Disease-modifying targets in neurodegenerative disorders : paving the way for disease modifying therapies

목차 (Table of Contents)

• CONTENTS
• List of Contributors = xi
• Editor Biographies = xiii
• Foreword = xiv
• Preface = xvi
• Chapter 1 The Multitude of Therapeutic Targets in Neurodegenerative Proteinopathies / R. Melki = 1
• Protein Misfolding and Aggregation = 1
• Mechanism of Assembly = 2
• Prion-Like Propagation of Protein Assemblies = 4
• Propagation Routes of Pathogenic Protein Aggregates = 5
• Limiting Steps in the Propagation of Pathogenic Protein Assemblies = 6
• Therapeutic Strategies Targeting the Physiological Levels of Aggregation-Prone Proteins Involved in Neurodegeneration = 7
• Therapeutic Strategies Targeting the Misfolding and Aggregation of Proteins Involved in Neurodegeneration = 7
• Therapeutic Strategies Targeting the Accumulation of Misfolded Pathologic Protein Aggregates = 8
• Therapeutic Strategies Targeting the Cell-to-Cell Propagation of Pathogenic Protein Aggregates = 9
• Therapeutic Strategies Aimed at Restoring the Damage Pathogenic Protein Aggregates Induce = 9
• Therapeutic Strategies Targeting Misfolded Pathologic Protein Aggregate-Mediated Neuroinflammation = 10
• Limitations of the Different Therapeutic Strategies = 11
• References = 12
• Chapter 2 Synuclein Misfolding as a Therapeutic Target / W. Peelaerts ; T.F. Outeiro = 21
• Introduction = 21
• The Conformational Landscape of α-Synuclein : the Native State = 22
• Cytosolic Folding States = 24
• Membrane-Bound Folding States = 24
• The Conformational Landscape of α-Synuclein : Misfolded Variants = 25
• Folding Intermediates = 25
• Oligomeric Variants = 27
• Fibrillar Variants = 29
• Misfolding in Complex Environments = 30
• Synuclein Strains = 32
• Glycation of α-SYN - an Age-Associated Posttranslational Modification = 32
• Misfolding of α-Synuclein as a Therapeutic Target = 33
• Preserving the Native State = 33
• Preventing the Formation of Folding Intermediates = 33
• Targeting Aggregation = 35
• Stabilizing Membrane Interactions = 38
• Conclusions = 38
• References = 39
• Chapter 3 Neuroinflammation as a Therapeutic Target in Neurodegenerative Diseases / R. Gordon ; T.M. Woodruff = 49
• Introduction = 50
• The Global Burden of Neurodegenerative Diseases and the Challenge of Developing Effective Therapeutics = 50
• Glial Cells in CNS Development, Homeostasis, and Pathology = 51
• Microglia = 51
• Astrocytes = 53
• Oligodendrocytes and Ependymal Cells = 54
• Chronic Neuroinflammation as a Common Pathophysiological Mediator in Progressive Neurodegenerative Diseases = 54
• Mechanisms of Neuroinflammation-Mediated Neurodegeneration = 56
• Alzheimer's Disease = 58
• Parkinson's Disease = 60
• Amyotrophic Lateral Sclerosis = 64
• Huntington's Disease = 65
• Frontotemporal Dementia and Lewy Body Dementia = 66
• Therapeutic Strategies Targeting Neuroinflammation in Progressive Neurodegenerative Diseases = 66
• Future Perspectives = 69
• Conclusions = 70
• References = 70
• Chapter 4A Stem Cells in Neurodegeneration : Mind the Gap / C. Claes ; J. Terryn ; C.M. Verfaillie = 81
• Introduction = 81
• Part Ⅰ: Stem Cells = 82
• Genome Editing of Stem Cells = 83
• The Generation of Specific Cell Types = 84
• Part Ⅱ: Stem Cells as Regenerative Therapy = 85
• Clinical Translation and Immunology = 88
• Keeping Track of Cell Transplants = 90
• Part Ⅲ: Stem Cells to Model Neurodegenerative Diseases = 91
• iPSC Characteristics : The Role of Development in Neurodegenerative Diseases = 91
• iPSC Technology : Disease Modeling and Drug Screening = 92
• Future Prospects = 96
• References = 96
• Chapter 4B The Potential of Stem Cells in Tackling Neurodegenerative Diseases / S. Libbrecht = 101
• Endogenous Stem Cells as a Therapeutic Target = 101
• What are Endogenous Stem Cells? = 101
• Adult Neurogenesis in a Neurodegenerative Environment = 104
• Adult Brain Regeneration to Tackle Neurodegeneration = 108
• References = 110
• Chapter 5 Preclinical Models of Alzheimer's Disease for Identification and Preclinical Validation of Therapeutic Targets : From Fine-Tuning Strategies for Validated Targets to New Venues for Therapy / B. Vasconcelos ; M. Bird ; I.-C. Stancu ; D. Terwel ; I. Dewachter = 115
• Introduction = 116
• Alzheimer's Disease : Clinical Features, Pathology, and Genetics Leading to the Formulation of the Amyloid Cascade Hypothesis = 116
• Transgenic Models Recapitulating Amyloid Pathology as Preclinical Models to Identify Targets for Anti-Aβ Therapies = 118
• Transgenic Models Recapitulating Tau-Pathology as Preclinical Models to Identify Targets for Anti-Tau-Directed Therapies = 124
• Transgenic Mouse Models Recapitulating Prion-Like Spreading and Propagation of Tau-Pathology : New Venues for Therapeutic Strategies = 128
• Transgenic Mouse Models Recapitulating Aβ-to-Tau Axis : New Venues to Identify Novel Therapeutic Targets Aiming at the Molecular and Cellular Mechanisms Linking Aβ and Tau = 132
• Conclusions = 137
• References = 138
• Chapter 6 Parkinson's Disease / M.R. Cookson = 157
• Introduction = 157
• Current Treatment Approaches in Parkinson's Disease = 158
• Pharmacological Approaches : Replacing Dopamine = 158
• Nonpharmacological Approaches : Deep Brain Stimulation and Cell Replacement = 160
• Drugs That are Being Evaluated Clinically for Disease Modification in PD = 160
• Novel Targets for Disease-Modifying Therapies in PD = 161
• α-Synuclein = 161
• LRRK2 = 165
• Recessive Genes = 166
• Conclusions = 167
• References = 168
• Chapter 7 Lewy Body Dementia / M. Delenclos ; S. Moussaud ; P.J. McLean = 175
• Lewy Body Dementia = 175
• Concept of Lewy Body Dementia = 175
• Clinical Symptoms = 177
• Genetic Association = 177
• Pathophysiology = 178
• Management of LBD = 182
• Current Symptomatic Treatment = 182
• Disease-Modifying Therapy = 183
• Concluding Remarks = 188
• References = 188
• Chapter 8 Frontotemporal Dementia / E. Wauters ; K. Sleegers ; M. Cruts ; C. Van Broeckhoven = 199
• Overview of Frontotemporal Dementia = 199
• Clinical Presentations = 200
• Pathological Heterogeneity = 201
• Genetics of FTD = 202
• FTD : A Heterogeneous Disorder = 205
• Disease Management = 206
• Pharmacologic Symptomatic Treatment = 206
• Nonpharmacologic Management = 209
• Novel Possibilities in Disease-Modifying Drug Development = 209
• Tau = 209
• Granulin = 214
• C9orf72 = 216
• TDP-43 = 219
• Cellular Waste Clearance Systems = 220
• Heterogeneity = Opportunity = 222
• Discussion : Essentials for the Development of a Disease-Modifying Therapy = 224
• Gaps in our Understanding of FTD = 224
• Toward Early and Targeted Intervention = 226
• Conclusions = 227
• References = 227
• Chapter 9 From Huntingtin Gene to Huntington's Disease-Altering Strategies / N. Deglon = 251
• Huntington's Disease = 251
• Huntingtin Gene and Transcripts = 253
• Huntingtin Protein = 257
• HD Pathogenic Mechanisms = 258
• Molecular Strategies for HD = 259
• ASO = 260
• RNA Interference = 261
• Genome Editing = 262
• Conclusions and Perspectives = 263
• References = 264
• Chapter 10 Amyotrophic Lateral Sclerosis : Mechanisms and Therapeutic Strategies = 277
• L. Van Den Bosch
• Introduction = 277
• Excitotoxicity = 280
• Hyperexcitability = 281
• Pathogenic Role of Non-neuronal Cells = 281
• Astrocyte Dysfunction = 281
• Oligodendrocyte Dysfunction = 282
• Microglial Dysfunction and T Cells = 282
• Shortage of Neurotrophic Factors = 283
• Mitochondrial Dysfunction = 284
• Axonal Defects = 284
• Altered Proteostasis and Autophagy = 285
• Altered RNA Metabolism and Stress Granule Formation = 286
• Hexanucleotide Repeats in C9ORF72 and Disturbances in Nucleocytoplasmic Transport = 286
• Conclusions = 287
• References = 288
• Index = 297