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Studies of Mitochondrial Dysfunction in Models of Rett Syndrome

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Studies of Mitochondrial Dysfunction in Models of Rett Syndrome Studies of Mitochondrial Dysfunction in Models of Rett Syndrome by Natalya O. Shulyakova A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Physiology University of Toronto © Copyright by Natalya O. Shulyakova 2016 Studies of Mitochondrial Dysfunction in Models of Rett Syndrome Natalya O. Shulyakova Doctor of Philosophy Department of Physiology University of Toronto 2016 Abstract Rett syndrome (RTT) is a neurodevelopmental disorder affecting primarily females that is predominantly caused by mutations in the MECP2 gene. RTT is characterized by a loss of previously acquired skills, ambulatory deficits, respiratory problems and overall retarded growth. Mitochondrial dysfunction and oxidative stress identified in MeCP2-deficient tissues raised the possibility that mitochondrial impairments may play role in the pathogenesis of RTT. To further investigate the role of mitochondrial dysfunction in the absence of MeCP2, I analyzed mitochondrial function and morphology in Mecp2-deficient mouse adult skin fibroblasts (ASF) and in Mecp2-null mouse ESC derived neurons using an array of fluorescent dyes coupled with flow cytometry and confocal microscopy. The heterogeneity of cellular responses in ASF prevented identification of consistent changes in mitochondrial function, making them an unsuitable model for studying mitochondrial dysfunctions. Mecp2-null mouse ESC were differentiated into enriched population of neurons. Mecp2-null neurons displayed hyperpolarized mitochondria, high levels of ROS, low ATP and impaired mitochondrial trafficking. Resveratrol and mitochondrial cocktail that target expression of mitochondrial genes and mitochondrial metabolism, but not simple ROS scavengers, were successful at ameliorating ROS levels and normalizing mitochondrial membrane potential. Since oxidative stress was reported in RTT ii mice, I tested whether resveratrol and mitochondrial cocktail could reverse or improve behavioral phenotype in RTT mice. Mitochondrial cocktail but not resveratrol improved exploratory, locomotor and social behavior deficits in RTT mice. Taken together these results suggest that both mitochondrial deficits and oxidative stress are not only the consequences of dysfunctional MeCP2, but are likely the causes of the RTT phenotype. Further, I determined that over-expression of mitochondrial Sirt3, known for its multifaceted effects on mitochondrial metabolism, is sufficient to protect neurons form various cytotoxic insults including oxidative stress. Overall, this study paves the way for potential new therapeutic strategies aimed at improving quality of life in RTT patients. iii Acknowledgments I would like to thank Dr. J. H. Eubanks for giving me the opportunity to pursue research in his laboratory and taking the time to teach me and guide me throughout my Doctoral project. Thank you for your continuous encouragement, support and advice. I would also like to thank my supervisory committee, Dr. S. Sugita and Dr. A. Tandon, and my co-supervisor, Dr. L. R. Mills. Their advice and guidance at my committee meetings were always greatly appreciated. In addition, I would like to acknowledge everyone in the lab for their contributions, help and encouragement. Richard Logan, Guanmimg Zhang, Min Lang, thank you for being there. It was a pleasure to learn and work with you. Thank you, Robert Wither, for teaching me the electrophysiology and behavioral techniques. Thank you, Elena Sidorova-Darmos, for making the life in the lab fun! A special thank you goes to Dr. Zhang for his input on EEG analysis, to Chiping Wu for implanting all of the mice that were used in these studies and also to Jack Lin and Hristo Netchev for their help with the data analysis. Finally, I would like to express my sincere gratitude to a special person in my life. Christopher, thank you for your continuous support, encouragement and help throughout these years! iv Table of Contents Acknowledgments .......................................................................................................................... iv List of Tables .............................................................................................................................. xvii List of Figures .............................................................................................................................. xix List of Appendices ...................................................................................................................... xxv List of Abbreviations ................................................................................................................. xxvi 1 Chapter1-General Introduction .................................................................................................. 1 1.1 Neurodevelopmental disorders ........................................................................................... 1 1.2 Rett Syndrome .................................................................................................................... 1 1.2.1 Clinical progression ................................................................................................ 2 1.2.2 Genetic basis ........................................................................................................... 5 1.2.3 Phenotypic variability ............................................................................................. 5 1.2.4 RTT in males ........................................................................................................... 7 1.3 Methyl-CpG-Binding Protein 2 (MeCP2) .......................................................................... 7 1.3.1 MeCP2 structure ..................................................................................................... 7 1.3.2 MeCP2 expression and localization ........................................................................ 9 1.3.3 MeCP2 function .................................................................................................... 10 1.3.4 Mouse models of Rett syndrome. ......................................................................... 11 1.4 Pathophysiology of Rett syndrome ................................................................................... 16 1.4.1 Neuropathology ..................................................................................................... 16 1.4.2 Epileptic seizures and electroencephalographic abnormalities ............................. 16 1.4.3 Autonomic deficits ................................................................................................ 17 1.4.4 Motor impairments ................................................................................................ 19 1.4.5 Anxiety–like behavior ........................................................................................... 20 v 1.5 Mitochondrial dysfunction in the pathogenesis of Rett syndrome ................................... 21 1.5.1 Mitochondria ......................................................................................................... 21 1.5.2 Mitochondrial structure ......................................................................................... 22 1.5.3 Mitochondrial ATP production ............................................................................. 23 1.5.4 Mitochondrial ROS production ............................................................................. 23 1.5.5 ROS signaling in regulating cellular processes .................................................... 25 1.5.6 Antioxidant systems .............................................................................................. 27 1.5.7 Oxidative stress and mitochondrial dysfunction ................................................... 28 1.5.8 Role of mitochondria in neuroplasticity ............................................................... 29 1.5.8.1 Mitochondria and neurogenesis .............................................................. 29 1.5.8.2 Mitochondria and neurite outgrowth ...................................................... 30 1.5.8.3 Mitochondria and synaptic plasticity ...................................................... 31 1.5.9 Mitochondrial abnormalities in Rett syndrome .................................................... 31 1.5.9.1 Alterations of mitochondrial structure .................................................... 31 1.5.9.2 Abnormalities in the expression levels of genes and proteins related to mitochondrial function ....................................................................... 33 1.5.9.3 Abnormalities in the mitochondrial ETC complexes ............................. 38 1.5.9.4 Evidence of oxidative stress ................................................................... 39 1.5.9.5 Is Rett syndrome a mitochondrial disease? ............................................ 40 1.6 Therapeutic options for Rett syndrome ............................................................................. 42 1.6.1 Gene therapy and read through compounds .......................................................... 42 1.6.2 Neurotrophins and growth factors ........................................................................ 43 1.6.3 Neurotransmitter systems ...................................................................................... 44 1.6.4 Antiepileptic compounds ...................................................................................... 45 1.6.5 Targeting metabolism and mitochondria .............................................................
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