Contents

Preface v

Contributors xvii

Chapter 1 Advances in our Understanding of Neurodegeneration 1

Kurt A. Jellinger

Introduction 1

Basic processes common to neurodegeneration 1

Neuronal death - the final pathway 36

Challenges of apoptosis in neurodegeneration 38

Conclusion 42

References 43

Chapter 2 Mitochondrial Mutagenesis in the Brain in Forensic and

Pathological Research 59

Nicole von Wurmb-Schwark

Introduction 59

Mitochondrial DNA damage and repair 60

mtDNA maintenance 70

mtDNA mutagenesis in the brain 73

References 79

Chapter 3 Genetic and Environmental Factors in Neurodegenerative

Diseases 89

Fabio Coppedè and Lucia Migliore

Causative genes in neurodegeneration 89

Environmental factors and neurodegeneration 92

Susceptibility genes in neurodegeneration 96

Oxidative stress 98

Apoptosis 103

Aging 105

Conclusions 106

References 107

Chapter 4 Nitric Oxide and Cellular Stress Response in Brain Aging and Neurodegenerative Disorders 115

Vittorio Calabrese, Cesare Mancuso, Carlo De Marco, Anna Maria Giuffrida Stella, and D. Allan Butterfield

Introduction 115

Nitric oxide 116

Heme oxygenase 120

Conclusions and perspectives 127

Acknowledgments 128

References 128

Chapter 5 Oxidative Stress and Radiation-Induced Late Normal

Tissue Injury 135

Introduction 135

Radiation-induced late effects 136

Reactive oxygen/nitrogen oxide species (ROS/RNOS) 141

Radiation-induced increase in ROS/RNOS generation 143

The role of oxidative stress in radiation-induced late effects 144

Treatment of radiation-induced late injury with RAS blockade 148

Putative mediators of chronic oxidative stress: Ang II and ionizing radiation 151

Acknowledgments 152

References 152

Chapter 6 The Cell Cycle and Oxidative Neuronal Cell Death 165

Brett C. Langley

Introduction 165

The terminally differentiated neuron and the cell division 166

The cell cycle and checkpoint function 167

Cell cycle regulators and neurodegeneration 169

Oxidative stress induction of the cell cycle 173

Is the cell cycle required for oxidative stress-induced death? 174

Conclusion 175

Acknowledgments 177

References 177

Chapter 7 Redox Imbalance 183

Daniela Berg

Introduction: free radicals and oxidative stress 183

Factors contributing to the generation of oxidative stress (OS) 184 Interaction of ROS with genetic influences, protein aggregation and

Lewy bodies (LBS) 188

Mitochondrial dysfunction 189

Consequences of redox imbalance 191

Conclusion and therapeutic outlook 192

References 193

Chapter 8 Genes and Oxidative Stress in Sporadic and Familial

Parkinsonism: cDNA Microarray Studies 201

E. Grünblatt, S. Mandel, P. Riederer, and M.B.H. Youdim

Introduction 201

Cell culture models 202

Animal models 204

Human post-mortem PD subjects 210

Conclusion 215

Acknowledgement 215

References 215

Chapter 9 Down Syndrome, Antioxidant Balance and the "Gene Dosage

Effect" Hypothesis 219

J.B. de Haan, P.J. Crack, M.A. Pritchard, and I. Kola

Introduction 219 Analysis of the HSA21 gene, Cu/Zn-superoxide dismutase-1 (SOD1) and its relationship to the antioxidant pathway 220 Evidence for the involvement of an altered antioxidant pathway in Down syndrome (DS) 223

Conclusions/discussion and future directions for therapeutic interventions 229

References 230

Chapter 10 The Role of Levodopa in the Chronic Neurodegenerative

Disorder - Parkinson's Disease 237

Thomas Müller

Introduction Diagnosis

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