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Targeting Kv2.1/Syntaxin Interaction for Neuroprotection by Chung-Yang

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Targeting Kv2.1/Syntaxin Interaction for Neuroprotection by Chung-Yang Title Page Targeting Kv2.1/Syntaxin Interaction for Neuroprotection by Chung-Yang Yeh B.A., Rutgers University, 2014 Submitted to the Graduate Faculty of School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2019 Committee Membership Page UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This thesis/dissertation was presented by Chung-Yang Yeh It was defended on June 27, 2019 and approved by Dandan Sun, Professor, Neurology Thanos Tzounopoulos, Professor, Otolaryngology Michael Palladino, Professor, Pharmacology & Chemical Biology Amantha Thathiah, Assistant Professor, Neurobiology Rajesh Khanna, Professor, Pharmacology, University of Arizona Dissertation Director: Elias Aizenman, Professor, Neurobiology ii Copyright © by Chung-Yang Yeh 2019 iii Abstract Targeting Kv2.1/Syntaxin Binding for Neuroprotection Chung-Yang Yeh, PhD University of Pittsburgh, 2019 The regulation of cytosolic potassium is a convergent factor in cell death programs of many mammalian cell types including central nervous system neurons. Physiological levels of potassium concentrations can suppress the activation of critical caspases and nucleases necessary for cell death. Under physiological conditions, several ion channels and exchangers sustain intracellular potassium levels. Conversely, tightly regulated molecular pathways facilitate the depletion of intracellular potassium after injury to very low concentrations, enabling cell death mechanisms to proceed. Several research groups have shown that preventing the loss of intracellular potassium after injury through various approaches can increase the survivability of several cell types. In neurons, the main regulator of intracellular potassium after injury is the delayed rectifier potassium channel Kv2.1. Strategies aimed to ameliorate Kv2.1-dependent neuronal cell death have been investigated over the past several years. We have come to understand that lethal oxidative damage set forth unique, zinc-dependent phosphorylation of Kv2.1, leading to enhanced membrane channel insertion and elevated potassium efflux currents. Critical to this pathway is the protein- protein interaction between Kv2.1 and the cell surface soluble NSF attachment protein receptor (SNARE) syntaxin 1A (syntaxin). Interrupting this interaction has been shown to improve neuronal survival in vitro. In this dissertation, I report several studies that further clarify the molecular interactions between Kv2.1 and syntaxin, and provide the first in vivo evidence that disrupting the Kv2.1-syntaxin binding is a viable neuroprotective strategy. We explored several approaches using both peptide-based and synthetic small molecules as the protective agent. To cap off these findings, I provide preliminary data that leverages the hepatitis virus protein NS5A to iv suppress Kv2.1-dependent cell death in ischemic stroke. We intend for the work presented here to serve as the basis to further unravel the role of Kv2.1 in other neurodegenerative conditions and eventually make the translational leap to improve clinical treatments. v Table of Contents Preface ........................................................................................................................................... xi 1.0 Introduction ............................................................................................................................. 1 1.1 The increasing burden of neurodegenerative diseases ................................................ 1 1.2 Apoptotic cell death in neurodegenerative diseases .................................................... 3 1.3 Apoptotic cell volume decreases and potassium regulation ....................................... 5 1.4 Kv2.1 in neuronal cell death .......................................................................................... 8 1.5 Oxidative stress and zinc dysregulation in neurodegenerative diseases .................. 10 1.6 Evidence of Kv2.1 in neurodegenerative diseases ..................................................... 11 1.7 The Kv2.1-syntaxin interaction ................................................................................... 13 1.8 Channel-targeted investigative approaches to neuroprotection .............................. 15 1.9 Thesis Goals .................................................................................................................. 17 2.0 Targeting a Potassium Channel/Syntaxin Interaction Ameliorates Cell Death in Ischemic Stroke ........................................................................................................................... 18 2.1 Section Summary .......................................................................................................... 18 2.2 Introduction .................................................................................................................. 19 2.3 Results ............................................................................................................................ 21 2.3.1 Establishing the sequence of TAT-C1aB ........................................................ 21 2.3.2 TAT-C1aB suppresses apoptotic Kv2.1-mediated K+ currents and provides neuroprotection from “slow” excitotoxicity in vitro without influencing NMDA- evoked Ca2+ responses .............................................................................................. 22 2.3.3 TAT-C1aB provides neuroprotection in vivo ................................................. 24 vi 2.4 Discussion ...................................................................................................................... 41 2.5 Materials and Methods ................................................................................................ 44 3.0 Defining the Kv2.1-syntaxin molecular interaction identifies a novel class of small molecule neuroprotectants ......................................................................................................... 51 3.1 Section Summary .......................................................................................................... 51 3.2 Introduction .................................................................................................................. 52 3.3 Results ............................................................................................................................ 55 3.3.1 Structural modeling of Kv2.1 C1aB H1LSPNKWKW9 peptide and its interactions with syntaxin.......................................................................................... 55 3.3.2 The Kv2.1 C1aB W7 syntaxin-binding structural motif is shared with munc18 W28 ............................................................................................................... 56 3.3.3 Experimental validation of C1aB/syntaxin interactions ................................ 56 3.3.4 Virtual screening of Kv2.1/syntaxin inhibitors identifies six small molecule candidates ................................................................................................................... 57 3.3.5 Cell-based screening of small molecule cpd5 reveals neuroprotective properties .................................................................................................................... 58 3.3.6 Cpd5 suppresses cell death-enabling K+ currents .......................................... 60 3.3.7 Cpd5 is a first-in-class inhibitor of Kv2.1 binding to syntaxin ..................... 61 3.3.8 Cpd5 does not alter either synaptic or intrinsic properties of neurons ....... 62 3.4 Discussion ...................................................................................................................... 78 3.5 Materials & Methods ................................................................................................... 82 4.0 Injury-dependent expression of HCV protein NS5A ameliorates striatal infarct in vivo ................................................................................................................................................ 91 vii 4.1 Section Summary .......................................................................................................... 91 4.2 Introduction .................................................................................................................. 92 4.3 Results ............................................................................................................................ 94 4.3.1 pAAV-4xMRE-NS5A.eGFP recapitulates the in vitro effects of 4xMRE- NS5A.eGFP ................................................................................................................. 94 4.3.2 Striatal injection of AAV9-4xMRE-NS5A.eGFP does not alter behavior, liver ...................................................................................................................................... 95 4.3.3 Focal ischemic stroke induces the expression of NS5A.eGFP in animals received striatal injection of AAV9-4xMRE-NS5A.eGFP ...................................... 96 4.3.4 Preventative treatment of AAV9-4xMRE-NS5A.eGFP reduces striatal infarct .......................................................................................................................... 97 4.4 Discussion .................................................................................................................... 104 5.0 General Discussion .............................................................................................................
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