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Targeting Tau Degradation by Small Molecule Inhibitors for Treatment of Tauopathies Mackenzie Martin University of South Florida, [email protected]

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Targeting Tau Degradation by Small Molecule Inhibitors for Treatment of Tauopathies Mackenzie Martin University of South Florida, Mmarti24@Health.Usf.Edu University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School 6-2-2016 Targeting Tau Degradation by Small Molecule Inhibitors for Treatment of Tauopathies Mackenzie Martin University of South Florida, [email protected] Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the Biochemistry Commons, and the Neurosciences Commons Scholar Commons Citation Martin, Mackenzie, "Targeting Tau Degradation by Small Molecule Inhibitors for Treatment of Tauopathies" (2016). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/6314 This Thesis is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Targeting Tau Degradation by Small Molecule Inhibitors for Treatment of Tauopathies by Mackenzie Dwayne Martin A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy with a concentration in Neuroscience Department of Molecular Medicine College of Medicine University of South Florida Major Professor: Chad Dickey, Ph.D. Daniel Lee, Ph.D. Yu Chen, Ph.D. Danielle Gulick, Ph.D. Date of Approval: June 1, 2016 Keywords: autophagy, aggregates, chaperones, Hsp70 Copyright © 2016, Mackenzie Dwayne Martin DEDICATION I dedicate this dissertation to all my family especially Sandra and Fernando Martin and Maya and Jason Jerald as well as to my best friend, David Knight, for all the love and support you have given throughout my life. Thank you!!! ACKNOWLEDGEMENTS I would like to thank my advisor, mentor and friend, Dr. Chad Dickey, for his guidance, support, patience, understanding and encouragement throughout graduate school. I would also like to thank Dr. Yu Chen, Dr. Daniel Lee, and Dr. Danielle Gulick for having served on my committee. Their time, efforts, and questions were greatly valued. I would like to also thank all of our collaborators that have helped in numerous projects. In addition I would like to express my appreciation and thanks for my lab colleagues and their continued motivation and drive to help me become a better scientist. Finally, I would like to thank the University of South Florida and all persons who have helped give me the opportunity to complete my graduate studies. TABLE OF CONTENTS List of Tables ................................................................................................................... iv List of Figures .................................................................................................................. v Abstract .......................................................................................................................... vii Chapter One: Rationale for Targeting Tau Degradation for Treatment of Tauopathies ............................................................................................................... 1 1.1 Tau Biology..................................................................................................... 1 1.2 Tau Aggregation ............................................................................................. 3 1.3 Tau Degradation ............................................................................................. 5 1.4 Tau Therapeutics ............................................................................................ 7 1.5 Conclusion .................................................................................................... 11 1.6 References ................................................................................................... 12 Chapter Two: Synthesis, Stereochemical Analysis, and Derivatization of Myricanol Provide New Probes That Promote Autophagic Tau Clearance .............. 22 2.1 Abstract ........................................................................................................ 22 2.2 Introduction ................................................................................................... 23 2.3 Results and Discussion ................................................................................ 25 2.3.1 Synthesis of 1................................................................................ 35 2.3.2 Enantiomers of 1 ........................................................................... 36 2.3.3 (-)-aS,11R-Myricanol (3) is the enantiomer responsible for anti-tau activity .............................................................................. 38 2.3.4 (-)-aS,11R-Myricanol (3) significantly accelerates tau clearance and selectively reduces distinct tau species ................. 40 2.3.5 (-)-aS,11R-Myricanol (3) clears tau through a non- proteasomal pathway .................................................................... 41 2.3.6 (-)-aS,11R-Myricanol (3) clears tau via autophagy ........................ 42 2.3.7 Synthesis of 16 and a cyclized tetralin derivative thereof, 13. ....... 43 2.3.8 Tau levels are decreased by 16-like tetralin derivative 13 ............. 44 2.4 Materials and Methods ................................................................................. 45 2.4.1 Methods ........................................................................................ 45 2.4.2 Reagents ....................................................................................... 45 2.4.3 Cell Culture ................................................................................... 46 2.4.4 Ex Vivo Slice Cultures ................................................................... 46 2.4.5 Western Blotting ............................................................................ 47 2.4.6 Densitometry (Quant) .................................................................... 47 2.4.7 SILAC/Proteomic Analysis ............................................................ 47 2.4.8 Statistics ........................................................................................ 48 i 2.5 References ................................................................................................... 48 Chapter Three: Inhibitory Activity Against Both Hsp70 Activity and Tau Aggregation In Vitro Best Predicts Cellular and Neuronal Tau Lowering Activity of Small Molecules ...................................................................................... 53 3.1 Abstract ........................................................................................................ 53 3.2 Introduction ................................................................................................... 54 3.3 Results and Discussion ................................................................................ 56 3.3.1 Summary of published Hsp70 inhibitors ........................................ 61 3.3.2 Diverse Hsp70 inhibitor scaffolds have differing effects on tau levels. ...................................................................................... 64 3.3.3 Summary of published tau aggregation inhibitor scaffolds. ........... 65 3.3.4 Diverse tau aggregation inhibitor scaffolds have differing effects on tau levels. ..................................................................... 67 3.3.5 Diverse Hsp70 inhibitor scaffolds have differing effects on tau aggregation in vitro. ................................................................. 68 3.3.6 Tau aggregation inhibitor scaffolds do not inhibit Hsp70 ATPase activity. ............................................................................ 69 3.3.7 Determination of LDH cytotoxicity of Hsp70 and Tau aggregation inhibitors in HEK293T cells. ...................................... 70 3.4 Materials and Methods ................................................................................. 70 3.4.1 Cell Culture ................................................................................... 70 3.4.2 Aggregation Kinetics (Thioflavin T) Assay And Immunoblot .......... 71 3.4.3 Hsp70 ATPase Assay. .................................................................. 71 3.4.4 Lactate Dehydrogenase (LDH) Assay ........................................... 72 3.4.5 Western Blotting ............................................................................ 72 3.5 References ................................................................................................... 73 Chapter Four: Final Perspectives .................................................................................. 78 4.1 Structure-Activity Relationship of Rhodacyanine Derivatives ....................... 80 4.2 References ................................................................................................... 83 Appendix A: Copyright Permissions .............................................................................. 84 Appendix B: Supporting Information for Chapter Two .................................................. 85 B.1 Synthetic racemic 1 reduces tau levels in a tauopathy cell model with low micromolar potency ................................................................................ 85 B.2 LC-MS spectra of 3-treated cell lysates........................................................ 86 B.3 Top activated and inactivated upstream regulators as determined by IPA software. ................................................................................................ 87 B.4 Top canonical pathways as determined by IPA software. ...........................
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