Metal-based Neurodegeneration: From Molecular Mechanisms to Therapeutic Strategies

Metal-based Neurodegeneration: From Molecular Mechanisms to Therapeutic Strategies......Page 3
Contents......Page 7
Preface......Page 11
1.1 Introduction – the importance of metal ions in brain function......Page 13
1.2 Metal ion transport and storage – iron......Page 16
1.3 Metal ion transport and storage – copper......Page 19
1.4 Metal ion transport and storage – zinc......Page 22
1.5 Metal ion transport and storage – other metals......Page 25
1.6 Metals and their homeostasis (with particular reference to iron and copper)......Page 26
References......Page 30
2.1 Introduction – the oxygen paradox......Page 33
2.2 Reactive oxygen species (ROS)......Page 34
2.3 Reactive nitrogen species (RNS)......Page 37
2.4 The targets of ROS and RNS......Page 39
2.5 Cytoprotection against oxidative damage......Page 42
2.6 Mitochondria, free radicals and signalling......Page 47
2.7 Cyclin-dependent kinases......Page 48
2.8 Apoptosis – programmed cell death......Page 50
2.9 ROS, RNS and signal transduction......Page 53
2.10 Molecules involved in the inflammatory pathway......Page 56
References......Page 63
3 Parkinson’s Disease......Page 65
3.1 Proteins involved in Parkinson’s disease......Page 66
3.2 Metal involvement in Parkinson’s disease......Page 74
3.3 Risk factors for Parkinson’s disease......Page 78
3.4 Mitochondrial dysfunction......Page 82
3.5 Role of dopamine in Parkinson’s disease......Page 83
References......Page 86
4 Alzheimer’s Disease......Page 89
4.1 Proteins involved in Alzheimer’s disease......Page 90
4.2 Metal involvement in Alzheimer’s disease......Page 95
4.3 Genetic and risk factors......Page 100
4.5 Oxidative stress......Page 101
References......Page 105
5.1 Introduction – an overview of trinucleotide expansion diseases......Page 107
5.2 PolyQ diseases......Page 108
5.3 Structural models of polyQ protein aggregation......Page 109
5.4 Mechanisms of cell death in polyQ diseases......Page 112
5.5 Huntington’s disease......Page 114
5.6 Other polyQ disease proteins......Page 117
References......Page 121
6.1 Incidence and patholophysiology of Friedreich’s ataxia......Page 124
6.2 Molecular basis of the disease – triplet repeat expansions......Page 126
6.3 Molecular basis of the disease – frataxin and its role in iron metabolism......Page 127
6.4 Other diseases associated with expansion of non-coding triplets......Page 130
References......Page 132
7.1 Introduction......Page 134
7.2 A brief history of prion diseases......Page 135
7.3 The ‘prion’ of ‘protein-only’ hypothesis and conformation-based prion inheritance......Page 136
7.4 Mechanisms of conformation-based prion transmission......Page 138
7.5 Pathways of prion pathogenesis......Page 142
7.6 Prion-metal interactions......Page 145
References......Page 146
8.2 Major genes involved in ALS......Page 149
8.3 Superoxide dismutase and ALS......Page 151
8.4 Contributors to disease mechanisms in ALS......Page 154
8.5 Other pathways that may cause damage to motor neurons......Page 158
8.6 Conclusions......Page 159
References......Page 160
9.2 Aceruloplasminaemia......Page 162
9.3 Wilson’s and Menkes diseases......Page 165
9.5 Neuroferritinopathy......Page 170
9.6 Multiple sclerosis......Page 171
9.7 HIV-associated dementia......Page 176
References......Page 177
10.1 Parkinson’s disease......Page 180
10.2 Alzheimer’s disease......Page 186
10.4 Friedreich’s ataxia and other diseases linked to non-coding triplet repeats......Page 191
10.6 Amyotrophic lateral sclerosis, ALS......Page 193
10.9 Wilson’s disease......Page 195
10.10 Multiple sclerosis......Page 196
10.11 Future direction for therapeutic agents......Page 197
References......Page 198
11.1 Parkinson’s disease animal models......Page 201
11.2 Alzheimer’s disease......Page 208
11.3 Huntington’s disease and polyQ......Page 211
11.4 Friedreich’s ataxia......Page 212
11.5 Prion diseases......Page 213
11.6 Amyotrophic lateral sclerosis, ALS......Page 215
11.8 Menkes disease......Page 217
11.10 Multiple sclerosis......Page 218
References......Page 219
12 Concluding Remarks......Page 223
12.1 Therapeutic strategies......Page 227
References......Page 230
Index......Page 232