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The Role of Actin Polymerization in Model Hirano Body Formation

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The Role of Actin Polymerization in Model Hirano Body Formation THE ROLE OF ACTIN POLYMERIZATION IN MODEL HIRANO BODY FORMATION by YUN DONG (Under the Direction of Marcus Fechheimer and Ruth Furukawa) ABSTRACT Hirano bodies are paracrystalline filamentous actin inclusions associated with multiple neurodegenerative diseases. The mechanism(s) of Hirano body formation remains largely unknown. Model Hirano bodies generated in Dictyostelium were utilized to identify their protein components and formation mechanism. From proteins identified in model Hirano bodies by mass spectrometry, mitochondrial proteins, profilin I and the Arp2/3 complex were further investigated. Mitochondria were not present in model Hirano bodies. Knockdown of profilin I reduces the size of model Hirano bodies. Inhibition of the Arp2/3 complex activity by CK666 reduced model Hirano body formation. When HSPC300, a subunit of an Arp2/3 complex activator, was knocked out, cells could not form model Hirano bodies. In contrast, when WASH, another Arp2/3 complex activator was knocked out, cells formed model Hirano bodies. These findings reveal that de novo actin polymerization is a key aspect of model Hirano body formation. INDEX WORDS: Hirano bodies, Arp2/3 complex, HSPC300, WASH, Profilin, CK666, Dictyostelium. THE ROLE OF ACTIN POLYMERIZATION IN MODEL HIRANO BODY FORMATION by YUN DONG B.S., Peking University, China, 2011 A Thesis Submitted to the Graduate Faculty of The University of Georgia in Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE ATHENS, GEORGIA 2015 ©2015 Yun Dong All Rights Reserved THE ROLE OF ACTIN POLYMERIZATION IN MODEL HIRANO BODY FORMATION by YUN DONG Major Professor: Marcus Fechheimer Ruth Furukawa Committee: Claiborne Glover James Lauderdale Walter Schmidt Electronic Version Approved: Julie Coffield Interim Dean of the Graduate School The University of Georgia May 2015 ACKNOWLEGEMENTS I would like to first thank my husband, Fan Yang, for being gentle, considerate, supportive and comforting. Without him or his tens of times of flying between Los Angeles and Athens, GA in these four years, I might not have been able to survive this whole process. I would like to also thank my parents for their support. I would especially thank Dr. Ruth Furukawa and Dr. Marcus Fechheimer for their support, guidance, inspiration and all the suggestions on my life decisions. I could not have achieved all these without them. Particularly, I would like to thank their emphasis on details and critical thinking, which will help me a lot no matter what career path I finally choose. I would like to thank my committee, Dr. Claiborne Glover, Dr. James Lauderdale and Dr. Walter Schmidt, for the suggestions on my project and the training on my scientific thinking. I would also like to thank Dr. Jacek Gaertig for his help during the early phase of my project, Dr. Scott Dougan for all kinds of help, and also all the other professors in CBIO that have questioned me to help me think deeper about the project. I would like to thank Dr. Robert Insall and Dr. Angelika Noegel, for kindly sending some of the strains, plasmids and antibodies that are critical to this project. I would not be able to obtain my results without all these. I would also thank my lab mate and friend Dr. Matt Furgerson, for all the help, support and encouragement. Also thanks to my lab mates Will Spears, Connor Sweetnam, Parker Evans, Sandip Manhans, Allison Wood, Ali Bobo and Nelson May, my time in the lab has been fun and iv satisfying. I feel so lucky to have met and worked with you guys, and have learned so much from all of you. I would also thank my fellow students, especially my friends Zhibo Ma, Anthony Gresko, Dr. Yue Qian, and Alicia Hudson, for your help and the time we spent together. Also thank you to the staff of CBIO, especially Carrie Harden and Angie Holiday, for taking care of all kinds of issues and making my life so much easier. v TABLE OF CONTENTS Pages ACKNOWLEGEMENTS ......................................................................................................... iv LIST OF TABLES .................................................................................................................. viii LIST OF FIGURES .................................................................................................................. ix CHAPTER 1 INTRODUCTION AND LITERATURE REVIEW .....................................................1 Hirano bodies ...........................................................................................................1 Formation of model Hirano bodies by introducing an altered form of a Dictyostelium actin binding protein .................................................................................................3 Actin Polymerization ................................................................................................7 The scope of this project ......................................................................................... 10 2 THE ARP2/3 COMPLEX AND PROFILIN I ARE CRUCIAL IN MODEL HIRANO KKKKKKBODY FORMATION .............................................................................................. 15 Abstract .................................................................................................................. 16 Introduction ............................................................................................................ 16 Methods.................................................................................................................. 18 Results .................................................................................................................... 20 vi Discussion .............................................................................................................. 24 3 CONCLUSION ......................................................................................................... 57 REFERENCES ......................................................................................................................... 61 vii LIST OF TABLES Pages Table 1.1: Proteins associated with Hirano bodies from human brain……..………………… 12 Table 1.2: Proteins colocalized with model Hirano bodies…………………………………… 13 Table 1.3: Protein components of model Hirano bodies identified by mass spectrometry…… 14 Table 2.1: Strains and plasmids used for transformation……………………………………... 28 viii LIST OF FIGURES Pages Figure 2.1: Localization of mitochondria and model HBs in Dictyostelium …..……………29 Figure 2.2: Localization of Arp2 and F-actin in Dictyostelium cells generating model HBs……………………………………………………………………………....31 Figure 2.3: Localization of Arp3 and F-actin in Dictyostelium cells generating model HBs ……………………………………………………………………………...33 Figure 2.4: CK666 disrupts the localization of Arp3 and F-actin……………………………35 Figure 2.5: Model HB formation is inhibited by CK666…………………………………….37 Figure 2.6: CK666 affects the distribution of model HB size and the number of cells that generates model HBs…...………………………………………………………..39 Figure 2.7: Model HBs form after CK666 was washed out………………………………….41 Figure 2.8: Localization of HSPC300 and F-actin in Dictyostelium cells generating model HBs ………….…………………………………………………………………..43 Figure 2.9: Localization of WASH and F-actin in Dictyostelium cells generating model HBs ………….…………………………………………………………………..45 Figure 2.10: No model HBs form in HSPC300--CT-myc……………………………………..47 Figure 2.11: Model HBs form in WshA--CT-myc…………………………………………….49 Figure 2.12: Localization of Profilin I and F-actin in Dictyostelium cells generating model HBs ……………………………………………………………………………...51 Figure 2.13: Model HBs form in profilin I knocked down cells……………………………....53 ix Figure 2.14: Profilin I affects the size of model HBs…………….…………………………...55 x CHAPTER 1 INTRODUCTION AND LITERATURE REVIEW Hirano bodies Neurodegenerative diseases are a range of incurable conditions which are characterized by loss of structure or function of neurons. Some of these diseases have specific insoluble protein aggregations which are associated with loss of function, such as Alzheimer’s disease (AD) with β-amyloid plaques [1] and neurofibrillary tau tangles [2], Parkinson’s disease with Lewy bodies containing α-synuclein [3], and Amyotrophic Lateral Sclerosis (ALS) with the aggregation of TDP43 [4]. Most of the neurodegenerative disease specific protein aggregations share the characteristic of the enriched beta-pleated sheet structure, ‘amyloid,’ resulting from protein misfolding [5]. Research on these aggregations reveals crucial facts of the causes and propagation of the diseases [5], such as the cell-to-cell transmission of protein aggregation of tau [6], β-amyloid fibrils [7], or α-synuclein [8]. In addition to these protein aggregations, Hirano bodies (HBs) are also associated with neurodegenerative diseases. HBs were first discovered in the hippocampus in patients in Guam with amyotrophic lateral sclerosis – Parkinson dementia complex [9]. HBs have been observed in the hippocampus of autopsied brains from patients with diverse conditions including AD [10, 11] and Pick’s disease [12], as well as in normal brains of elderly individuals [11]. HBs are predominantly found in the hippocampus, and also in other nerve cells, including cortical and anterior horn cells, and glial cells [13]. HBs are not specific to neurons, as they are also found in skeletal muscle [14]. 1 HBs are ovoid or spindle-like eosinophilic inclusions, mainly composed of filamentous actin that can be stained with fluorescent phalloidin [15]. Ultrastructurally, HBs contain electron-
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