Elsevier S & T

Molecular Neurology

Waxman, Stephen

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Table of contents

Molecular Neurologyiii
Copyright Pageiv
Contentsv
Contributor's Listvii
Prefacexi
Section I: Principles of Molecular Neurology1
Chapter 1: Genetics as a Tool in Neurology1
I. Introduction1
II. Structure and Function of Genes and Chromosomes2
III. Genetic Medicine4
IV. The Neurogenetic Evaluation8
V. Identification of Human Disease Genes10
VI. Methods for Human Molecular Genetic Analysis11
VII. Treatment of Genetic Diseases14
References15
Chapter 2: Neurology and Genomic Medicine19
I. Introduction19
II. Basic Concepts20
III. The Human Genome Project (HGP) and Haplotype Mapping (HapMap) Project22
IV. Family History22
V. Genetic Mechanisms23
VI. Pharmacogenetics23
VII. Gene-Gene and Gene-Environment Interactions23
VIII. Comparative Genomic Hybridization (CGH)26
IX. Mitochondria and the Mitochondrial Genome (mtDNA)27
X. Summary27
References27
Chapter 3: Mitochondrial Function and Dysfunction in the Nervous System29
I. Introduction29
II. Structure and Functions of Mitochondria29
III. Mitochondria in Mechanisms of Neuronal Cell Death and Neurological Disease35
IV. Roles of Mitochondrial Dysfunction in Common Neurodegenerative Diseases39
V. Conclusions40
References40
Chapter 4: Neuronal Channels and Receptors43
I. Introduction43
II. Nomenclature44
III. Structure and Function48
IV. Physiological Roles52
V. Neurological Disorders Caused by Channelopathies53
References56
Chapter 5: Protein Misfolding, Chaperone Networks, and the Heat Shock Response in the Nervous System59
I. Introduction59
II. Role of Molecular Chaperones in Protein Folding Quality Control60
III. Regulation of Chaperone Expression: The Heat Shock Response65
IV. Role of Molecular Chaperones in Neurodegenerative Diseases68
V. Chaperone Hypotheses70
VI. Therapeutic Avenues72
References72
Chapter 6: Metabolic Biopsy of the Brain77
I. Phosphorus Magnetic Resonance Spectroscopy77
II. The Phosphocreatine Shuttle Hypothesis79
III. Magnetization Transfer Measurements of ATP and Phosphocreatine Synthesis80
IV. Hydrogen (Proton) Spectroscopy83
V. Carbon Spectroscopy84
VI. MR Spectroscopic Measurements of Cerebral Lactate85
VII. The Astrocyte-Neuron Lactate Shuttle Hypothesis86
VIII. Cerebral Ammonia Metabolism88
IX. Summary94
References95
Chapter 7: Gene Therapy Approaches in Neurology101
I. Why Use Gene Transfer in the Development of Novel Therapies?101
II. Gene Transfer Strategies102
III. Development of Neurological Gene Therapy110
IV. Conclusions„Future Developments118
References118
Chapter 8: Programmed Cell Death and Its Role in Neurological Disease125
I. Introduction: Neurologists and Cell Death125
II. Cell Death: History and Classification126
III. Current Status of Programmed Cell Death Studies126
IV. Trophic Factors and the Concept of Cellular Dependence134
V. Apoptosis Induced by Unfolded, Misfolded, or Alternatively Folded Proteins136
VI. Does Programmed Cell Death Play a Role in Neurodegeneration?137
VII. Are Programmed Cell Death Pathways Appropriate Therapeutic Targets in Neurodegeneration?138
VIII. Death and Resurrection: The Neural Stem Cell Response to Neurodegeneration138
Acknowledgments139
References139
Section II: Disorders of Development145
Chapter 9: Developmental Neurology: A Molecular Perspective145
References147
Chapter 10: Metabolic Diseases of the Nervous System Development149
I. Glucose Transporter Type 1 Deficiency151
II. Menkes Disease153
III. Segawa Disease (Dopa-Responsive Dystonia)154
IV. Disorders of Pyruvate Metabolism154
V. Glycosylation Disorders156
VI. Organic Acidurias156
VII. Urea Cycle Disorders157
VIII. Galactosemia157
IX. Phenylketonuria158
X. Lesch-Nyhan Disease159
XI. Pantothenate Kinase Deficiency160
XII. Smith-Lemli-Opitz Syndrome160
References160
Chapter 11: Genetic Disorders of Neuromuscular Brain Disease163
I. The Motor Unit during Development163
II. Structures and Function of the Neuromuscular System164
III. Diseases of Developing Nerve, the Neuromuscular Junction and Muscle169
References176
Section III: Stroke and Trauma177
Chapter 12: Molecular Mechanisms of Ischemic177
I. Introduction177
II. Hypoxia/Ischemia177
III. Excitotoxicity178
IV. Free Radicals179
V. Inflammation180
VI. Growth Factors181
VII. Gene Expression in Cerebral Ischemia182
VIII. Apoptosis183
IX. Summary183
References183
Chapter 13: Hemorrhagic Brain Disease187
I. Introduction187
II. Angiogenesis and Vasculogenesis188
III. Mendelian Forms of Hemorrhagic Brain Disease191
IV. Primary Hemorrhagic Brain Diseases (Vascular Lesions)191
V. Secondary Hemorrhagic Brain Diseases200
VI. Future Research202
References202
Chapter 14: The Dawn of Molecular and Cellular Therapies for Traumatic Spinal Cord Injury207
I. The Current Clinical Picture207
II. Surmounting Barriers to Axon Regeneration209
III. Cellular Therapies for SCI213
IV. Molecular Adaptations after SCI216
V. Conclusions217
Acknowledgments217
References217
Section IV: Degenerative Diseases221
Chapter 15: Parkinson Disease: Molecular Insights221
I. Introduction221
II. History221
III. Diagnosis222
IV. Pathology223
V. Etiology: Genetics and Environment223
VI. Genes Implicated in PD224
VII. Models of Pathogenesis230
VIII. Therapy233
IX. Summary235
References235
Chapter 16: The Molecular Basis of Alzheimer’s Disease241
I. Clinical Features of Alzheimer’s Disease241
II. Neuropathology of Alzheimer’s Disease242
III. Amyloid Biology and the Genetics of Early-Onset Alzheimer’s Disease243
IV. Alzheimers Disease„A Progressive Neuropathologic Syndrome245
V. Tau Biology in Alzheimer’s Disease246
VI. Genetics of Late-Onset Alzheimer’s Disease247
VII. Animal Models of Alzheimer’s Disease248
VIII. What Makes the Neurons Die?249
IX. Abnormal Protein Conformation„A Unifying Factor in Neurodegeneration?250
X. Emerging Diagnostic Tools250
XI. Disease-Modifying Strategies of Tomorrow251
XII. Summary and Conclusions252
References252
Chapter 17: Polyglutamine Disorders Including Huntington’s Disease257
I. Introduction257
II. Clinical and Genetic Features258
III. Protein Misfolding and Failures in Protein Quality Control260
IV. Transcriptional Dysregulation264
V. Mitochondrial Dysfunction266
VI. Excitotoxicity and Calcium Homeostasis266
VII. Axonal Transport Defects267
VIII. Neuronal Dysfunctions versus Neuronal Cell Death268
IX. Cell Autonomous versus Non-cell Autonomous Effects269
X. Conclusion269
References270
Chapter 18: Friedreich’s Ataxia and Related DNA Loss-of-Function Disorders277
I. Summary277
II. Epidemiology277
III. Pathology of Friedreich Ataxia278
IV. Clinical Phenotype of Friedreich Ataxia278
V. Ancillary Tests280
VI. Frataxin Gene Structure and Expression280
VII. DNA Mutations281
VIII. Frataxin Function283
IX. Animal Models283
X. Pathogenesis285
XI. Treatment: Directions and Perspectives286
XII. Related Loss-of-Function Disorders286
References291
Chapter 19: DYT1, An Inherited Dystonia295
I. Early-Onset Primary Dystonia and Identifying DYT1297
II. Gene and Protein Properties298
III. Neuropathology299
IV. Cellular and Animal Models of Disease299
V. Invertebrates300
VI. Mouse300
VII. DYT1 Role in Focal Dystonia301
VIII. DYT1 Phenotype and Endophenotype302
IX. Future Directions302
References303
Chapter 20: Motor Neuron Disease: Amyotrophic Lateral Sclerosis307
I. ALS Background307
II. Clinical Manifestations of ALS308
III. Animal Models of Motor Neuron Diseases308
IV. Molecular Hypotheses in ALS310
V. Axonal Pathology311
VI. Neuroinflammation313
VII. Cell Autonomy in ALS„Contributions from Nonneuronal Cells Pathophysiology313
VIII. Regional Differences in ALS and SOD1 Pathophysiology314
IX. Targeting Therapies to Molecular Pathways314
X. Targeting ALS Subgroups Using RNAi and Antisense Technologies316
XI. Predictive Value of Preclinical Models316
References316
Chapter 21: Genetic Disorders of the Autonomic Nervous System321
I. Introduction321
II. Developmental Abnormalities of the Autonomic Nervous System321
III. Functional Abnormalities of the Autonomic Nervous System327
IV. Future Directions329
References329
Chapter 22: Multiple Sclerosis as a Neurodegenerative Disease333
I. Focal Distribution of Sodium Channels in Myelinated Axons334
II. Demyelination in Multiple Sclerosis334
III. Axonal Degeneration in Multiple Sclerosis334
IV. Sodium Channels and Axonal Injury335
V. Energetics, Ionic Homeostasis, and Axonal Injury336
VI. Molecular Identity of Axonal Sodium Channels337
VII. Sodium Channels and Recovery of Conduction in Demyelinated Axons337
VIII. Na 1.2 and Na 1.6 in Normal and Dysmyelinated Axons337
IX. Axonal Sodium Channels in Demyelinated Axons: Lessons from EAE338
X. Axonal Sodium Channels in Injured Axons: EAE338
XI. Axonal Sodium Channels in MS339
XII. Nav1.2 Channels in Demyelinated Axons: Functional Role339
XIII. Nav1.6 Channels in Demyelinated Axons: Functional Role340
XIV. Sodium Channels in Microglia and Macrophages341
XV. From Neurodegeneration to Neuroprotection?342
Acknowledgments345
References345
Section V: Disorders of Excitation and Transmission347
Chapter 23: Acquired Epilepsy: Cellular and Molecular Mechanisms347
I. Introduction347
II. Temporal Lobe Epilepsy348
III. Post-Traumatic and Post-Stroke Epilepsy360
VI. Rasmussen’s Syndrome361
V. Post-Infectious Epilepsy362
VI. Epilepsy Caused by Neoplasms and Other Mass Lesions363
VII. Glia, Brain Microenvironment, and Epilepsy363
VIII. Summary and Conclusions364
References365
Chapter 24: Genetic Epilepsies371
I. Introduction: A Genetic Approach to Seizure Disorders371
II. Familial Idiopathic Epilepsy Syndromes372
III. The Channelopathy Concept of Idiopathic Epilepsies379
IV. The Next Step: Monogenic Disorders as Model Systems for Common Epilepsies380
References381
Chapter 25: Tourette’s Syndrome385
I. Clinical Description and Natural History386
II. Coexisting Conditions387
III. Prevalence388
IV. Neuropsychological Findings388
V. Etiology and Pathogenesis389
VI. Integrative Hypotheses„Neural Oscillations397
VII. Future Directions402
Acknowledgments402
References402
Section VI: Disorders of Sleep and Circadian Rhythms409
Chapter 26: Disorders of Sleep and Circadian Rhythms409
I. Introduction409
II. General Aspects of Sleep and Circadian Rhythms410
III. Sleep and Circadian Neurology411
IV. Neurobiology of Sleep and Circadian Rhythms413
V. Disorders of Sleep and Circadian Rhythms418
VI. Conclusions424
Acknowledgments424
References424
Section VII: Pain427
Chapter 27: Chronic Pain as a Molecular Disorder427
I. Incidence of Chronic Pain427
II. Neurons Involved in Damage Sensing428
III. Damage Sensing428
IV. Chemical Mediators of Nociception429
V. Mechanosensation430
VI. Thermoreception431
VII. Voltage-gated Channels and the Transmission of Information to the Central Nervous System432
VIII. Microglial Interactions and Chronic Pain434
IX. Human Functional Imaging Studies436
X. Conclusion436
References436
Chapter 28: Migraine as a Cerebral Ionopathy with Impaired Central Sensory Processing439
I. Migraine Is a Common Disabling Episodic Disorder439
II. The Migraine Attack: Clinical Phases and Pathophysiology440
III. The Premonitory Phase and the Hypo thalamus440
IV. The Migraine Aura441
V. The Headache Phase441
VI. The Migraine Trigger Threshold: Repeated Recurrence of Attacks446
VII. Conclusions454
References455
Section VIII: Peripheral Nerve Disease463
Chapter 29: Myelin Protein Zero and CMT1B: A Tale of Two Phenotypes463
I. Introduction463
II. Biological Background464
III. The Clinical Phenotypes of CMT1B468
IV. Myelin Protein Zero (MPZ)468
V. Cellular and Molecular Mechanisms of Neuropathy Caused by MPZ Mutations470
VI. R69C Mutation471
VII. H10P Mutation471
VIII. Summary and Conclusions472
References473
Section IX: Neuro-Immunology475
Chapter 30: Demyelinating Diseases: Immunological Mechanisms in the Pathogenesis of Multiple Scleros475
I. Introduction475
II. Autoimmunity versus Self-Tolerance475
III. Immune Reactivity in the CNS476
IV. MS„Immune Pathogenesis?479
V. Animal Models of MS-Experimental Autoimmune Encephalomyelitis (EAE)480
VI. B cell Autoimmunity in Multiple Sclerosis487
VII. Immune Demyelination488
VIII. Beneficial Brain Autoimmunity?490
References491
Chapter 31: Autoimmune and Genetic Disorders of the Neuromuscular Junction and Motor Nerve Terminal499
I. Introduction499
II. Autoimmune Disorders501
III. Genetic Disorders509
IV. General Concepts510
References511
Chapter 32: Paraneoplastic Neurologic Syndromes517
I. Definition and Frequency517
II. Immune-mediated Pathogenic Mechanisms518
III. The Immune Response as an Aid to the Diagnosis of PNS523
IV. Diagnostic Criteria of PNS524
V. The Clinical Manifestations of Paraneoplastic Immunity: Effects on the Nervous System525
VI. The Clinical Manifestations of Paraneoplastic Immunity: Effects on the Tumor529
VII. Treatment of Paraneoplastic Syndromes529
References530
Section X: Mitochondrial Disorders535
Chapter 33: Mitochondrial Disorders535
I. Disorders Due to Mutations in mtDNA539
II. Disorders Due to Mutations in nDNA543
III. Other nDNA Mutations547
IV. Conclusions549
Acknowledgments549
References549
Section XI: Infectious Disorders553
Chapter 34: Molecular Neurology of HIV-1 Infection and AIDS553
I. Introduction553
II. The Influence of Highly-Active Antiretroviral Therapy on the Epidemiology of HIV- Associated Dem554
III. Neuropathology of HIV Infection and Pathogenesis of HIV-Associated Dementia554
IV. HIV Entry into the Brain and Development of Minor Cognitive-Motor Disorder and HIV-Associated De555
V. The Role of Chemokine Receptors in HIV-1 Infection and HIV-Associated Dementia557
VI. Chemokines and HIV/gp120 Influence Neural Stem and Progenitor Cells558
VII. The Role of Macrophages and Microglia in HIV-Induced Neuronal Injury and HIV- Associated Dement558
VIII. Molecular Mechanisms of Neuronal Injury and Death in HIV-Associated Dementia559
IX. Prevention and Therapy of HIV-Associated Dementia: Previous and Potential Future Strategies562
Acknowledgments565
References565
Index573

Book details

Vendor Elsevier S & T
SKU 9780123695093
ISBN-13 9780080546186
Author Waxman, Stephen
Category Medical
Subject Neuroscience

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Why a book on molecular neurology? Molecular neuroscience is advancing at a spectacular rate. As it does so, it is revealing important clues to the pathogenesis and pathophysiology of neurological diseases, and to the therapeutic targets that they present. Medicines work by targeting molecules. The more specific the targeting, the more specific the actions, and the fewer the side effects. This book highlights, for graduate and MD-PhD students, research fellows and research-oriented clinical fellows, and researchers in the neurosciences and other biomedical sciences, the principles underlying molecular medicine as related to neurology. Written by internationally recognized experts, this well-illustrated and well-referenced book presents the most up-to-date principles and disease examples relevant to molecular neurology, and reviews the concepts, strategies, and latest progress in this field. This book will interest anyone studying the molecular basis of neurology, or developing new therapies in neurology.

* Describes the newest molecular aspects of neurological disorders
* Provides an introduction to neurological disorders for basic scientists
* Updates clinicians and clinical researchers on the most recent developments

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