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Lisa Strother Phd Thesis INVESTIGATION OF MOLECULAR AND CELLULAR MECHANISMS UNDERPINNING THE NEUROTOXICITY OF HOMOCYSTEINE AND ITS METABOLITES IN MODELS OF NEURODEGENERATION Lisa Strother A Thesis Submitted for the Degree of PhD at the University of St Andrews 2018 Full metadata for this item is available in St Andrews Research Repository at: http://research-repository.st-andrews.ac.uk/ Please use this identifier to cite or link to this item: http://hdl.handle.net/10023/17067 This item is protected by original copyright Investigation of molecular and cellular mechanisms underpinning the neurotoxicity of homocysteine and its metabolites in models of neurodegeneration Lisa Strother CONTENTS LIST OF FIGURES ................................................................................................................. vii ACKNOWLEDGEMENTS ....................................................................................................... x ABSTRACT ............................................................................................................................. xii DECLARATIONS .................................................................................................................. xiv LIST OF ABBREVIATIONS ................................................................................................ xvii CHAPTER 1: INTRODUCTION AND BACKGROUND ....................................................... 1 1.1 INTRODUCTION ............................................................................................................ 2 1.1.1 Homocysteine metabolism ............................................................................................ 2 1.1.2 Genetic Risk Factors for elevated homocysteine .......................................................... 4 1.2 NON-GENETIC FACTORS DETERMINING HOMOCYSTEINE ELEVATION ... 5 1.2.1 Influence of gender on homocysteine levels ................................................................. 5 1.2.2 Influence of diabetes on homocysteine levels ............................................................... 5 1.2.3 Influence of pregnancy on homocysteine levels ........................................................... 6 1.2.4 Influence of ageing on homocysteine levels ................................................................. 7 1.2.5 Influence of caffeine intake on homocysteine levels .................................................... 8 1.2.6 Influence of alcohol on homocysteine levels ................................................................ 9 1.3 MALADAPTIVE EFFECTS OF HCy FOR HEALTH ............................................... 10 1.3.1 Evidence for a role of homocysteine in cardiovascular disease .................................. 10 1.4 HCy IN NEURODEGENERATIVE DISORDERS ...................................................... 11 1.4.1 Homocysteine increases the risk of developing psychiatric disorders ........................ 11 1.4.2 Mild cognitive impairment and Alzheimer’s disease .................................................. 13 i 1.4.3 Parkinson’s disease ..................................................................................................... 15 1.4.4 Stroke .......................................................................................................................... 16 1.5 MECHANISMS OF HOMOCYSTEINE TOXICITY ...................................................... 18 1.5.1 Overview of toxicity.................................................................................................... 18 1.5.2 Homocysteine thiolactone ........................................................................................... 19 1.5.3 Homocysteine directly activates the NMDA receptor ................................................ 20 1.5.4 Homocysteine preferentially activates GluN2A subunits: implications for downstream signalling .............................................................................................................................. 23 1.5.5 Homocysteine increases levels of intracellular calcium ............................................. 24 1.5.6 Nitric oxide in neuronal function ................................................................................ 25 1.5.7 The role of mitochondria in energy balance................................................................ 28 1.5.8 Homocysteine, oxidative stress and mitochondrial dysfunction ................................. 29 CHAPTER 2: MATERIALS AND METHODS ................................................................. 33 2.1.1 MATERIALS ............................................................................................................. 34 2.2.1 Culture of SH-SY5Y Neuroblastoma Cells ............................................................. 34 2.2.2 Cryopreservation of stocks for future use............................................................... 34 2.2.3 Plating cells for experimentation ............................................................................. 35 2.2.4 Measures of cell viability – Lactate Dehydrogenase Assay ................................... 36 2.2.5 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay ..... 36 2.2.6 Crystal violet assay .................................................................................................... 37 2.2.7 Determination of cell number by DAPI labelling ................................................... 38 2.2.8 Immunocytochemistry .............................................................................................. 38 ii 2.2.9 MitoTracker Red Staining ....................................................................................... 40 2.2.10 DAF2-DA staining ................................................................................................... 42 2.2.11 Mitochondrial Membrane Potential ...................................................................... 43 2.2.12 H2DCF-DA ............................................................................................................... 44 2.2.13 Protein extraction .................................................................................................... 44 2.2.14 Protein concentration determination .................................................................... 45 2.2.15 Subcellular fractioning ........................................................................................... 45 2.2.16 Western blot analysis .............................................................................................. 46 2.2.17 Oxyblot ..................................................................................................................... 49 2.2.18 ELISA ....................................................................................................................... 50 2.2.19 DNA extraction ........................................................................................................ 52 2.2.20 DNA methylation detection .................................................................................... 53 2.2.21 Statistics.................................................................................................................... 53 CHAPTER 3: ESTABLISHING A NOVEL METHOD FOR THE LONG-TERM CULTURE OF SH-SY5Y NEURONAL CELLS EXHIBITING BIOMARKERS OF AGEING ............. 55 3.1 Introduction .................................................................................................................... 56 3.2. Results ............................................................................................................................... 59 3.2.1 Optimisation of SH-SY5Y cell differentiation and maintenance................................ 59 3.2.2 Differentiated SH-SY5Y cells are viable in culture for 4 weeks ................................ 61 3.2.3 SH-SY5Y cells differentiated by this novel protocol express neuronal markers ........ 62 3.2.4 Differentiation with retinoic acid followed by mitotic inhibitions using 5-FDU produces SH-SY5Y cells of a dopaminergic phenotype ...................................................... 65 iii 3.2.5 SH-SY5Y cells differentiated using this novel protocol form synapses and exhibit electrophysiological activity ................................................................................................ 66 3.2.6 Cells prepared using this protocol show accumulations of oxidative damage to lipids with time in culture .............................................................................................................. 69 3.2.7 In this culture system, SH-SY5Y cells exhibit an increase in ROS generation over time and reduction of mitochondrial activity ............................................................................... 70 3.3 Discussion ...................................................................................................................... 73 CHAPTER 4: HOMOCYSTEINE THIOLACTONE AS A NEUROTOXIN ........................ 76 4.1 Introduction .................................................................................................................... 77 4.2 Results ............................................................................................................................ 79 4.2.1 Neither homocysteine nor homocysteine thiolactone are cytotoxic to undifferentiated SH-SY5Y cells ..................................................................................................................... 79 4.2.2 Retinoic acid differentiation upregulates
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