Metal-Based Neurodegeneration: From Molecular Mechanisms to Therapeutic Strategies

Table of Contents:
Preface xi 1 Brain Function, Physiology and the Blood–Brain Barrier 1 1.1 Introduction – An Overview of Brain Structure and Function 1 1.1.1 The Forebrain 1 1.1.2 The Midbrain 4 1.1.3 The Hindbrain 4 1.2 The Cell Types of the Brain 7 1.2.1 Neurons 7 1.2.2 Glial Cells 11 1.3 The Blood–Brain Barrier 19 References 21 2 Role of Metal Ions in Brain Function, Metal Transport, Storage and Homoeostasis 23 2.1 Introduction – The Importance of Metal Ions in Brain Function 23 2.2 Sodium, Potassium and Calcium Channels and Pumps 24 2.3 Calcium and Signal Transduction 30 2.4 Zinc, Copper and Iron 37 2.5 Zinc 37 2.6 Copper 41 2.7 Iron 42 References 48 3 Immune System and Neuroinflammation 51 3.1 General Introduction 51 3.1.1 Innate Immune Response and Neuroinflammation 51 3.1.2 Adaptive Immunity and Neuroinflammation 58 3.1.3 Adaptive Immunity and Neuroinflammation 59 3.1.4 Other Factors Contributing to Neuroinflammation 60 3.1.5 Anti-inflammatory Systems to Regulate Microglia Activation 60 3.2 Apoptosis 63 3.2.1 Iron Metabolic Regulators and Effectors during Inflammation 68 References 72 4 Oxidative Stress in Neurodegenerative Diseases 75 4.1 Introduction – The Oxygen Paradox 75 4.2 Reactive Oxygen Species 76 4.3 Reactive Nitrogen Species 79 4.4 Cellular Defence Mechanisms against Oxidative Stress 82 4.5 ROS, RNS and Cellular Signalling 87 4.6 ROS, RNS and Oxidative Damage 91 4.7 Epigenetics 97 4.7.1 Histone Modifications 100 4.8 Misfolded Protein Aggregates in Neurodegenerative Diseases 101 4.9 The Amyloid State – Structure, Nucleation and Aggregation 102 References 107 5 Ageing and Mild Cognitive Impairment (MCI) 111 5.1 Introduction 111 5.1.1 Gene Involvement and Epigenetics 112 5.1.2 DNA Methylation 112 5.1.3 Histone Post-translational Modifications 113 5.2 Prevalence of MCI 114 5.2.1 MCI Presentation 114 5.3 Brain Regions Involved 115 5.3.1 Neurochemical Observations 116 5.3.2 Factors Involved in the Ageing Process 117 5.3.3 Mitochondria and the Ageing Process 117 5.3.4 Free Radical Theory of Ageing 118 5.3.5 Iron, Copper and Zinc in Ageing 119 5.3.6 Risk Factors for Cognitive Decline 121 5.3.7 APOe4 Isoforms and MCI 122 5.3.8 Ageing and Immunity 122 5.4 Proteostasis 126 5.5 Conclusion 127 References 128 6 Parkinson’s Disease 131 6.1 Risk Factors for PD 131 6.2 Genetics of PD 134 6.3 SNCA 135 6.4 LRRK2 135 6.5 Parkin 135 6.6 DJ-1 135 6.7 PINK1: PTEN-Induced Kinase 136 6.8 Epigenetics 136 6.9 miRNA 136 6.10 Proteins Involved in PD 137 6.11 Synucleins 137 6.12 LRRK2 or PARK 8 142 6.13 PINK1 or PTEN-Induced Putative Kinase 1, PARK6 143 6.14 Parkin, PARK2 144 6.15 Synphilin-1 146 6.16 UCHL 1, Park 5 147 6.17 DJ-1, PARK 7 147 6.18 Metal Involvement in Parkinson’s Disease 148 6.18.1 Iron 148 6.18.2 Zinc 153 6.18.3 Copper 154 6.19 Neurotransmitters Involved in PD 154 6.20 Mitochondrial Dysfunction 156 6.21 PD and Inflammation 156 6.22 Receptors Involved in the Inflammatory Response 159 6.22.1 Toll-Like Receptors 159 6.22.2 Glucocorticoid Receptor, GR 159 6.22.3 CD200/CD200R 160 6.22.4 Vitamin D Receptor (VDR) 160 6.22.5 Peroxisome Proliferators-Activated Receptors 161 6.23 Oxidative Stress and PD 161 References 163 7 Alzheimer’s Disease 169 7.1 Introduction 169 7.2 Epidemiology and Risk Factors for AD 171 7.3 Genetics of AD 173 7.3.1 Epigenetics 174 7.4 Proteins Involved in Alzheimer’s Disease 175 7.5 Metal Involvement in Alzheimer’s Disease 179 7.6 Zinc Homoeostasis in AD 181 7.7 Copper Homoeostasis in AD 181 7.8 Iron Homoeostasis in AD 183 7.9 Neurotransmitters Involved in AD 185 7.9.1 Acetyl choline 185 7.9.2 Glutamate 187 7.10 Mitochondrial Function in Alzheimer’s Disease 189 7.11 Neuroinflammation and AD 191 7.12 Oxidative Stress 191 References 195 8 Huntington’s Disease and Polyglutamine Expansion Neurodegenerative Diseases 203 8.1 Introduction 203 8.2 An Overview of Trinucleotide Expansion Diseases 204 8.3 Poly-Q Diseases 204 8.4 Poly-Q Protein Aggregation and Poly-Q Disease Pathogenesis 208 8.5 Huntington’s Disease 211 8.6 Other Poly-Q Disease Proteins 215 8.7 Spinocerebellar Ataxias 218 References 221 9 Friedreich’s Ataxia and Diseases Associated with Expansion of Non-Coding Triplets 227 9.1 Incidence and Pathophysiology of Friedreich’s Ataxia 227 9.2 Molecular Basis of the Disease: Triplet Repeat Expansions 228 9.3 Molecular Basis of the Disease: Frataxin and Its Role in Iron Metabolism 230 9.4 Other Diseases Associated with Expansion of Non-Coding Triplets 233 References 236 10 Creutzfeldt–Jakob and Other Prion Diseases 239 10.1 Introduction 239 10.2 A Brief History of Prion Diseases 240 10.3 Structural Aspects of the Cellular Form of PrPC 241 10.4 ‘Prion’ or ‘Protein-Only’ Hypothesis – Conformation-Based Prion Inheritance 244 10.5 Models of PsPC to PsPSc Conversion 246 10.6 Formation of Prion Aggregates 248 10.7 Pathways of Prion Pathogenesis 253 References 256 11 Amyotrophic Lateral Sclerosis 261 11.1 Introduction 261 11.2 Major Genes Involved in ALS 262 11.3 Superoxide Dismutase and ALS 265 11.4 Contributors to Disease Mechanisms in ALS 269 11.5 Excitotoxicity and Decreased Glutamate Uptake by Astroglia 269 11.6 Endoplasmic Reticulum Stress 270 11.7 Inhibition of the Proteasome 270 11.8 Mitochondrial Damage 271 11.9 Aberrant Secretion of Mutant SOD1 271 11.10 Extracellular Superoxide Generation 271 11.11 Axonal Disorganization and Disrupted Transport 272 11.12 Microhaemorrhages of Spinal Capillaries 272 11.13 Glial Cells in ALS 273 11.14 ALS and Apoptosis 273 11.15 Prion-Like Phenomena in ALS 274 11.16 Conclusions 276 References 276 12 Alcoholic Brain Damage 283 12.1 General Introduction 283 12.2 Anatomy of Alcohol-Induced Damage 285 12.3 Genetics of Alcohol-Induced Brain Damage 286 12.3.1 Epigenetics 286 12.3.2 MicroRNAs 287 12.3.3 Genetics 288 12.4 Factors Associated with Alcohol Brain Damage 291 12.5 Factors Involved in Alcohol-Induced Brain Damage 292 12.5.1 Neuropeptides 292 12.5.2 Neurotransmitters 293 12.5.3 Acetaldehyde 294 12.5.4 Signalling Pathways 295 12.5.5 Neuroinflammation and Alcohol 296 12.5.6 Astrocytes and Alcohol 297 12.5.7 Microglia and Alcohol 300 12.5.8 NF-kB 301 12.5.9 Toll-Like Receptors 302 12.5.10 Oligodendrocytes and Alcohol 303 12.5.11 Alcohol and Mitochondria 303 12.5.12 Alcoholic Brain Damage and Oxidative Stress 304 References 305 13 Other Neurological Diseases 309 13.1 Introduction 309 13.2 Wilson’s and Menkes Diseases 309 13.3 Neurodegeneration with Brain Iron Accumulation 316 13.4 Aceruloplasminaemia 316 13.5 Neuroferritinopathy 318 13.6 Other Neurodegenerative Disorders with Brain Iron Accumulation 320 13.7 Multiple Sclerosis 323 13.8 HIV-Associated Neurocognitive Disorder 329 References 332 14 Therapeutic Strategies to Combat the Onset and Progression of Neurological Diseases 337 14.1 Introduction 337 14.2 Chelation of Excessive Metal Ions 338 14.2.1 Chelation in Parkinson’s Disease 341 14.2.2 Chelation Therapy in AD 341 14.2.3 Chelation in Friedreich Ataxia 343 14.3 Ageing and Cognitive Decline 344 14.3.1 Saturated/Unsaturated Fat Intake 344 14.3.2 Berries 345 14.3.3 Creatine Supplementation 346 14.3.4 Sirtuins 347 14.3.5 Immunity 347 14.3.6 Mitochondria Mutations 348 14.4 Parkinson’s Disease 348 14.4.1 Nutraceutical 349 14.4.2 NASIs and COX2 Inhibitors 351 14.4.3 Physical Exercise 351 14.4.4 Dopamine Agonists 352 14.4.5 Monoamine Oxidase Inhibitors 354 14.4.6 L-DOPA 355 14.4.7 Mitochondria and PD 356 14.4.8 Sirtuins 356 14.4.9 Creatine 357 14.4.10 CoQ10 358 14.4.11 Surgical Treatment for PD 358 14.5 Alzheimer’s Disease 359 14.5.1 Epigenetic Modifications 359 14.5.2 Sirtuins 359 14.5.3 Tau Kinase Inhibitors 359 14.5.4 Neurotransmitters 360 14.5.5 Anti-inflammatory Drugs 360 14.5.6 Strategies to Remove Ab 360 14.5.7 Ab Immunotherapy 363 14.6 Huntington’s Disease and Other Poly-Q Diseases 364 14.7 Friedreich’s Ataxia and Other Non-Coding Nucleotide Repeat Diseases 367 14.8 Creutzfeld–Jakob and Other Prion Diseases 370 14.9 Amyotrophic Lateral Sclerosis 372 14.10 Alcohol Abuse 373 14.11 Other Neurological Diseases 378 14.11.1 Wilson’s and Menkes Diseases 378 14.11.2 Neurodegeneration with Brain Iron Accumulation 379 14.12 Multiple Sclerosis 381 14.13 HIV-Associated Neurocognitive Disorder 386 References 387 15 Concluding Remarks 395 15.1 New Innovative Therapeutics 400 15.1.1 Stem Cells 402 15.2 Biochemical Biomarkers of Neurodegenerative Diseases 404 15.2.1 Parkinson’s Disease 404 15.2.2 Alzheimer’s Disease 404 15.2.3 Alcohol Brain Damage 405 15.2.4 Epilogue 405 References 406 Index

About the Author :
Robert Crichton and Roberta Ward, Unit of Biochemistry, Université Catholique de Louvain, Belgium