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Interplay Between Mitochondrial Dysfunction and Epigenetic Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2018 Interplay between mitochondrial dysfunction and epigenetic alterations in environmental linked Parkinson's Disease Adhithiya Charli Manohar Charle Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Part of the Toxicology Commons Recommended Citation Manohar Charle, Adhithiya Charli, "Interplay between mitochondrial dysfunction and epigenetic alterations in environmental linked Parkinson's Disease" (2018). Graduate Theses and Dissertations. 16631. https://lib.dr.iastate.edu/etd/16631 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Interplay between mitochondrial dysfunction and epigenetic alterations in environmental linked Parkinson's Disease by Adhithiya Charli Manohar Charle A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Toxicology Program of Study Committee: Anumantha G. Kanthasamy, Major Professor Arthi Kanthasamy Guru Rao Aileen Keating Eric Underbakke Dennis Lavrov The student author, whose presentation of the scholarship herein was approved by the program of study committee, is solely responsible for the content of this dissertation. The Graduate College will ensure this dissertation is globally accessible and will not permit alterations after a degree is conferred. Iowa State University Ames, Iowa 2018 Copyright © Adhithiya Charli Manohar Charle, 2018. All rights reserved. ii To my father V.T.M. Charle and mother Antonyammal, thank you for being my biggest source of support and inspiration. Thank you God for all the blessings and for making me who I am. iii TABLE OF CONTENTS Page LIST OF FIGURES ............................................................................................................ v LIST OF TABLES ............................................................................................................. vi ACKNOWLEDGMENTS ................................................................................................ vii ABSTRACT ....................................................................................................................... ix CHAPTER I. GENERAL INTRODUCTION ................................................................... 1 Dissertation Organization .............................................................................................. 1 Introduction.................................................................................................................... 2 Literature Review .......................................................................................................... 6 Parkinson's disease-A mitochondria and gene based investigation ......................... 6 An unseen dimension through the chromosomes ................................................... 21 CHAPTER II. ALTERATION IN MITOCHONDRIAL DYNAMICS INDUCED BY TEBUFENPYRAD NAD PYRIDABEN IN A DOPAMINERGIC NEURONAL CELL CULTURE MODEL ............................................................................................. 32 Abstract ........................................................................................................................ 33 Introduction.................................................................................................................. 34 Materials and Methods ................................................................................................ 35 Results ......................................................................................................................... 43 Discussion .................................................................................................................... 48 References.................................................................................................................... 54 Figures ......................................................................................................................... 59 CHAPTER III. MITOCHONDRIA-IMPAIRING PESTICIDE TEBUFENPYRAD PROMOTES PKCδ ACTIVATION THAT FUNCTIONS AS A LAMINB1 KINASE TO INDUCE NUCLEAR MEMBRANE DAMAGE IN DOPAMINERGIC NEURONAL MODELS OF PARKINSON'S DISEASE ................. 69 Abstract ........................................................................................................................ 70 Introduction.................................................................................................................. 71 Materials and Methods ................................................................................................ 74 Results ......................................................................................................................... 82 Discussion .................................................................................................................... 89 References.................................................................................................................... 94 Figures ....................................................................................................................... 100 iv CHAPTER IV. MITOCHONDRIAL NEUROTOXIC PESTICIDES PROMOTE EPIGENETIC DYSREGULATION BY HISTONE H3 AND H4 HYPERACETYLATION IN DOPAMINERGIC NEURONAL MODELS OF PARKINSON'S DISEASE ............................................................................................... 108 Abstract ...................................................................................................................... 109 Introduction................................................................................................................ 110 Materials and Methods .............................................................................................. 113 Results ....................................................................................................................... 124 Discussion .................................................................................................................. 134 References.................................................................................................................. 140 Figures ....................................................................................................................... 149 CHAPTER V. GENERAL CONCLUSIONS ................................................................. 160 REFERENCES ............................................................................................................... 168 v LIST OF FIGURES Page Figure 1.1 Dr. James Parkinson and his book essay on 'Shaking Palsy'. ...................... 3 Figure 1.2 Clinical symptoms and time progression of PD.. ......................................... 4 Figure 1.3 Summary of PD-associated genes (PARK genes) ................................... 18 Figure 1.4 Illustrative hypothesis on the action of mitochondrial complex I inhibitors on D1 and D2 receptors at the synapse of dopaminergic neurons ........................................................................................................ 22 Figure 1.5 Pictorial scheme highlighting chromosomes 5 and 11 of dopaminergic neurons ........................................................................................................ 24 Figure 5.1 Scheme illustrating the integrated mechanisms triggered by mitochondrial complex I inhibiting pesticides .......................................... 167 vi LIST OF TABLES Page Table 1.1 PARK genes and dpamine receptors in corresponding chromosomes. ................. 23 Table 1.2 Other important genes housed in chromosome 5. ............................................... 27 Table 1.3 Other important genes housed in chromosome 11. ............................................. 30 vii ACKNOWLEDGEMENTS I would like to convey my deepest gratitude and would like to sincerely thank my major professor Dr. Anumantha G. Kanthasamy for providing me the opportunity to join his lab, for his constant guidance and for providing the continuous impetus throughout my graduate studies His expertise and invaluable comments greatly helped me and were critical to the completion of this dissertation. I would also like to thank my committee members, Drs. Arthi Kanthasamy, Guru Rao, Aileen Keating, Eric Underbakke and Dennis Lavrov, for all their help, comments and support to improve my quality of research. I would also like to thank Dr. Vellareddy Anantharam for his help in getting the resources required for my study. Also, I would like to thank Dr. Huajun Jin and Mr. Gary Zenitsky for their assistance and support in the preparation of my manuscripts. It has been an absolute pleasure to work with the Kanthasamy group and being a part of it. I am very thankful to my mentor Dr.Huajun Jin and my dear previous colleagues Drs. Muhammet Ay, Dilshan Harischandra, Nikhil Panicker, Matthew Neal, Dongsuk Kim, Qi Xu, Shivani Ghaisas, Monica Langley and Neeraj Singh. In addition, I would like to thank my current lab colleagues Dharmin Rokad, Jie Luo, Ahmed Abdalla, Souvarish Sarkar, Vivek Lawana, Naveen Kondru, Sireesha Manne, Bharathi Palanisamy, Emir Malovic, Minhong Huang, Prita Pandiya,
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