions to HD 1.3 mHTT pathogenesis 1.3.1 The dominant pathological features of mHTT - a gain-of- toxic function? 1.3.2 Cellular pathologies and non-neuronal contributions to HD 1.4 The neurovascular unit and the blood-brain barrier 1.4.1 Structure and function 1.4.2 Genes that form the BBB 1.4.3 Signaling in the NVU – development and maintenance of the BBB 1.4.4 The BBB in HD and other neurodegenerative diseases 1.5 Modeling HD with patient derived iPSCs 1.6 Overview of dissertation 1.7 Figures CHAPTER 1: Altered neurodevelopment of Huntington’s disease iPSC-derived neural cells and pharmacological rescue by Isx-9 35 2.1 Summary of Chapter 1 2.2 Introduction 2.3 Results 2.3.1 Differentiation of iPSCs with expanded HD and non-disease CAG repeats 2.3.2 RNA-Seq analysis of differentiated iPSCs 2.3.3 RNA-Seq analysis Suggests altered neurodevelopment in HD lines iii 2.3.4 Cellular pathways related to neuronal function are altered in HD iPSC-neural cells 2.3.5 Comparison of HD iPSC lines to mouse striatal gene expression indicates altered maturation 2.3.6 ChIP-Seq analysis reveals HD chromatin signatures and epigenetic changes to genes within functional pathways consistent with altered neuronal maturation 2.3.7 Transcription factor motifs from ChIP-Seq analysis are involved in neuronal development 2.3.8 Isx-9 corrects CAG repeat-associated neurodevelopmental and neuronal phenotypes in differentiated HD iPSCs 2.3.9 Isx-9 improves cognition and synaptic pathology in R6/2 mice 2.4 Discussion 2.4.1 Altered gene expression of neurodevelopmental pathways and synaptic homeostasis in HD lines 2.4.2 Epigenetic signatures may provide insights into differential transcriptional programs that impact neurodevelopment and maturation 2.4.3 Neurodevelopment and neurogenesis: A therapeutic target for Huntington’s disease? 2.5 Figures 2.6 References 2.7 Materials and Methods CHAPTER 2: Blood-brain barrier and angiogenic deficits in Huntington’s disease iPS cell- derived Brain Endothelial Cells 128 3.1 Summary of Chapter 2 3.2 Introduction 3.3 Results 3.3.1 Generation and transcriptome analysis of unaffected control human iPSC-derived BECs 3.3.2 The transcriptome of HD iPSC-derived BECs reveals potential angiogenic and barrier defects 3.3.3 HD-BECs have a higher angiogenic ability compared to control BECs 3.3.4 HD iPSC-derived BECs have functional deficits in angiogenesis and barrier properties 3.3.5 Transcytosis is impaired in HD-BECs. 3.3.6 Barrier deficits of HD iPSC-derived BECs are maintained in presence of healthy control astrocytes 3.4 Discussion 3.5 Figures 3.6 References iv 3.7 Materials and Methods CHAPTER 3: Aberrant gene expression and alternative splicing drive cellular pathologies in ALS 174 4.1 Summary of Chapter 3. 4.2 Introduction 4.3 Results 4.3.1 Changes in gene expression reveals TGFB, ERBB2, and NRG1 pathogenic network activation in C9ORF72 iPSC-derived motor neurons. 4.3.2 RNA binding proteins and alt-splicing in ALS 4.4 Discussion 4.5 Figures 4.6 References 4.7 Materials and Methods CHAPTER 4: Conclusions and Future Directions 186 5.1 Transcriptional Dysregulation in HD 5.2 Neurodevelopmental deficits in HD 5.3 Altered BEC function in HD 5.4 Neuronal and BEC signaling 5.4.1 Neural Stem Cell and Brain endothelial cells interactions 5.5 Transcriptional dysregulation in ALS 5.6 Conclusions 5.7 Figures 5.8 References APPENDIX 1: MIND, a novel chemical class of NRF2 activators, with therapeutic potential in models of Huntington’s disease. Cell Chemical Biology 2016 197 APPENDIX 2: Tables 236 v LIST OF FIGURES Page Introduction Figure 1.1 24 Figure 1.2 25 Chapter 1 Figure 2.1 62 Figure 2.1 63 Figure 2.2 64 Figure 2.2 65 Figure 2.3 66 Figure 2.4 67 Figure 2.5 68 Figure 2.5 69 Figure 2.6 70 Figure 2.7 71 Figure 2.7 71 Figure 2.8 73 Figure 2.8 74 Figure 2.9 75 Figure 2.9 76 Figure 2.10 77 Figure 2.10 78 vi Figure 2.11 79 Figure 2.12 80 Figure 2.12 81 Figure 2.13 82 Figure 2.14 83 Figure 2.14 84 Figure 2.14 85 Figure 2.15a,b 86 Figure 2.15c 87 Figure 2.16 88 Figure 2.16 89 Figure 2.17 90 Figure 2.18 91 Figure 2.18 92 Figure 2.18 93 Figure 2.19 94 Figure 2.19 95 Figure 2.20 96 Figure 2.21 97 Figure 2.22 98 Figure 2.23 99 Figure 2.23 100 vii Chapter 2 Figure 3.1 144 Figure 3.1 145 Figure 3.2 146 Figure 3.3 147 Figure 3.3 148 Figure 3.4 149 Figure 3.4 150 Figure 3.5 151 Figure 3.5 152 Figure 3.6 153 Figure 3.6 154 Figure 3.7 155 Figure 3.8 156 Figure 3.8 157 Chapter 3 Figure 4.1 180 Figure 4.1 181 Figure 4.2 182 Figure 4.3 183 Chapter 4 Figure 5.1 195 viii LIST OF TABLES Page Chapter 1 Table 2.1a 101 Table 2.1b 101 Table 2.1c 101 Table 2.1d 101 Table 2.2 102 Table 2.2 103 Chapter 2 Table 3.1 158 Table 3.2 159 Table 3.2 160 Table 3.3 161 Table 3.4 162 Table 3.5 163 Table 3.6 164 ix ACKNOWLEDGMENTS There are many individuals I have interacted with throughout my PhD. I would like to acknowledge each and every one of you for any help, support, guidance, or friendship you’ve shown me. Those moments are what I will look back on when I think of my time at UCI and are the moments which have made my experience at UCI so great. I would specifically like to thank my graduate advisor Leslie Thompson for being a wonderful mentor and friend. For allowing me to pursue my interests and always making me feel like my opinion mattered. Your encouragement and countless hours of direct support truly helped to shape me into the scientist I am today. Leslie has always considered my physical and mental health vitally important and I have greatly appreciated this. Leslie, you are one of the most amazing woman, scientist, and person I have ever known, and you’ve always inspired me to be the best I can be. My other mentor, Malcolm Casale, helped me to find my passion for computational biology. Malcolm has been a shining example of strength and selflessness, and has helped to directly and indirectly motivate me to try my best. Malcolm, you have been a true friend and I will always cherish the time we’ve spent together as friends and as lab mates. I’ve learned so much from you and will take all of it with me into the future. Chris Quan worked alongside me for the last two years of my PhD and although our relationship started off as mentor and mentee he quickly became a colleague with as much insight and input into our shared project as any other PhD would’ve contributed. Chris, thank you for all of your hard work in the lab and especially for your friendship. I will cherish all of the laughs we had. x Joan Steffan, thank you for your support and insight into autophagy. The entire Thompson lab has been such a great pleasure to work with. Thank you all for your help and friendship over the years. Jack Reidling, for all the signatures and keeping the lab in order, as well as your personal support. Sylvia Yeung, I would like to thank you for the help with the mouse work. The other students in the lab: Joseph Ochaba, Julia Overman, Eva Morozko, and Isabella Sanchez you have all be great lab mates and friends. Everyone that shared lab space with me at Gross Hall you have been wonderful to work with and I appreciate you all as friends. Jennifer Stocksdale, thank you for all the orders and discussions on food. Sarah Hernandez and Charlie Geater, thank you for the frustrating but great discussions on academia and science. Andrea Reyes-Ortiz, you’ve been a superb student and lab mate.
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