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By Yulong Sun a Thesis Submitted in Conform MOLECULAR MECHANISMS OF AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEMENTIA: NEW INSIGHTS INTO THE FORMATION OF TDP-43 PROTEIN ASSEMBLIES by Yulong Sun A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Medical Biophysics University of Toronto © Copyright by Yulong Sun 2018 Molecular Mechanisms of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: New Insights into the Formation of TDP-43 Protein Assemblies Yulong Sun Doctor of Philosophy Department of Medical Biophysics University of Toronto 2018 Abstract Advances in modern medicine in the past century have dramatically improved the average life expectancy in the western world. Unfortunately, the molecular mechanisms that maintain the integrity of proteins in the body appear to be unable to keep pace. This has led to a growing prevalence of late-onset diseases involving abnormal accumulation of proteins, especially in the last century. The increase in occurrence of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and transmissible spongiform encephalopathies such as prion disease, has become a great burden to the healthcare system. All of these diseases are currently incurable and fatal, but they share the common hallmark of misfolding and aggregation of proteins within the effected neurons. The discovery and characterization of such proteins have often led to the identification of potential targets for treatment and drug design. In the case of ALS, progressive death of upper and lower motor neurons leads to full-body paralysis, and patient death from respiratory failure. The cause of ALS is currently unknown, but remarkably, regardless of the type of ALS (familial or sporadic), the RNA binding protein, TDP-43, is found in 97% of cases as neuronal inclusions, suggesting a mechanistic role in disease pathogenesis. ii In this thesis, several techniques are used to enable detailed biophysical characterization the TDP-43 aggregation process in solution and in model membranless organelles. Equilibrium turbidity measurements of the protein under aggregating conditions and the inhibitory effects of native-state stabilizing oligonucleotides on aggregation are presented. The modulatory effects of physiological concentrations of electrolytes on TDP-43 aggregation and their implications are also discussed. A novel technique called spatially targeted optical microproteomics (STOMP) is presented as a method to interrogate the proteomic contents of small cellular features in mammalian tissue in hope of identifying common proteins in neuronal inclusions and stress granules. Although the STOMP technique still requires refinement, the biophysical studies on TDP-43 presented here begin to unravel the complex and largely unknown etiology of what is currently a devastating and incurable disease. iii ACKNOWLEDGMENTS I am indebted to a number of individuals who supported me over the course of my education in my graduate studies. Foremost, I am grateful to my family – particularly my parents - Dr. Ping Sun and Jane Luo – for providing me the opportunity to receive a western education. Although their efforts of pushing me to pursue a medical degree was not fruitful, I hope my sister Ruthie does so of her own choosing. I thank also my Ph.D. supervisor, Dr. Avi Chakrabartty, for his expert guidance while allowing me to think independently and design my own projects. I thank the members of supervisory committee, Dr. Paul Fraser, Dr. Thomas Kislinger, and previously, Dr. Brad Wouters, for their thoughtful suggestions and criticisms, which have helped to shape the work presented here. I owe thanks to the past and present members of the Chakrabartty Lab who provided words of encouragement and laid the foundations for the work presented here. Dr. P. Eli Arslan, Dr. Kevin C. Hadley, Dr. Philbert Ip, Dr. Aaron Kerman, Dr. Rishi Rakhit, Dr. Priya R. Sharda, Dr. Vanessa Morris, and Natalie Galant have my thanks, as does our collaborators from the labs of Dr. Chris M. Yip and Dr. Andrew Emili from the University of Toronto, and Dr. Sultan Darvesh from Dalhousie University. I also thank the newest members of the Chakrabartty lab and the research students – Alison, Joe, Ryan, Meghan and Jethro - for infusing some young blood back into the group. I wish to thank my fiancée, Dr. Linda Chau, for her 4 years of patience as I completed my degree. iv TABLE OF CONTENTS Acknowledgments ............................................................................................................................................ iv Table of Contents ............................................................................................................................................ v List of Figures and Tables ........................................................................................................................... ix CHAPTER I Introduction: TDP-43, a Central Protein in the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (ALS/FTD) Disease Spectrum ............................................. 1 Introduction ................................................................................................................................................. 3 Rising prevalence of neurodegenerative diseases ............................................................................. 3 ALS/FTD is a spectrum disorder ...................................................................................................... 4 Physiological Functions and Pathobiology of TDP-43 .................................................................. 6 Physiological functions of TDP-43.................................................................................................... 6 Pathological functions of TDP-43 ..................................................................................................... 7 Insights into TDP-43 Aggregation from Structural Studies .......................................................... 9 Domain structure of TDP-43 ............................................................................................................. 9 The ubiquitin-like fold of the NTD ................................................................................................. 11 The N-terminus is involved in aggregation and splicing .............................................................. 11 Tandem RRMs contain canonical folds but are uniquely arranged ............................................ 14 Role of RRM domains in aggregation ............................................................................................. 15 The C-terminal region has a dynamic structure ............................................................................. 15 The C-terminal Domain: Prions, Droplets and Aggregation ...................................................... 17 The C-terminal domain resembles yeast prions ............................................................................. 17 Human proteins containing PrLD form membraneless organelles ............................................ 18 TDP-43 undergoes phase transitions through its PrLD ............................................................... 19 LLPS as drivers for aggregation ....................................................................................................... 21 Spreading and propagation of ALS/FTD ...................................................................................... 22 Chapter Remarks ..................................................................................................................................... 24 Concluding remarks on current literature ....................................................................................... 24 Acknowledgements ............................................................................................................................ 25 Thesis Rationale ....................................................................................................................................... 26 References .................................................................................................................................................. 29 CHAPTER II Binding of TDP-43 to the 3’UTR of its Cognate mRNA Enhances its Solubility ..................... 45 Introduction ............................................................................................................................................... 47 Results ......................................................................................................................................................... 49 Recombinant vYFP-TDP-43 is natively dimeric ........................................................................... 49 TG12 inhibits TDP-43 aggregation at sub-stoichiometric concentrations by maintaining dimer configuration .............................................................................................................. 51 Naturally occurring nucleotide targets reduce the level of TDP-43 aggregation ...................... 54 Aggregation inhibition is achieved through RRM1 binding ........................................................ 55 Effect of oligonucleotides on pre-formed vYFP-TDP-43 aggregates ........................................ 56 Morphology of TDP-43 aggregates ................................................................................................. 57 Discussion .................................................................................................................................................
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