Oxidative Stress and Redox Signalling in Parkinson’s Disease (Issues in Toxicology, Volume 34)

Parkinson's Disease is the second most common neurodegenerative disorder affecting millions of people worldwide. In order to find neuroprotective strategies, a clear understanding of the mechanisms involved in the dopaminergic death of cells that progresses the disease is needed. Oxidative stress can be defined as an imbalance between the production of reactive species and the ability to detoxify them and their intermediates or by-products. Oxidative damage to lipids, proteins, and DNA has been detected in autopsies from individuals with Parkinson’s Disease and so links can be made between oxidative stress and Parkinson’s Disease pathogenesis. This book provides a thorough review of the mechanisms by which oxidative stress and redox signalling mediate Parkinson’s Disease. Opening chapters bring readers up to speed on basic knowledge regarding oxidative stress and redox signalling, Parkinson’s Disease, and neurodegeneration before the latest advances in this field are explored in detail. Topics covered in the following chapters include the role of mitochondria, dopamine metabolism, metal homeostasis, inflammation, DNA-damage and thiol-signalling. The role of genetics and gene-environment interactions are also explored before final chapters discuss the identification of potential biomarkers for diagnosis and disease progression and the future of redox/antioxidant based therapeutics. Written by recognized experts in the field, this book will be a valuable source of information for postgraduate students and academics, clinicians, toxicologists and risk assessment groups. Importantly, it presents the current research that might later lead to redox or antioxidant – based therapeutics for Parkinson’s disease. Cover......Page 1 Oxidative Stress and Redox Signalling in Parkinson’s Disease......Page 2 Preface......Page 8 Contents......Page 10 1.1 Introduction......Page 18 1.2 Clinical Manifestations of Parkinson’s Disease......Page 19 1.3 Neuropathology......Page 20 1.3.1 Selective Vulnerability of the Nigrostriatal Dopamine Neuron......Page 21 1.3.2.1 Mitochondrial DNA Damage......Page 23 1.3.2.2 Complex I Inhibition......Page 24 1.3.3 Oxidative Stress......Page 25 1.3.4 Dopamine Metabolism......Page 26 1.3.5 Neuroinflammation......Page 28 1.4 Genetics of Parkinson’s Disease......Page 29 1.5.1 Pesticides......Page 30 1.5.3 Pathogens......Page 31 1.6 Gene–Environment Interaction......Page 32 References......Page 33 2.1 Introduction......Page 44 2.2.1 Reactive Oxygen and Nitrogen Species: Sources......Page 45 2.2.2 Antioxidant Systems......Page 48 2.2.3.1 Oxidative DNA Damage......Page 50 2.2.3.2 Oxidative Damage to Lipids......Page 51 2.2.3.3 Oxidative Protein Modifications: Redox Sensors and Transducers......Page 52 2.3.1 Cellular Organization of the SNpc......Page 54 2.3.2.1 Bioenergetics and Central Carbon Metabolism......Page 56 2.3.2.2 Oxidative Stress......Page 59 2.3.2.2.2 Dopamine (DA).Oxidative stress in PD is also associated with the pro-oxidant properties of DA. Mutant α-synuclein downregulates .........Page 60 References......Page 61 3.1 Reactive Oxygen Species (ROS)......Page 78 3.1.1 Mitochondria and ROS Production......Page 79 3.2 Parkinson’s Disease......Page 80 3.3 Mitochondrial Dysfunction in PD......Page 81 3.3.1 ETC Complex Deficiency in PD......Page 82 3.3.3 Mitochondrial Ca2+ Buffering in PD......Page 84 3.3.4 PD-Related Genes and Mitochondrial Dysfunction......Page 85 3.4 Mitochondrial Dysfunction in Toxicant-Induced PD......Page 86 3.4.1.1 6-OHDA: An Experimental Catecholaminergic Neurotoxicant......Page 87 3.4.1.2 MPTP: Evidence for CI and the Toxic Exposure Hypothesis of PD......Page 88 3.4.2 Rotenone: A Case for Complex I Inhibition......Page 90 3.4.3 Paraquat: Redox Cycling Agent......Page 92 3.4.3.2 Mechanism of Toxicity: Redox Cycling and ROS Generation......Page 93 3.4.3.3 Role of Mitochondria in PQ Toxicity......Page 94 3.4.3.5 Using PQ for Developing Animal Models of PD......Page 96 3.4.3.6 Diquat Use with PQ: Example of Another Redox Cycling Agent......Page 97 3.4.4 Maneb: A Role of Complex III in PD Pathogenesis......Page 98 3.4.5 Other Environmental Toxins......Page 99 3.5 Concluding Remarks......Page 100 References......Page 102 4.1 The Life of Dopamine: Synthesis, Storage and Metabolism......Page 114 4.2 3,4-Dihydroxyphenylacetaldehyde (DOPAL) and Biogenic Aldehydes Derived from Neurotransmitters......Page 117 4.3.1 Mechanisms for Elevation of DOPAL......Page 118 4.3.2 Relevance of Altered Dopamine Metabolism/Trafficking to PD......Page 119 4.4 Toxicity and Protein Reactivity of DOPAL and Biogenic Aldehydes......Page 120 4.4.2 Protein Reactivity and Targets......Page 121 4.5 The Role of Biogenic Aldehydes in Disease......Page 122 4.6 Summary......Page 123 References......Page 124 5.1 Oxidative Stress and Susceptibility of Dopaminergic Neurons in Parkinson’s Disease......Page 133 5.2 Dopamine Regulation and Metabolism......Page 134 5.3.1 Metabolism of Dopamine by Monoamine Oxidase......Page 135 5.3.3 Modification of Protein by Oxidized Dopamine......Page 136 5.3.4 Mitochondrial Dysfunction and Dopamine Oxidation......Page 139 5.4 The Role of Dopamine in Toxin-Induced Toxicity......Page 141 5.5.1 In vitro Exogenous Dopamine and l-DOPA Treatment......Page 142 5.5.2 Exogenous Dopamine Administration in vivo......Page 143 5.5.3 Dysregulation of Dopamine Handling in vivo......Page 144 5.6 Dopamine and α-Synuclein......Page 145 5.7 Dopamine Storage Disruption in PD......Page 146 5.8 Summary and Conclusions......Page 147 References......Page 148 6.1 Introduction......Page 161 6.2 Glutathione......Page 162 6.3 Thiol Redox Signalling and Thiol–Disulfide Exchange......Page 163 6.4 Cellular Reductases......Page 165 6.4.1 Thioredoxins......Page 166 6.4.2 Glutaredoxins......Page 167 6.4.3 Peroxiredoxins......Page 168 6.5 Glutathione Synthesis in the Brain......Page 169 6.6 Glutathione and Models of Oxidative Stress in Dopaminergic Neurons......Page 171 6.7.1 Glutathione Peroxidase......Page 172 6.7.2 Glutathione S-Transferases......Page 173 6.8 GSH and Transport in the Brain: Multidrug Resistance Proteins (MDRP) and the Blood–Brain Barrier (BBB)......Page 175 6.9.1 Glutathione-S-Transferase......Page 176 6.9.3 PTEN-Induced Putative Kinase 1 (PINK1)......Page 177 6.10 Free Radicals as Messengers to Modulate Transcription Factors: Effects on Thiol Redox Regulation......Page 178 References......Page 179 7.1 Introduction......Page 201 7.2.1 Regulation of Inflammatory Genes in Glial Cells by NF-κB......Page 202 7.2.2 Nuclear Regulation of NF-κB Function in Glial Cells......Page 203 7.3.1 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP)......Page 205 7.3.2 6-Hydroxydopamine (6-OHDA)......Page 208 7.3.3 Lipopolysaccharide (LPS)......Page 209 7.4 Neuroinflammation and Protein Aggregation in PD and Protein-Misfolding Disorders......Page 210 7.4.1 Neuroinflammation in Protein-Misfolding Disorders......Page 211 7.4.2 Oxidative Stress in Protein-Misfolding Disorders......Page 212 7.4.3 Unfolded Protein Response in Protein-Misfolding Disorders......Page 213 7.5 Conclusions......Page 214 References......Page 215 8.1 Neuronal Degeneration in Parkinson’s Disease......Page 227 8.1.2 Sources of Oxidative Stress and Selective Vulnerability......Page 228 8.1.2.1 Dopamine Metabolism......Page 229 8.1.2.2 Mitochondrial Dysfunction......Page 230 8.1.2.3 Iron Accumulation......Page 231 8.1.2.5 Glutathione Loss and Associated Thiol Perturbations......Page 232 8.1.3 Increased Oxidative Stress and Selective Cell Death......Page 233 8.3.1 Akt Structure and Function......Page 234 8.3.2 Evidence of Akt1 Involvement in PD......Page 236 8.3.3 Redox Regulation of Akt1 Activity......Page 237 8.4.1 Redox Regulation of MAP3K-ASK1......Page 240 8.4.1.1.1 Thioredoxin.Thioredoxin (Trx1) was the first ASK1-inhibitory protein to be described.149 It is a thiol disulfide oxidoreductase .........Page 242 8.4.1.1.3 DJ-1.The autosomal recessive PD-related gene DJ-1 has been shown to inhibit ASK1 activity directly by binding at the N-terminal .........Page 244 8.4.1.1.5 Akt1.The role of Akt1 in inhibiting ASK1 activation has been discussed earlier in this chapter, wherein Akt1-mediated phosphoryl.........Page 245 8.4.1.2.2 Daxx.Chang et al. first demonstrated Daxx (death-domain associated protein), to be involved in the ASK1 signalosome, further act.........Page 246 8.4.1.3 Evidences of ASK1 Involvement in PD......Page 247 8.4.2.1 JNK......Page 248 8.4.2.2 p38 MAPKs......Page 249 8.5 Conclusions......Page 250 Acknowledgements......Page 251 References......Page 252 9.1 Brain Iron Homeostasis......Page 272 9.1.1 Brain Iron Transport and Distribution......Page 273 9.1.2 Regulation of Brain Iron Homeostasis......Page 274 9.2 Iron Metabolism and Parkinson’s Disease......Page 275 9.2.2 Iron Accumulation Accelerates the Symptomatology of Parkinson’s Disease......Page 276 9.2.3.1 Changes in Iron-Uptake Proteins......Page 277 9.2.3.2 Changes in Iron-Release Proteins......Page 278 9.2.3.3 Changes in Iron-Storage Proteins......Page 279 9.2.3.4 Changes in the Distribution of Intracellular Iron......Page 280 9.2.5 Iron, ROS and Apoptosis of Dopaminergic Neurons in the Substantia Nigra of Parkinson’s Disease......Page 281 9.3 Iron-Related Therapeutic Approaches for PD......Page 283 References......Page 285 10.1 Introduction......Page 294 10.2 Misfolded Protein Aggregation and Accumulation in PD......Page 295 10.2.1 α-Synuclein: Mutations and Misfolding......Page 296 10.2.1.1 Redox Regulation of α-Synuclein Aggregation......Page 298 10.3.1 Protein Synthesis......Page 300 10.3.2 Protein Folding, Unfolding and Disaggregation by Chaperones......Page 301 10.3.3 Protein Degradation Pathways......Page 304 10.3.3.1 The Ubiquitin Proteasome System (UPS)......Page 305 10.3.3.2 The Autophagosome–Lysosome System......Page 308 10.3.4.1 Endoplasmic Reticulum Stress and the Unfolded Protein Response......Page 310 10.3.4.2 Mitochondria Protein Quality Control......Page 312 References......Page 314 11.1 Introduction......Page 342 11.2.1 Evidence of Mitochondrial Deficits in Postmortem PD Brains......Page 344 11.2.2 Evidence of Autophagic Impairment in Postmortem PD Brains......Page 345 11.3.1 Rotenone......Page 347 11.3.2 PQ and Maneb......Page 349 11.3.3 MPTP or MPP+......Page 351 11.3.4 6-OHDA......Page 353 11.4 Genetic Evidence for Mitochondrial Deficits and Autophagic Impairment in PD......Page 354 11.4.1 aSyn......Page 355 11.4.2 Parkin/PINK1......Page 357 11.4.3 DJ-1......Page 361 11.4.4 ATP13A2......Page 364 11.5 Interrelationships Between Autophagic Impairment and Mitochondrial Dysfunction......Page 366 11.6 Summary and Future Directions......Page 367 References......Page 369 12.1 Introduction......Page 406 12.1.1 Do Genes Influence Lifespan......Page 407 12.1.2 Which Genes Influence Lifespan......Page 408 12.2 Apolipoprotein E......Page 410 12.2.1 LDL Receptors......Page 411 12.2.2 Effects of Polymorphisms on APOE Function......Page 412 12.2.3 APOE and Parkinson’s Disease......Page 413 12.3 FOXO3A and FOXO Family......Page 414 12.3.1 FOXO3A Biological Functions......Page 415 12.3.2 FOXO3A and Protein Homeostasis......Page 417 12.4 Role of Other Genes Emerged from Animal Studies in Aging......Page 418 12.4.1 Are Aging-Modifying Genes Discovered in Laboratory Animals Relevant for PD......Page 421 References......Page 422 13.1 Biomarkers......Page 440 13.2 Oxidative Stress......Page 441 13.3 Candidate Biomarkers for ROS-Induced Stress......Page 443 13.3.1 Halogenation......Page 444 13.4 Candidate Biomarkers for RNS-Induced Stress......Page 446 13.4.1 Nitration......Page 447 13.4.1.1 Nitrated Species of Serum Proteins Such as α-Synuclein as Possible Biomarkers......Page 448 13.4.1.2 Nitration, Halogenation and the Thyroid Gland: A New Field for Searching Biomarkers for Parkinson’s Disease......Page 450 13.4.2 S-nitros(yl)ation......Page 451 13.5 Conclusions......Page 452 References......Page 453 14.1 Introduction......Page 464 14.2 Heterocyclic Amines......Page 465 14.3.1 Flavonoids......Page 467 14.3.1.1 Isoflavones......Page 469 14.3.1.2 Flavones......Page 470 14.3.1.3 Flavanones......Page 472 14.3.1.4 Flavanols......Page 473 14.3.1.5 Anthocyanins......Page 475 14.3.1.6 Flavonols......Page 477 14.3.2.1 Curcuminoids......Page 479 14.3.2.2 Phenolic Acids......Page 481 14.3.2.3 Stilbenes......Page 482 14.3.2.4 Lignans......Page 483 14.4.1 Vitamin A......Page 484 14.4.2 Vitamin B......Page 486 14.4.3 Vitamin C......Page 487 14.4.4 Vitamin D......Page 488 14.4.5 Vitamin E......Page 490 14.5 Summary......Page 491 References......Page 492 Subject Index......Page 522 Parkinson's Disease is the second most common neurodegenerative disorder affecting millions of people worldwide. In order to find neuroprotective strategies, a clear understanding of the mechanisms involved in the dopaminergic death of cells that progresses the disease is needed. Oxidative stress can be defined as an imbalance between the production of reactive species and the ability to detoxify them and their intermediates or by-products. Oxidative damage to lipids, proteins, and DNA has been detected in autopsies from individuals with Parkinson’s Disease and so links can be made between oxidative stress and Parkinson’s Disease pathogenesis.
This book provides a thorough review of the mechanisms by which oxidative stress and redox signalling mediate Parkinson’s Disease. Opening chapters bring readers up to speed on basic knowledge regarding oxidative stress and redox signalling, Parkinson’s Disease, and neurodegeneration before the latest advances in this field are explored in detail. Topics covered in the following chapters include the role of mitochondria, dopamine metabolism, metal homeostasis, inflammation, DNA-damage and thiol-signalling. The role of genetics and gene-environment interactions are also explored before final chapters discuss the identification of potential biomarkers for diagnosis and disease progression and the future of redox/antioxidant based therapeutics.
Written by recognized experts in the field, this book will be a valuable source of information for postgraduate students and academics, clinicians, toxicologists and risk assessment groups. Importantly, it presents the current research that might later lead to redox or antioxidant – based therapeutics for Parkinson’s disease.