BOOK
Protein Folding Disorders Of The Central Nervous System
Ghiso Jorge A | Rostagno Agueda A
(2017)
Additional Information
Book Details
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Contents | xi | ||
| Preface | v | ||
| List of Contributors | vii | ||
| List of Figures | xv | ||
| List of Tables | xix | ||
| Chapter 1 Misfolding, Aggregation, and Amyloid Formation: The Dark Side of Proteins | 1 | ||
| 1.1 Introduction | 1 | ||
| 1.2 Molecules associated with extra- and intracellular deposits of misfolded proteins | 3 | ||
| 1.3 Protein folding and misfolding: Gauging the nature of the pathogenic species | 7 | ||
| 1.4 Modulation of fibril formation: Lessons from cerebral amyloidosis | 10 | ||
| 1.4.1 Mutations | 11 | ||
| 1.4.2 Protein concentration: Effect of enhanced synthesis versus downregulated clearance | 13 | ||
| 1.4.3 Acidic pH | 15 | ||
| 1.4.4 Presence of metal ions | 17 | ||
| 1.4.5 Post-translational modifications | 17 | ||
| 1.5 Mechanisms of disease associated with protein misfolding | 19 | ||
| 1.5.1 Formation of ion channel-like structures | 19 | ||
| 1.5.2 Induction of apoptotic cell death mechanisms | 20 | ||
| 1.5.3 Mitochondrial dysfunction and oxidative stress | 21 | ||
| 1.5.4 Inflammation-mediated pathways | 22 | ||
| 1.6 Concluding remarks | 23 | ||
| Acknowledgments | 24 | ||
| References | 24 | ||
| Chapter 2 Oligomers at the Synapse: Synaptic Dysfunction and Neurodegeneration | 33 | ||
| 2.1 Introduction | 33 | ||
| 2.2 Mechanisms of oligomer toxicity are related to protein conformation and misfolding | 34 | ||
| 2.3 Protein oligomers that interfere with synaptic function and the disorders they cause | 36 | ||
| 2.3.1 Alpha synuclein | 36 | ||
| 2.3.2 Tau | 38 | ||
| 2.3.3 Amyloid beta | 40 | ||
| 2.3.4 BRI2 | 42 | ||
| 2.3.5 Huntingtin | 44 | ||
| 2.4 Other oligomeric proteins implicated in neurodegenerative disease | 46 | ||
| 2.5 A case study of one mechanism by which oligomers disrupt synaptic function: AβO interference with zinc modulation of neurotransmission | 47 | ||
| 2.6 Conclusion | 49 | ||
| Acknowledgment | 49 | ||
| References | 49 | ||
| Chapter 3 Prion-like Protein Seeding and the Pathobiology of Alzheimer’s Disease | 57 | ||
| 3.1 Alzheimer’s disease (AD) and the amyloid (Aβ) cascade hypothesis | 57 | ||
| 3.1.1 Aβ plaque load and dementia | 59 | ||
| 3.1.2 Tauopathy and dementia | 60 | ||
| 3.1.3 Clinical trials | 61 | ||
| 3.1.4 Animal models and AD | 62 | ||
| 3.1.5 Complexity | 63 | ||
| 3.2 The prion paradigm | 65 | ||
| 3.3 The prion paradigm and AD | 67 | ||
| 3.3.1 Similarities between Aβ seeds and PrP-prions | 67 | ||
| 3.3.2 Evidence for the prion-like seeding of Aβ in humans | 69 | ||
| 3.3.3 Similarities between tau seeds and PrP-prions | 70 | ||
| 3.4 Wide range of prion-like mechanisms | 71 | ||
| Acknowledgments | 72 | ||
| References | 72 | ||
| Chapter 4 The Tau Misfolding Pathway to Dementia | 83 | ||
| 4.1 Introduction to tauopathies | 83 | ||
| 4.2 Microtubule-associated protein (MAP) tau: Isoforms and normal physiology | 84 | ||
| 4.3 Post-translational modifications of tau and the implications in creating a toxic molecule | 85 | ||
| 4.3.1 Tau phosphorylation | 86 | ||
| 4.3.2 Acetylation | 88 | ||
| 4.3.3 Ubiquitination and protein degradation | 89 | ||
| 4.3.4 Proteolysis of tau | 90 | ||
| 4.4 Tau: Normal biological function and pathological gain of function | 91 | ||
| 4.4.1 Microtubules and tau in AD | 91 | ||
| 4.4.2 AD P-tau has a prion-like behavior | 91 | ||
| 4.4.3 Tau self-assembly and “AD P-tau-like” protein behavior is induced by hyperphosphorylation | 92 | ||
| 4.4.4 Pseudophosphorylation of tau as a means to study toxic gain of function | 93 | ||
| 4.4.5 Toxic gain of function observed in a tauopathy models | 96 | ||
| 4.5 Effects of tau propagation on cellular function and AD pathology | 96 | ||
| 4.5.1 Tau and mitochondria | 96 | ||
| 4.5.2 Tau in the nucleus | 98 | ||
| 4.6 Conclusions | 99 | ||
| References | 101 | ||
| Chapter 5 The Biology and Pathobiology of α-Synuclein | 109 | ||
| 5.1 Introduction | 109 | ||
| 5.2 Structure, misfolding, and aggregation | 111 | ||
| 5.3 Membrane binding and cellular function | 116 | ||
| 5.4 α-Syn proteostasis: proteasome, autophagy, and lysosomal pathways | 117 | ||
| 5.5 Prion-like properties of α-syn | 118 | ||
| 5.6 In vivo modeling of synucleinopathies | 122 | ||
| 5.7 Concluding remarks | 123 | ||
| References | 123 | ||
| Chapter 6 Impact of Loss of Proteostasis on Central Nervous System Disorders | 131 | ||
| 6.1 Introduction | 131 | ||
| 6.2 Ubiquitin-proteasome system | 132 | ||
| 6.3 Autophagy-lysosome pathway | 138 | ||
| 6.4 Molecular chaperones | 141 | ||
| 6.5 Unfolded protein response | 146 | ||
| 6.6 Concluding remarks and perspectives | 148 | ||
| Acknowledgments | 152 | ||
| References | 152 | ||
| Chapter 7 Protein Misfolding and Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis | 163 | ||
| 7.1 Introduction | 163 | ||
| 7.1.1 Amyotrophic lateral sclerosis: Clinical and genetic features | 163 | ||
| 7.1.2 Pathways leading to ALS | 164 | ||
| 7.1.3 ALS, a disease of protein misfolding and aggregation | 165 | ||
| 7.1.4 Mitochondrial dysfunction in ALS | 166 | ||
| 7.2 Misfolded proteins that associate with mitochondria in ALS | 167 | ||
| 7.2.1 SOD1, the first ALS protein found in mitochondria | 167 | ||
| 7.2.1.1 SOD1 function and dysfunction | 167 | ||
| 7.2.1.2 Mutant SOD1 is localized inside mitochondria | 167 | ||
| 7.2.1.3 Mutant SOD1 can affect mitochondria from the outside | 169 | ||
| 7.2.2 RNA binding proteins: TDP-43 and FUS, unexpected links to mitochondria | 170 | ||
| 7.2.3 The ER–mitochondria connection, a pathogenic target in ALS | 171 | ||
| 7.2.4 Mitochondrial quality control: VCP and OPTN/TBK1 | 172 | ||
| 7.2.4.1 VCP and the mitochondrial outer membrane protein degradation systems in ALS\r | 172 | ||
| 7.2.4.2 OPTN and TBK1: The selective autophagy pathway of mitochondrial degradation in ALS | 174 | ||
| 7.2.5 CHCHD10, the first mitochondrial protein causative of fALS | 175 | ||
| 7.3 Conclusions | 177 | ||
| References | 177 | ||
| Chapter 8 Impact of Mitostasis and the Role of the Anti-oxidant Responses on Central Nervous System Disorders | 185 | ||
| 8.1 Introduction | 185 | ||
| 8.2 Mitostasis in the nervous system | 187 | ||
| 8.2.1 Mitochondria dynamics: Fusion, fission, and motility | 189 | ||
| 8.2.2 Mitophagy | 190 | ||
| 8.2.3 UPRmt: A Mitochondria-specific unfolded protein response | 192 | ||
| 8.3 Nrf2/Keap1 signaling pathway | 193 | ||
| 8.4 Concluding remarks and perspectives | 196 | ||
| Acknowledgments | 197 | ||
| References | 197 | ||
| Chapter 9 Propagation of Misfolded Proteins in Neurodegeneration: Insights and Cautions from the Study of Prion Disease Prototypes | 203 | ||
| 9.1 Introduction | 203 | ||
| 9.2 Propagation of PrPSc | 208 | ||
| 9.3 Prion strains and species barrier effects | 209 | ||
| 9.4 Allelic forms of PrPC and internal species barrier effects for infections | 211 | ||
| 9.5 Prion-like properties of other neurodegenerative diseases | 213 | ||
| 9.6 Re-purposing inhibitors of prion replication and pathogenic pathways? | 216 | ||
| References | 217 | ||
| Chapter 10 Endoplasmic Reticulum Stress Response in Neurodegenerative Diseases | 225 | ||
| 10.1 Introduction | 225 | ||
| 10.2 UPRER pathways | 226 | ||
| 10.3 Parkinson’s disease | 228 | ||
| 10.4 Demyelinating diseases | 230 | ||
| 10.5 Amyotrophic lateral sclerosis | 232 | ||
| 10.6 Autosomal dominant retinitis pigmentosa | 232 | ||
| 10.7 Conclusions | 234 | ||
| References | 234 | ||
| Chapter 11 Proteomic Analysis of Huntingtin-Associated Proteins Provides Clues to Altered Cell Homeostasis in Huntington’s Disease | 239 | ||
| 11.1 Introduction | 239 | ||
| 11.2 Huntingtin and its various cellular functions | 240 | ||
| 11.2.1 HTT associates with proteins involved in RNA metabolism | 241 | ||
| 11.2.2 HTT associates with mRNA encoding HTT itself | 242 | ||
| 11.3 HEAT repeats in huntingtin | 243 | ||
| 11.4 RNA granules are reversible RNA–protein assemblies that may become aggregates | 244 | ||
| 11.5 HTT associates with mis-spliced HTT exon1 mRNA | 244 | ||
| 11.6 Concluding remarks | 245 | ||
| References | 246 | ||
| Chapter 12 Overcoming the Obstacle of the Blood–Brain Barrier for Delivery of Alzheimer’s Disease Therapeutics | 249 | ||
| 12.1 Introduction | 249 | ||
| 12.2 RMT strategies for the transport of agents to treat AD | 252 | ||
| 12.3 Cell penetrating peptides | 258 | ||
| 12.4 Conclusion | 259 | ||
| References | 261 | ||
| Chapter 13 Immunotherapies for Alzheimer’s Disease | 267 | ||
| 13.1 Introduction | 267 | ||
| 13.2 Aβ immunotherapies | 267 | ||
| 13.2.1 Epitopes to target | 267 | ||
| 13.2.2 Mechanism of action | 269 | ||
| 13.3 Tau immunotherapies | 271 | ||
| 13.3.1 Epitopes to target | 271 | ||
| 13.3.2 Mechanism of action | 272 | ||
| 13.4 Other considerations for Aβ and tau antibody therapies | 273 | ||
| 13.5 Imaging studies to assess brain penetration and target engagement of Aβ or tau antibodies as well as associated clearance of aggregates | 275 | ||
| 13.6 Conclusions | 276 | ||
| Acknowledgments | 276 | ||
| References | 276 | ||
| Chapter 14 Role of the Microbiome in Polyphenol Metabolite-Mediated Attenuation of β-amyloidand tau Protein Misfolding in Alzheimer’s Disease | 281 | ||
| 14.1 Introduction | 281 | ||
| 14.2 Grape-derived polyphenols | 282 | ||
| 14.3 GDP and protein misfolding in AD | 283 | ||
| 14.4 GDP attenuates AD neuropathology while promoting synaptic plasticity | 287 | ||
| 14.5 Role of the microbiome in brain GDP bioavailability | 293 | ||
| 14.6 Clinical intervention and future directions | 298 | ||
| Acknowledgments | 299 | ||
| References | 300 | ||
| Index | 305 |