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MODELING AND ANALYZING CELLULAR DEFECTS ASSOCIATED WITH MOVEMENT DISORDERS IN CAENORHABDITIS ELEGANS by CHUAN XU GUY A. CALDWELL, COMMITTEE CHAIR KIM A. CALDWELL, CO-CHAIR JANIS O’DONNELL CAROL DUFFY PATRICK A. FRANTOM A DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biological Sciences in the Graduate School of The University of Alabama TUSCALOOSA, ALABAMA 2018 Copyright Chuan Xu 2018 ALL RIGHTS RESERVED ABSTRACT As a powerful modern organism, Caenorhabditis elegans has been widely used to study pathologies behind movement disorders including Parkinson’s disease (PD) and dystonia. PD is the second most common neurodegenerative disease, in which more than 90% of cases are idiopathic. The etiology of PD has long been thought to involve both genetic and environmental factors. The classical pathological hallmarks of PD are the progressive loss of dopaminergic neurons within the substantia nigra, accompanied by the accumulation of - synuclein (-syn) in the form of Lewy bodies. Here, we identified four compounds (cyclosporin A, meclofenoxate hydrochloride, sulfaphenazole, and choline) that can rescue mitochondrial phospholipid depletion induced neurodegeneration in C. elegans with -syn expression in dopaminergic neurons. To examine putative epigenetically-regulated modifiers of -syn induced dopaminergic neurodegeneration in C. elegans, we demonstrated a specific microRNA, mir-239, when mutated, showed a robust resistance to neurotoxicity resulted from -syn. By functionally investigating a suite of expression-validated targets of mir-239 regulation via conditional knockdown using a dopaminergic neuron-specific RNAi-sensitive -syn strain, we discerned a subset of downstream targets contributing to neuroprotection afforded by mir-239. These findings support the predictive nature of C. elegans in validating potential modifiers of -syn neurotoxicity and discovering potential neuroprotective chemicals associated with PD. Human torsinA, encoded by the DYT1 gene, is an ER resident chaperone protein that has been identified to be responsible for a human movement disorder ii called early-onset torsion dystonia. Here we revealed that tor-2, the C. elegans homologue of human torsinA, was indicated as a possible regulator in the trafficking process of an AMPA receptor subunit, GLR-1; implying a possible connection between the glutamatergic transmission and the etiology of dystonia. The combined outcomes of these studies of movement disorders strongly support C. elegans is a very desirable model organism for the analysis of cell biology and genetic features associated with PD and dystonia. iii DEDICATION I would like to dedicate this dissertation to everyone who helped me and supported me over the past years to achieve this masterpiece. In particular, this manuscript is dedicated to my parents and my best friend Zhiwei for providing me unwavering support and strength in all my endeavors. iv LIST OF ABBREVIATIONS AND SYMBOLS 6-OHDA 6-Hydroxydopamine Alpha AD Alzheimer disease AD Autosomal dominant ADE neuron Anterior deirid neuron AMPA Amino-3-hydroxy-5-methylisoxazoleproprionic acid AR Autosomal recessive ATP Adenosine triphosphate β Beta Botox Botulinum toxin bp base pair C Celsius cDNA Complementary DNA CDP Cytidine diphosphate CEP neuron Cephalic neuron C. elegans Caenorhabditis elegans CGC Caenorhabditis genetics center Cho Choline CL Phospholipid cardiolipin v CNS Central nervous system CNIHs Cornichon homologs CsA Cyclosporine A D2 Dopamine 2 DA Dopamine DG Diacylglycerol DMAE Dimethylethanolamine DMSO Dimethyl sulfoxide DNA Deoxyribonucleic acid dsRNA Double-stranded RNA ε Epsilon E. coli Escherichia coli EOTD Early-onset torsion dystonia ER Endoplasmic reticulum ETA Ethanolamine EV Empty vector FDA Food and drug administration GTP Guanosine triphosphate GWAS Genome-wide association study iGluRs ionotropic glutamate receptors IOD Integrated optical density IPTG Isopropyl β-D-1-thiogalactopyranoside vi kDa Kilodalton L4 Larval stage 4 L-DOPA L-3,4-dihydroxyphenylalanine LINC Linker of nucleoskeleton and cytoskeleton LSD Lysosomal storage disorder MAMs Mitochondrial associated membranes MFX Meclofenoxate hydrochloride MGs Monoglycerides miRNAs MicroRNAs MMP Mitochondrial membrane potential MPP+ 1-Methyl-4-phenylpyridinium mRNA Messenger RNA mPTP Mitochondrial permeability transition pore l Microliter mg Milligram ml Milliliter mM Millimolar n Number N/A Not applicable NBIA Neurodegeneration with brain iron accumulation ncRNA Non-coding ribonucleic acid NE Nuclear envelope vii NGM Nematode growth medium NMDA N-methyl-d-aspartate Ω Omega PARK Parkinson disease gene PBMCs Peripheral blood mononuclear cells PC Phosphatidyl choline p-Cho Phosphorylated-choline PCR Polymerase chain reaction PD Parkinson’s disease PE Phosphatidyl ethanolamine p-ETA Phosphorylated ETA PM Plasma membrane Pre-miRNA Precursor miRNA Pri-mRNA Primary miRNA PS Phosphatidylserine qRT-PCR Quantitative reverse transcription-PCR Ran Ras-related nuclear protein REP1 Repeat sequence RISC RNA-induced silencing complex RNA Ribonucleic acid RNAi RNA interference RNase Ribonuclease viii Roc Ras of complex ROS Reactive oxidative species rRNA Ribosomal ribonucleic acid SCI Spinal cord injury SD Standard deviation SNPs Single nucleotide polymorphisms SUL Sulfaphenazole TARPs Transmembrane AMPAR regulatory proteins TBI Traumatic brain injury tRNA Transfer ribonucleic acid UTR Untranslated region VGLUT Vesicular glutamate transporter VNC Ventral nerve cord WT Wildtype Proteins/Genes Aβ Amyloid-beta AMPARs AMPA receptors ANO3 Anoctamin3 ATP1A3 ATPase Na+/K+ transporting subunit alpha 3 ATP13A2 Lysosomal type 5P-type ATPase syn Alpha synuclein ix CACNA1B Calcium voltage-gated channel subunit alpha 1B CED-10 Cell-corpse engulfment protein CoA Coenzyme A COL6A3 Collagen Type VI alpha3 chain CRLS-1 Cardiolipin synthase CYP2C9 Cytochrome P450 family 2 subfamily C polypeptide 9 DAT-1 Dopamine transporter DGCR8 DiGeorge syndrome critical region 8 DJ-1 Oncogene DJ-1 DNAJC6 DnaJ heat shock protein family (Hsp40) member C6 DNAJC13 DnaJ heat shock protein family (Hsp40) member C13 DPCK Dephospho-CoA kinase EIF4G1 Eukaryotic translation initiation factor 4 gamma 1 FBX07 F-Box protein 7 GBA Glucocerebrosidase GCH1 GTP cyclohydrolase 1 GFP Green fluorescent protein GIGYF2 GRB10 interacting GYF protein 2 GNAL G protein subunit alpha L GTPase Guanosine triphosphatase HPCA Hippocalcin HSL Hormone-sensitive lipase x HTRA2 HtrA serine peptidase 2 KCTD17 Potassium channel tetramerization domain containing 17 KMT2B Lysine methyltransferase 2B LIPE Hormone-sensitive lipase LRRK2 Leucine-rich repeat kinase 2 MAGUKs Membrane-associated guanylate kinases MAPKKK Mitogen-activated protein kinase kinase kinase MECR Mitochondrial trans-2-enoyl-CoA reductase NCEH-1 Neutral cholesterol ester hydrolase 1 PANK Pantothenate kinase PDR-1 Parkinson's disease related PINK-1 PTEN induced putative kinase 1 PLA2G6 Phospholipase A2 group VI PNKD2 Paroxysmal nonkinesigenic dyskinesia 2 PPAT Phosphopantetheine adenylyltransferase Ppcdc Phosphopantothenoylcysteine decarboxylase PRRT2 Proline rich transmembrane protein 2 PRKN Parkin PRKRA Protein activator of interferon induced protein kinase PSD-1 Phosphatidylserine decarboxylase RAB-8 Ras-related protein 8 ROL-6 Roller 6 (collagen) xi SGCE Sarcoglycan epsilon SLC2A1 Solute carrier family 2 member 1 SLC17A5 Solute carrier family 17 member 5 Soluble N-ethylmaleimide-sensitive factor attachment SNARE protein receptor SNB-1 Synaptobrevin-1 SNCA Synuclein, alpha LRK-1 Leucine-rich repeat serine/threonine-protein kinase 1 SPR Sepiapterin reductase SYNJ1 Synaptojanin 1 TAF1 TATA-Box binding protein associated factor 1 TH Tyrosine hydroxylase THAP1 THAP domain containing 1 TOR-2 Torsin2 (torsinA) TOR1A Torsin family1 member A TUBB4A Tubulin Beta4 A class Iva UCHL-1 Ubiquitin C-terminal hydrolase L1 VGLUT Vesicular glutamate transporter VPS35 Vacuolar protein sorting 35 VPS41 Vacuolar protein sorting-associated protein 41 xii ACKNOWLEDGMENTS First of all, I would like to thank my academic advisors Prof. Guy A. Caldwell and Prof. Kim A. Caldwell for offering me the opportunity to perform scientific research in their wonderful lab at this institution. I am also grateful for their mentorship and endless support to not only my study, but also my life. I appreciate them very much from the bottom of my heart. Secondly, I want to thank my colleagues in Caldwell Lab. Your assistance, the happy memories, and funny moments we shared during my Ph.D. study will always bear in my mind. Additionally, I am thankful for the help of former and current undergraduate students, Michael Teal, Samantha Glukhova and especially Blake Parker who helped me with my projects in the past several years. I also want to take this opportunity to thank our wonderful lab manager Dr. Laura Berkowitz and Post Doctor Xiaohui Yan who provides me great help in my research. I thank The University of Alabama, the Department of Biological Sciences and Chinese Scholarship Council (CSC) for the funding support. And my graduate committee members, Dr. Janis O’Donnell, Dr. Carol Duffy, Dr. Patrick A. Frantom, Dr. Stevan Marcus, thank you for guiding me throughout my entire graduate study. In the end, I want to thank you for the support and encouragement from my family members and friends which enabled me to persist, focus on and achieve the goals of my Ph.D. study. xiii CONTENTS ABSTRACT ........................................................................................................
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  • DART-04: Prenatal Development Studies of Dimethylaminoethanol

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    NTP DEVELOPMEntAL And REprODUCTIVE TOXICITY TECHNICAL REPOrt ON THE PRENATAL DEVELOPMEnt STUDIES OF DIMETHYLAMINOETHANOL BITArtrATE (CASRN 5988-51-2) IN SprAGUE DAWLEY (Hsd:SprAGUE DAWLEY® SD®) RAts (GAVAGE STUDIES) NTP DART 04 JUNE 2020 NTP Developmental and Reproductive Toxicity Technical Report on the Prenatal Development Studies of Dimethylaminoethanol Bitartrate (CASRN 5988-51-2) in Sprague Dawley (Hsd:Sprague Dawley® SD®) Rats (Gavage Studies) DART Report 04 June 2020 National Toxicology Program Public Health Service U.S. Department of Health and Human Services ISSN: 2690-2052 Research Triangle Park, North Carolina, USA Dimethylaminoethanol Bitartrate, NTP DART 04 Foreword The National Toxicology Program (NTP), established in 1978, is an interagency program within the Public Health Service of the U.S. Department of Health and Human Services. Its activities are executed through a partnership of the National Institute for Occupational Safety and Health (part of the Centers for Disease Control and Prevention), the Food and Drug Administration (primarily at the National Center for Toxicological Research), and the National Institute of Environmental Health Sciences (part of the National Institutes of Health), where the program is administratively located. NTP offers a unique venue for the testing, research, and analysis of agents of concern to identify toxic and biological effects, provide information that strengthens the science base, and inform decisions by health regulatory and research agencies to safeguard public health. NTP also works to develop and apply new and improved methods and approaches that advance toxicology and better assess health effects from environmental exposures. The NTP Technical Report series for developmental and reproductive toxicity studies began in 2019.