BOOK
Oxidative Stress and Redox Signalling in Parkinsons Disease
Rodrigo Franco | Jonathan A Doorn | Jean-Christophe Rochet
(2017)
Additional Information
Book Details
Abstract
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.
"The book should be of interest to all individuals who are interested in PD."
"With a comprehensive and integrated view on the biology of PD, the Editors and Authors of the book are likely to be instrumental in stimulating a deeper understanding and promoting renewed collaborations on this multifaceted topic, leading to improved understanding of PD."
Michael Aschner
Dr Franco is an Assistant Professor of Neuroscience at the Redox Biology Center, University of Nebraska-Lincoln. Prior to this position, he was post-doctoral fellow at the National Institute of Environmental Health Sciences, USA. His research interests include the role of oxidative stress and redox signaling in the regulation of cell death pathways, and in neuronal cell death associated with neurological disorders. He has been awarded the Layman Award and the SIGMA XI Outstanding Young Scientist Award.
Dr Doorn is an Associate Professor of Medicinal and Natural Products Chemistry at the University of Iowa, College of Pharmacy. Before this, he was a post-doctoral fellow at the University of Colorado Health Sciences Center, Depts. of Pharmaceutical Sciences and Pharmacology, USA. His postdoctoral work involved studying the role of lipid peroxidation products and protein carbonylation in alcoholic liver disease. Dr Doorn received his Ph.D. from the University of Michigan, School of Public Health, Toxicology Program.
Dr Rochet is an associate professor in the Department of Medicinal Chemistry and Molecular Pharmacology (College of Pharmacy) at Purdue University. Before his arrival at Purdue, Dr Rochet received his PhD degree at the University of Alberta in Biochemistry in 1998 and then worked as a post-doctoral fellow studying mechanisms of alpha-synuclein self-assembly in Parkinson’s disease in the laboratory of Dr. Peter Lansbury at Harvard Medical School. Dr.Rochet’s research group has a long-standing interest in Parkinson’s disease.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Cover | Cover | ||
| Oxidative Stress and Redox Signalling in Parkinson’s Disease | i | ||
| Preface | vii | ||
| Contents | ix | ||
| Chapter 1 - Etiology and Pathogenesis of Parkinson’s Disease | 1 | ||
| 1.1 Introduction | 1 | ||
| 1.2 Clinical Manifestations of Parkinson’s Disease | 2 | ||
| 1.3 Neuropathology | 3 | ||
| 1.3.1 Selective Vulnerability of the Nigrostriatal Dopamine Neuron | 4 | ||
| 1.3.2 Mitochondrial Dysfunction in PD | 6 | ||
| 1.3.2.1 Mitochondrial DNA Damage | 6 | ||
| 1.3.2.2 Complex I Inhibition | 7 | ||
| 1.3.3 Oxidative Stress | 8 | ||
| 1.3.4 Dopamine Metabolism | 9 | ||
| 1.3.5 Neuroinflammation | 11 | ||
| 1.4 Genetics of Parkinson’s Disease | 12 | ||
| 1.5 Environmental Exposures and the Risk of Parkinson’s Disease | 13 | ||
| 1.5.1 Pesticides | 13 | ||
| 1.5.2 Metals | 14 | ||
| 1.5.3 Pathogens | 14 | ||
| 1.6 Gene–Environment Interaction | 15 | ||
| 1.7 Conclusions | 16 | ||
| Acknowledgements | 16 | ||
| References | 16 | ||
| Chapter 2 - Oxidative Stress and Redox Signalling in the Parkinson’s Disease Brain | 27 | ||
| 2.1 Introduction | 27 | ||
| 2.2 Oxidative Stress and Antioxidant Systems | 28 | ||
| 2.2.1 Reactive Oxygen and Nitrogen Species: Sources | 28 | ||
| 2.2.2 Antioxidant Systems | 31 | ||
| 2.2.3 Oxidative Damage to Biomolecules | 33 | ||
| 2.2.3.1 Oxidative DNA Damage | 33 | ||
| 2.2.3.2 Oxidative Damage to Lipids | 34 | ||
| 2.2.3.3 Oxidative Protein Modifications: Redox Sensors and Transducers | 35 | ||
| 2.3 What Makes the Dopaminergic Neurons in the SNpc Vulnerable | 37 | ||
| 2.3.1 Cellular Organization of the SNpc | 37 | ||
| 2.3.2 Redox Basis of the Vulnerability of SNpc DAergic Neurons | 39 | ||
| 2.3.2.1 Bioenergetics and Central Carbon Metabolism | 39 | ||
| 2.3.2.2 Oxidative Stress | 42 | ||
| 2.3.2.2.1\rIron (Fe) and Neuromelanin.In the brain, Fe is most abundant in areas rich in DAergic neurons. Increased Fe deposition and incre... | 43 | ||
| 2.3.2.2.2\rDopamine (DA).Oxidative stress in PD is also associated with the pro-oxidant properties of DA. Mutant α-synuclein downregulates ... | 43 | ||
| 2.4 Conclusions and Perspectives | 44 | ||
| Acknowledgements | 44 | ||
| References | 44 | ||
| Chapter 3 - Mitochondrial Dysfunction in Parkinson’s Disease | 61 | ||
| 3.1 Reactive Oxygen Species (ROS) | 61 | ||
| 3.1.1 Mitochondria and ROS Production | 62 | ||
| 3.2 Parkinson’s Disease | 63 | ||
| 3.3 Mitochondrial Dysfunction in PD | 64 | ||
| 3.3.1 ETC Complex Deficiency in PD | 65 | ||
| 3.3.2 Altered Mitochondrial Morphology | 67 | ||
| 3.3.3 Mitochondrial Ca2+ Buffering in PD | 67 | ||
| 3.3.4 PD-Related Genes and Mitochondrial Dysfunction | 68 | ||
| 3.4 Mitochondrial Dysfunction in Toxicant-Induced PD | 69 | ||
| 3.4.1 6-OHDA and MPTP: Classic Toxicant Models | 70 | ||
| 3.4.1.1 6-OHDA: An Experimental Catecholaminergic Neurotoxicant | 70 | ||
| 3.4.1.2 MPTP: Evidence for CI and the Toxic Exposure Hypothesis of PD | 71 | ||
| 3.4.2 Rotenone: A Case for Complex I Inhibition | 73 | ||
| 3.4.3 Paraquat: Redox Cycling Agent | 75 | ||
| 3.4.3.1 Characteristics and Risk of Exposure | 76 | ||
| 3.4.3.2 Mechanism of Toxicity: Redox Cycling and ROS Generation | 76 | ||
| 3.4.3.3 Role of Mitochondria in PQ Toxicity | 77 | ||
| 3.4.3.4 PQ and Excitotoxicity | 79 | ||
| 3.4.3.5 Using PQ for Developing Animal Models of PD | 79 | ||
| 3.4.3.6 Diquat Use with PQ: Example of Another Redox Cycling Agent | 80 | ||
| 3.4.4 Maneb: A Role of Complex III in PD Pathogenesis | 81 | ||
| 3.4.5 Other Environmental Toxins | 82 | ||
| 3.5 Concluding Remarks | 83 | ||
| References | 85 | ||
| Chapter 4 - Dopamine Metabolism and the Generation of a Reactive Aldehyde | 97 | ||
| 4.1 The Life of Dopamine: Synthesis, Storage and\rMetabolism | 97 | ||
| 4.2 3,4-Dihydroxyphenylacetaldehyde (DOPAL) and Biogenic Aldehydes Derived from Neurotransmitters | 100 | ||
| 4.3 Generation of DOPAL and Biogenic Aldehydes at Aberrant Levels | 101 | ||
| 4.3.1 Mechanisms for Elevation of DOPAL | 101 | ||
| 4.3.2 Relevance of Altered Dopamine Metabolism/Trafficking to PD | 102 | ||
| 4.4 Toxicity and Protein Reactivity of DOPAL and Biogenic Aldehydes | 103 | ||
| 4.4.1 Mechanisms of Toxicity | 104 | ||
| 4.4.2 Protein Reactivity and Targets | 104 | ||
| 4.5 The Role of Biogenic Aldehydes in Disease | 105 | ||
| 4.6 Summary | 106 | ||
| References | 107 | ||
| Chapter 5 - Dopamine Oxidation and Parkinson’s Disease | 116 | ||
| 5.1 Oxidative Stress and Susceptibility of\rDopaminergic Neurons in Parkinson’s Disease | 116 | ||
| 5.2 Dopamine Regulation and Metabolism | 117 | ||
| 5.3 Pathological Dopamine Oxidation | 118 | ||
| 5.3.1 Metabolism of Dopamine by Monoamine Oxidase | 118 | ||
| 5.3.2 Oxidation of the Catechol Ring of Dopamine | 119 | ||
| 5.3.3 Modification of Protein by Oxidized Dopamine | 119 | ||
| 5.3.4 Mitochondrial Dysfunction and Dopamine Oxidation | 122 | ||
| 5.4 The Role of Dopamine in Toxin-Induced Toxicity | 124 | ||
| 5.5 Dopamine Toxicity | 125 | ||
| 5.5.1 In vitro Exogenous Dopamine and l-DOPA Treatment | 125 | ||
| 5.5.2 Exogenous Dopamine Administration in vivo | 126 | ||
| 5.5.3 Dysregulation of Dopamine Handling in vivo | 127 | ||
| 5.6 Dopamine and α-Synuclein | 128 | ||
| 5.7 Dopamine Storage Disruption in PD | 129 | ||
| 5.8 Summary and Conclusions | 130 | ||
| References | 131 | ||
| Chapter 6 - Glutathione and Thiol Redox Signalling in Parkinson’s Disease | 144 | ||
| 6.1 Introduction | 144 | ||
| 6.2 Glutathione | 145 | ||
| 6.3 Thiol Redox Signalling and Thiol–Disulfide Exchange | 146 | ||
| 6.4 Cellular Reductases | 148 | ||
| 6.4.1 Thioredoxins | 149 | ||
| 6.4.2 Glutaredoxins | 150 | ||
| 6.4.3 Peroxiredoxins | 151 | ||
| 6.5 Glutathione Synthesis in the Brain | 152 | ||
| 6.6 Glutathione and Models of Oxidative Stress in Dopaminergic Neurons | 154 | ||
| 6.7 Glutathione Conjugating Enzymes | 155 | ||
| 6.7.1 Glutathione Peroxidase | 155 | ||
| 6.7.2 Glutathione S-Transferases | 156 | ||
| 6.8 GSH and Transport in the Brain: Multidrug Resistance Proteins (MDRP) and the Blood–Brain Barrier (BBB) | 158 | ||
| 6.9 Parkinson’s Disease Genetic Models and Redox Signalling | 159 | ||
| 6.9.1 Glutathione-S-Transferase | 159 | ||
| 6.9.2 DJ-1 | 160 | ||
| 6.9.3 PTEN-Induced Putative Kinase 1 (PINK1) | 160 | ||
| 6.9.4 Parkin | 161 | ||
| 6.10 Free Radicals as Messengers to Modulate Transcription Factors: Effects on Thiol Redox Regulation | 161 | ||
| 6.11 Conclusions | 162 | ||
| References | 162 | ||
| Chapter 7 - Neuroinflammation and Oxidative Stress in Models of Parkinson’s Disease and Protein-Misfolding Disorders | 184 | ||
| 7.1 Introduction | 184 | ||
| 7.2 Molecular Pathways Regulating Neuroinflammation in Glial Cells | 185 | ||
| 7.2.1 Regulation of Inflammatory Genes in Glial Cells by NF-κB | 185 | ||
| 7.2.2 Nuclear Regulation of NF-κB Function in Glial Cells | 186 | ||
| 7.3 Neurotoxic Models of Parkinson’s Disease: Reactive Oxygen Species and Neuroinflammatory Mechanisms | 188 | ||
| 7.3.1 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) | 188 | ||
| 7.3.2 6-Hydroxydopamine (6-OHDA) | 191 | ||
| 7.3.3 Lipopolysaccharide (LPS) | 192 | ||
| 7.4 Neuroinflammation and Protein Aggregation in PD and Protein-Misfolding Disorders | 193 | ||
| 7.4.1 Neuroinflammation in Protein-Misfolding Disorders | 194 | ||
| 7.4.2 Oxidative Stress in Protein-Misfolding Disorders | 195 | ||
| 7.4.3 Unfolded Protein Response in Protein-Misfolding Disorders | 196 | ||
| 7.5 Conclusions | 197 | ||
| References | 198 | ||
| Chapter 8 - Redox Signalling in Dopaminergic Cell Death and Survival | 210 | ||
| 8.1 Neuronal Degeneration in Parkinson’s Disease | 210 | ||
| 8.1.1 Relatively Selective Dopaminergic Degeneration | 211 | ||
| 8.1.2 Sources of Oxidative Stress and Selective Vulnerability | 211 | ||
| 8.1.2.1 Dopamine Metabolism | 212 | ||
| 8.1.2.2 Mitochondrial Dysfunction | 213 | ||
| 8.1.2.3 Iron Accumulation | 214 | ||
| 8.1.2.4 Calcium Channel Expression and Calcium Homeostasis | 215 | ||
| 8.1.2.5 Glutathione Loss and Associated Thiol Perturbations | 215 | ||
| 8.1.3 Increased Oxidative Stress and Selective Cell Death | 216 | ||
| 8.2 Redox Signalling and Cell Survival/Death | 217 | ||
| 8.3 Redox Regulation of DAergic Cell-Survival Pathways | 217 | ||
| 8.3.1 Akt Structure and Function | 217 | ||
| 8.3.2 Evidence of Akt1 Involvement in PD | 219 | ||
| 8.3.3 Redox Regulation of Akt1 Activity | 220 | ||
| 8.4 Redox Regulation of DAergic Cell-Death Pathways | 223 | ||
| 8.4.1 Redox Regulation of MAP3K-ASK1 | 223 | ||
| 8.4.1.1 Inhibitory Redox-Regulated ASK1 Partners | 225 | ||
| 8.4.1.1.1\rThioredoxin.Thioredoxin (Trx1) was the first ASK1-inhibitory protein to be described.149 It is a thiol disulfide oxidoreductase ... | 225 | ||
| 8.4.1.1.2\rGlutaredoxin.Grx1 was shown to be another thiol disulfide oxidoreductase inhibiting ASK1 activation by associating with it. Unli... | 227 | ||
| 8.4.1.1.3\rDJ-1.The autosomal recessive PD-related gene DJ-1 has been shown to inhibit ASK1 activity directly by binding at the N-terminal ... | 227 | ||
| 8.4.1.1.4\rPeroxiredoxin.Prx1 is one of the members of a family of thiol-based peroxidase enzymes, and acts as a signalling molecule and co... | 228 | ||
| 8.4.1.1.5\rAkt1.The role of Akt1 in inhibiting ASK1 activation has been discussed earlier in this chapter, wherein Akt1-mediated phosphoryl... | 228 | ||
| 8.4.1.2 Activating Redox-Regulated ASK1 Partners | 229 | ||
| 8.4.1.2.1\rTumor Necrosis Factor-α.TNF-α has been extensively proven to activate ASK1.149,202 TNF-α can activate ASK1 directly by increasin... | 229 | ||
| 8.4.1.2.2\rDaxx.Chang et al. first demonstrated Daxx (death-domain associated protein), to be involved in the ASK1 signalosome, further act... | 229 | ||
| 8.4.1.3 Evidences of ASK1 Involvement in PD | 230 | ||
| 8.4.2 MAPKs – p38 and JNK | 231 | ||
| 8.4.2.1 JNK | 231 | ||
| 8.4.2.2 p38 MAPKs | 232 | ||
| 8.5 Conclusions | 233 | ||
| Acknowledgements | 234 | ||
| References | 235 | ||
| Chapter 9 - Iron Metabolism in Parkinson’s Disease | 255 | ||
| 9.1 Brain Iron Homeostasis | 255 | ||
| 9.1.1 Brain Iron Transport and Distribution | 256 | ||
| 9.1.2 Regulation of Brain Iron Homeostasis | 257 | ||
| 9.2 Iron Metabolism and Parkinson’s Disease | 258 | ||
| 9.2.1 Symptoms of Parkinson’s Disease | 259 | ||
| 9.2.2 Iron Accumulation Accelerates the Symptomatology of Parkinson’s Disease | 259 | ||
| 9.2.3 Mechanism of Iron Accumulation in the Substantia Nigra of Parkinson’s Disease Brains | 260 | ||
| 9.2.3.1 Changes in Iron-Uptake Proteins | 260 | ||
| 9.2.3.2 Changes in Iron-Release Proteins | 261 | ||
| 9.2.3.3 Changes in Iron-Storage Proteins | 262 | ||
| 9.2.3.4 Changes in the Distribution of Intracellular Iron | 263 | ||
| 9.2.4 Iron and the Aggregation of α-Synuclein | 264 | ||
| 9.2.5 Iron, ROS and Apoptosis of Dopaminergic Neurons in the Substantia Nigra of Parkinson’s Disease | 264 | ||
| 9.3 Iron-Related Therapeutic Approaches for PD | 266 | ||
| 9.4 Conclusions | 268 | ||
| References | 268 | ||
| Chapter 10 - Protein Oxidation, Quality-Control Mechanisms and Parkinson’s Disease | 277 | ||
| 10.1 Introduction | 277 | ||
| 10.2 Misfolded Protein Aggregation and Accumulation in PD | 278 | ||
| 10.2.1 α-Synuclein: Mutations and Misfolding | 279 | ||
| 10.2.1.1 Redox Regulation of α-Synuclein Aggregation | 281 | ||
| 10.3 Protein Quality-Control Mechanisms in PD | 283 | ||
| 10.3.1 Protein Synthesis | 283 | ||
| 10.3.2 Protein Folding, Unfolding and Disaggregation by Chaperones | 284 | ||
| 10.3.3 Protein Degradation Pathways | 287 | ||
| 10.3.3.1 The Ubiquitin Proteasome System (UPS) | 288 | ||
| 10.3.3.2 The Autophagosome–Lysosome System | 291 | ||
| 10.3.4 Protein Quality Control in Organelles | 293 | ||
| 10.3.4.1 Endoplasmic Reticulum Stress and the Unfolded Protein Response | 293 | ||
| 10.3.4.2 Mitochondria Protein Quality Control | 295 | ||
| 10.4 Conclusions and Perspectives | 297 | ||
| Acknowledgements | 297 | ||
| References | 297 | ||
| Chapter 11 - At the Intersection Between Mitochondrial Dysfunction and Lysosomal Autophagy: Role of PD-Related Neurotoxins and Gene Products | 325 | ||
| 11.1 Introduction | 325 | ||
| 11.2 Neuropathological Evidence for Mitochondrial Deficits and Autophagic Impairment in PD | 327 | ||
| 11.2.1 Evidence of Mitochondrial Deficits in Postmortem PD Brains | 327 | ||
| 11.2.2 Evidence of Autophagic Impairment in Postmortem PD Brains | 328 | ||
| 11.3 Toxicological Evidence for Mitochondrial Deficits and Autophagic Impairment in PD | 330 | ||
| 11.3.1 Rotenone | 330 | ||
| 11.3.2 PQ and Maneb | 332 | ||
| 11.3.3 MPTP or MPP | 334 | ||
| 11.3.4 6-OHDA | 336 | ||
| 11.4 Genetic Evidence for Mitochondrial Deficits and Autophagic Impairment in PD | 337 | ||
| 11.4.1 aSyn | 338 | ||
| 11.4.2 Parkin/PINK1 | 340 | ||
| 11.4.3 DJ-1 | 344 | ||
| 11.4.4 ATP13A2 | 347 | ||
| 11.5 Interrelationships Between Autophagic Impairment and Mitochondrial Dysfunction | 349 | ||
| 11.6 Summary and Future Directions | 350 | ||
| References | 352 | ||
| Chapter 12 - Genes, Aging, and Parkinson’s Disease | 389 | ||
| 12.1 Introduction | 389 | ||
| 12.1.1 Do Genes Influence Lifespan | 390 | ||
| 12.1.2 Which Genes Influence Lifespan | 391 | ||
| 12.2 Apolipoprotein E | 393 | ||
| 12.2.1 LDL Receptors | 394 | ||
| 12.2.2 Effects of Polymorphisms on APOE Function | 395 | ||
| 12.2.3 APOE and Parkinson’s Disease | 396 | ||
| 12.2.4 APOE Oxidative Stress | 397 | ||
| 12.3 FOXO3A and FOXO Family | 397 | ||
| 12.3.1 FOXO3A Biological Functions | 398 | ||
| 12.3.2 FOXO3A and Protein Homeostasis | 400 | ||
| 12.3.3 FOXO3A and Parkinson’s Disease | 401 | ||
| 12.4 Role of Other Genes Emerged from Animal Studies in Aging | 401 | ||
| 12.4.1 Are Aging-Modifying Genes Discovered in Laboratory Animals Relevant for PD | 404 | ||
| References | 405 | ||
| Chapter 13 - Biomarkers of Oxidative Stress in Parkinson’s Disease | 423 | ||
| 13.1 Biomarkers | 423 | ||
| 13.2 Oxidative Stress | 424 | ||
| 13.3 Candidate Biomarkers for ROS-Induced Stress | 426 | ||
| 13.3.1 Halogenation | 427 | ||
| 13.3.2 Methionine Oxidation | 429 | ||
| 13.3.3 Glycation and Carbonylation | 429 | ||
| 13.4 Candidate Biomarkers for RNS-Induced Stress | 429 | ||
| 13.4.1 Nitration | 430 | ||
| 13.4.1.1 Nitrated Species of Serum Proteins Such as α-Synuclein as Possible Biomarkers | 431 | ||
| 13.4.1.2 Nitration, Halogenation and the Thyroid Gland: A New Field for Searching Biomarkers for Parkinson’s Disease | 433 | ||
| 13.4.2 S-nitros(yl)ation | 434 | ||
| 13.5 Conclusions | 435 | ||
| References | 436 | ||
| Chapter 14 - Dietary Anti-, Pro-Oxidants in the Etiology of Parkinson’s Disease | 447 | ||
| 14.1 Introduction | 447 | ||
| 14.2 Heterocyclic Amines | 448 | ||
| 14.3 Polyphenolic Compounds | 450 | ||
| 14.3.1 Flavonoids | 450 | ||
| 14.3.1.1 Isoflavones | 452 | ||
| 14.3.1.2 Flavones | 453 | ||
| 14.3.1.3 Flavanones | 455 | ||
| 14.3.1.4 Flavanols | 456 | ||
| 14.3.1.5 Anthocyanins | 458 | ||
| 14.3.1.6 Flavonols | 460 | ||
| 14.3.2 Non-Flavonoids | 462 | ||
| 14.3.2.1 Curcuminoids | 462 | ||
| 14.3.2.2 Phenolic Acids | 464 | ||
| 14.3.2.3 Stilbenes | 465 | ||
| 14.3.2.4 Lignans | 466 | ||
| 14.4 Vitamins | 467 | ||
| 14.4.1 Vitamin A | 467 | ||
| 14.4.2 Vitamin B | 469 | ||
| 14.4.3 Vitamin C | 470 | ||
| 14.4.4 Vitamin D | 471 | ||
| 14.4.5 Vitamin E | 473 | ||
| 14.5 Summary | 474 | ||
| References | 475 | ||
| Subject Index | 505 |