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2018-02-06-Warren Final Dissertation MITOCHONDRIAL DYSFUNCTION IN THE STRIATUM: IMPLICATIONS FOR L-DOPA INDUCED DYSKINESIA By Emily Booth Warren Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Pharmacology February 28, 2018 Nashville, TN Approved: Christine Konradi, Ph.D. Aaron B. Bowman, Ph.D. Joshua P. Fessel, M.D., Ph.D. Eugenia Gurevich, Ph.D. Qi Zhang, Ph.D. To Kirti and Amy, who have endured. ii ACKNOWLEDGEMENTS I am profoundly grateful to the vast number of people who have supported me throughout my PhD program. First, I would like to thank my advisor, Christine Konradi, for her mentorship, guidance, and training. I am also indebted to the members of my committee, Qi Zhang, Eugenia Gurevich, Josh Fessel, and Aaron Bowman, for their patience and assistance throughout my graduate career. I am especially appreciative of Aaron’s generosity over the last few months of my graduate work, by providing me a place in his own lab and a rare opportunity to continue to grow in a new setting. I would like to thank the Department of Pharmacology for continuing to support me as I completed my dissertation, with an especial thanks to Karen Gieg for her tireless efforts. I am also grateful to Dehui Mi and Josh Bauer of the High Throughput Screening Core, Sean Schaffer and Bob Matthews of the Cell Imaging Shared Resource, and Donald Stec and Markus Voehler of the Small Molecule and Biomolecular NMR facilities. A large portion of the work in this dissertation depended on the expertise of these members of these core facilities, and all have been exceptionally willing to help and answer my endless questions. I would also like to thank the friends that I have made here at Vanderbilt, and especially those that have been lab members as well, both at the beginning of this journey and at the end. Sharing this experience has been instrumental in completing it. I am grateful to my family for their belief in me and their unwavering support, and I would not be where I am today without them. Finally, I am intensely thankful to my friends, Kirti Sarkar and Amy Hassenberg, who have been there for me since before I even considered applying to graduate school. They have heard more about this project and this process than anyone, and I am more indebted to them than words can say. iii TABLE OF CONTENTS Page ACKNOWLEDGEMENTS .................................................................................................... iii LIST OF TABLES .............................................................................................................. VIII LIST OF FIGURES.............................................................................................................. IX LIST OF ABBREVIATIONS ................................................................................................. XI Chapter I. Introduction .................................................................................................................. 1 1. Physiology and pharmacology of Parkinson’s Disease and L-DOPA Induced Dyskinesia ............................................................................................................. 2 1.1. PD and LID in the clinic ...................................................................................... 2 1.2. Physiology and pathophysiology of the basal ganglia in PD and LID .................. 7 1.2.1. Functional Anatomy of the Basal Ganglia ..................................................... 7 1.2.2. Pathological Network Alterations of the Basal Ganglia in PD and LID ......... 10 1.3. Molecular physiology of the SNc and Striatum ................................................. 12 1.3.1. Neurotransmitters ....................................................................................... 12 Dopamine .......................................................................................................... 12 Glutamate and GABA ........................................................................................ 14 1.3.2. Receptors Implicated in the pathogenesis of PD and LID ........................... 18 GPCRs .............................................................................................................. 18 Ionotropic Receptors ......................................................................................... 21 1.3.3. Second Messenger Cascades Implicated in the Pathogenesis of PD and LID ................................................................................................................... 23 Gβγ ................................................................................................................... 23 Gɑs/i- and cAMP-linked cascades ...................................................................... 25 2+ Gɑq- and Ca -linked cascades .......................................................................... 27 DAergic Regulation of Glutamatergic Activity..................................................... 32 1.4. Molecular correlates of DA denervation and LID .............................................. 34 1.4.1. Animal models used to study DA depletion and LID ................................... 34 1.4.2. Receptors and Transporters ....................................................................... 36 1.4.3. Supersensitization of D1 signaling ............................................................... 38 1.4.4. Transcriptional Deregulation in the Direct Pathway ..................................... 40 1.5. Summary.......................................................................................................... 41 2. Mitochondrial Form and Function ......................................................................... 42 2.1. The mitochondrial genome and proteome ........................................................ 42 2.1.1. mtDNA structure and replication ................................................................. 43 2.1.2. mtRNA and related proteins........................................................................ 47 2.1.3. Mitochondrial proteostasis and the UPRmt .................................................. 48 2.1.4. A summary of mitochondrial transporters: The SLC25A family and related transporters ................................................................................................ 52 2.2. Glucose catabolism and bioenergetics ............................................................. 56 2.2.1. Glycolysis and the Pentose-Phosphate Pathway ........................................ 56 iv Noteworthy in Neurons and Glia: ....................................................................... 59 2.2.2. The Tricarboxylic Acid (TCA) Cycle ............................................................ 61 Noteworthy in Neurons and Glia: ....................................................................... 64 2.2.3. Oxidative Phosphorylation and the Respiratory Chain ................................ 65 Noteworthy in Neurons and Glia: ....................................................................... 68 2.2.4. Phosphate Handling and the Creatine/Phosphocreatine Shuttle ................. 70 Noteworthy in Neurons and Glia: ....................................................................... 71 2.3. Mitochondrial Dynamics ................................................................................... 72 2.3.1. Fission ........................................................................................................ 73 2.3.2. Fusion ........................................................................................................ 74 2.3.3. Transport and trafficking ............................................................................. 75 2.3.4. Biogenesis and Mitophagy .......................................................................... 76 3. Contributions of Mitochondrial Dysfunction to Neurodegeneration ....................... 78 3.1. Disorders of mtDNA – convergence and divergence ........................................ 78 3.1.1. Common clinical features ........................................................................... 79 3.1.2. Representative mtDNA point mutations and their specific disorders ........... 80 3.1.3. Mendelian sources of mitochondrial disorders – mtDNA deletions and depletions ................................................................................................... 82 Defects of the mtDNA Replisome ...................................................................... 83 Defects of Nucleotide Handling.......................................................................... 84 3.1.4. Mitochondrial disorders of both genomes or neither (LS and KSS) ............. 85 3.2. Disorders of mitochondrial signaling ................................................................. 87 3.2.1. Calcium ...................................................................................................... 87 3.2.2. Reactive Oxygen Species ........................................................................... 91 3.3. Mitochondrial Dysfunction in PD and LID ......................................................... 96 3.3.1. The Genetics of PD and LID ....................................................................... 97 3.3.2. The Contribution of Mitochondrial Dysfunction to Nigral Degeneration in Idiopathic PD ............................................................................................ 100 3.3.3. Mitochondrial Dysfunction in LID .............................................................
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