Beckerman Cellular Signaling in Health and Disease

1. Auflage 2009
ISBN: 978-0-387-98173-4
Verlag: Springer-Verlag
Format: PDF
Kopierschutz: Wasserzeichen (»Systemvoraussetzungen)

E-Book, Englisch, 470 Seiten

In today's world, three great classes of non-infectious diseases - the metabolic syndromes (such as type 2 diabetes and atherosclerosis), the cancers, and the neurodegenerative disorders - have risen to the fore. These diseases, all associated with increasing age of an individual, have proven to be remarkably complex and difficult to treat. This is because, in large measure, when the cellular signaling pathways responsible for maintaining homeostasis and health of the body become dysregulated, they generate equally stable disease states. As a result the body may respond positively to a drug, but only for a while and then revert back to the disease state. Cellular Signaling in Health and Disease summarizes our current understanding of these regulatory networks in the healthy and diseased states, showing which molecular components might be prime targets for drug interventions. This is accomplished by presenting models that explain in mechanistic, molecular detail how a particular part of the cellular signaling web operates properly in health and improperly in disease. The stability of the health- and disease-associated states is dynamic and supported by multiple feedback loops acting positively and negatively along with linkages between pathways. During the past few years an ongoing series of important discoveries have been made that advance our understanding of how the body works and may guide us on how to better deal with these diseases. These include the discovery of chronic inflammation as a causal factor in all of these disease classes, the appearance of reactive oxygen species as a messenger molecule that can act both positively and negatively, the propensity of proteins to misfold into aggregation- and disease-prone forms, and the rise of epigenetics including the emergence of small non-coding RNA with important regulatory functions out of the so-called junk RNA. Chapters are devoted to each of these classes of findings with additional details integrated into the chapters dealing directly with the diseases. The connections responsible for maintaining stability are explored in depth.

Autoren/Hrsg.

Beckerman, Martin

Inhaltsverzeichnis

1;Preface;6
2;Contents;8
3;Part I: Metabolic Syndromes;19
3.1;Introduction;20
3.1.1;1.1 The Cellular Signaling Machinery Makes Homeostasis Possible;21
3.1.2;1.2 Inflammation Is Present in Diseases;21
3.1.3;1.3 Cholesterol Together with Inflammation Promotes Atherosclerosis;23
3.1.4;1.4 Signaling Pathways Responsible for Maintaining Cellular Homeostasis Are Uncovered and Explored;23
3.1.5;1.5 Biophysical Techniques Provide Detailed Information on the Three-Dimensional Structure of Macromolecules;24
3.1.6;1.6 Signaling Pathways Have Been Illuminated Through Intensive Efforts Spanning the Last 50 Years;25
3.1.7;1.7 Mutated, Misfolded Proteins Cause Cancer;26
3.1.8;1.8 The Microenvironment Is an Important Ingredient in Cancer Metastasis;27
3.1.9;1.9 Neurons Are Cells Highly Specialized for Long-Range Signaling;29
3.1.10;1.10 Amyloids Are an Essential Ingredient in Many Diseases;29
3.1.11;1.11 Reactive Oxygen and Nitrogen Species Carry Out Signaling in Ways That Contribute to Health and Disease;32
3.1.12;Further Reading;32
3.2;Energy Balance;35
3.2.1;2.1 Hormonal Signaling by the Endocrine Pancreas;37
3.2.2;2.2 In Response to Signals from the Pancreas, the Liver Maintains Glucose and Lipid Homeostasis;38
3.2.3;2.3 Energy in the Form of Lipids Is Stored and Released When Needed in Adipose Tissue;40
3.2.4;2.4 Adipose Tissue Functions as an Endocrine Organ;41
3.2.5;2.5 Ghrelin Released by Endocrine Cells in the Stomach Acts in Short-Term Feeding and Long-Term Energy Management;42
3.2.6;2.6 Satiation Signals Are Sent by Cells in the Gastrointestinal Tract;42
3.2.7;2.7 Brown Adipose Tissue Carries Out Adaptive (Diet-Induced and Cold-Induced, Nonshivering) Thermogenesis;43
3.2.8;2.8 Muscle Cells and beta-Oxidation;45
3.2.9;2.9 AMPK Is an Intracellular Energy Sensor and Regulator;47
3.2.10;2.10 AMPK Is Activated by Upstream Kinases and by Depleted Energy Supply as Indicated by Increased AMP/ATP Ratios;49
3.2.11;2.11 The Hypothalamic Network Provides Feedback Signals to Peripheral Tissues;51
3.2.12;2.12 Leptin Signaling and Regulation of Energy Balance in the Hypothalamus;53
3.2.13;2.13 Ghrelin Signaling and Regulation of Energy Balance in the Hypothalamus;55
3.2.14;Further Reading;56
3.3;Insulin Signaling and Type 2 Diabetes;60
3.3.1;3.1 Type 2 Diabetes Develops in a Series of Stages from Overnutrition;61
3.3.2;3.2 Adipose Tissue Functions as an Immune Organ;62
3.3.3;3.3 Metabolic Overload Occurs in Energy-Responsive Tissues;63
3.3.4;3.4 Signal Transduction Begins with the Insulin Receptor and Its Substrate Proteins;65
3.3.5;3.5 Phosphoinositide-3-OH Kinase (PI3K) and the PTEN Lipid Phosphatase;67
3.3.6;3.6 Activation of Protein Kinase B (PKB) and Protein Kinase C (PKC);69
3.3.7;3.7 GLUT4 Transport Biomechanics and Regulation;71
3.3.8;3.8 The TOR Cassette Is the Downstream Target of Akt Signals;73
3.3.9;3.9 Feedback Regulation of Akt by TORC2 and IRS by TORC1/S6K;75
3.3.10;3.10 Insulin Resistance Develops from Inflammation and Metabolic Overload;75
3.3.11;3.11 Glucose-Stimulated Hormone Release by Pancreatic Islet Cells;78
3.3.12;3.12 KATP Channels and Their Regulation by Cellular Fuel Status;80
3.3.13;3.13 Islet beta-Cell Failure and Diabetic Complications;81
3.3.14;Further Reading;82
3.4;Metabolic Program Execution and Switching;86
3.4.1;4.1 Nuclear Receptors Are Ligand-Activated Transcription Factors;86
3.4.2;4.2 Nuclear Receptors Contain Five or Six Domains;88
3.4.3;4.3 The CAR Activates and Deactivates in a Manner Distinct from Other Nuclear Receptors;89
3.4.4;4.4 Peroxisome Proliferator-Activated Receptors Are Lipid Sensors and Effectors;90
3.4.5;4.5 Nuclear Receptors Require Coactivators and Corepressors;92
3.4.6;4.6 PGC-1 Scaffold Protein in Regulation of Lipid Homeostasis;95
3.4.7;4.7 FoxOs Mediate Survival, Metabolic, and Stress Responses;95
3.4.8;4.8 14-3-3 Protein Function as Small, Mobile Phosphoprotein Binding Modules;97
3.4.9;4.9 Gluconeogenesis in the Liver Is Stimulated by Glucagon and Repressed by Insulin;98
3.4.10;4.10 Catecholamine Signaling Targets PGC1alpha to Promote Diet-Induced Thermogenesis in Brown Adipose Tissue;100
3.4.11;4.11 Caloric Restriction Extends Lifespan by Activating Protective Stress Responses;101
3.4.12;4.12 SIRT1 Promotes Fatty Acid Oxidation in Liver and Skeletal Muscle;102
3.4.13;Further Reading;103
3.5;Cholesterol;106
3.5.1;5.1 Membrane Lipids Form Gels and Liquid States;106
3.5.2;5.2 Feedback Regulation of Cholesterol Synthesis by Insigs;109
3.5.3;5.3 Feedback Regulation of Cholesterol Synthesis by SREBPs;110
3.5.4;5.4 SREBPs, Liver X Receptors, and Farnesoid X Receptors Regulate Transcription;112
3.5.5;5.5 Lipoproteins Are Carriers of Cholesterol and Triglycerides;113
3.5.6;5.6 Apolipoproteins are Amphipathic, Lipid-Binding Constituents of the Lipoproteins;114
3.5.7;5.7 Cholesterol Comes in Two Forms - As a Sterol, i.e., as a Free Cholesterol (FC) Molecule, and as a Cholesterol Ester (CE);117
3.5.8;5.8 ABC Transporters Export Cholesterol from Macrophages;118
3.5.9;Further Reading;119
3.6;Atherosclerosis;121
3.6.1;6.1 The Arterial Wall Consists of Three Layers;121
3.6.2;6.2 Cells Are Continually Subjected to Forces;123
3.6.3;6.3 Atherosclerotic Lesions Occur Preferentially in Regions of Disturbed Blood Flow;124
3.6.4;6.4 Cells Utilize Multiple Mechanotransduction Pathways That Convey Information About Blood Flow;126
3.6.5;6.5 Mechanotransduction Pathways Relay Information About Blood Flow to Endothelial Caveolae and Nitric Oxide Synthase;126
3.6.6;6.6 oxLDL Is Atherogenic and Acts in Opposition to eNOS and NO;127
3.6.7;6.7 Cell Adhesion Molecules and Chemokines Mediate Leukocyte Migration into Sites of Inflammation;129
3.6.8;6.8 Leukocyte Migration Occurs Through a Multistep Adhesion Cascade;131
3.6.9;6.9 Selectins Are Key Mediators of Leukocyte Tethering and Rolling;132
3.6.10;6.10 Slip and Catch Bonds Play Important Roles in Selectin-Mediated Rolling;133
3.6.11;6.11 Leukocyte Arrest Through the Joint Actions of Chemokines and Integrins;135
3.6.12;6.12 Epithelial Cell-to-Cell Adhesions Are Maintained by Junctional Complexes;137
3.6.13;6.13 Leukocytes Enter the Intima by Passing In-Between Epithelial Cells and by Passing Through Them;139
3.6.14;6.14 Rupture of the Fibrous Cap and Not the Lesion Itself Causes Thrombosis;140
3.6.15;Further Reading;142
3.7;Chronic Inflammation;145
3.7.1;7.1 The NF-kappaB Signaling Node Consists of IKKs, IkappaBs, and NF-kappaBs;146
3.7.2;7.2 Protein Ubiquitination Plays a Central Role in Cellular Signaling;149
3.7.3;7.3 TNFalpha Signaling Occurs Through Complex I and Complex II;151
3.7.4;7.4 Reactive Oxygen Species (ROS) Influences the Choice Between Survival and Death;152
3.7.5;7.5 Toll-like Receptor 4 Responds to Bacterial Lipopolysaccharides and Mammalian Lipids;153
3.7.6;7.6 Downstream and into the Nucleus with NF-kappaBs;155
3.7.7;7.7 Glucocorticoids Terminate Inflammatory Responses and Restore Homeostasis;156
3.7.8;7.8 LXRs and PPARgamma in Transrepression of Inflammation Through SUMOylation;157
3.7.9;7.9 The Local Microenvironment Is a Key Organizational Unit in Health and Disease;159
3.7.10;7.10 The Inflammatory Response Is a Biphasic One with Distinct Clear Up and Reconstruction Phases;160
3.7.11;7.11 Macrophages Are Inflammatory Cells with Key Roles in the Body’s Response to Infection and Injury;161
3.7.12;7.12 Fibroblasts Are Connective Tissue Cells;163
3.7.13;7.13 Mesenchymal Stem Cells Are Located Throughout the Body;164
3.7.14;Further Reading;164
3.8;Redox Signaling;168
3.8.1;8.1 Hydrogen Peroxide and Nitric Oxide Are Signaling Molecules;169
3.8.2;8.2 Nox Enzymes;170
3.8.3;8.3 Oxidation of Sulfhydryls and Hydrogen Peroxide Signaling;172
3.8.4;8.4 Nitric Oxide Synthases and Nitric Oxide Signaling;175
3.8.5;8.5 The Frank-Starlings Law and Excitation-Contraction Coupling;177
3.8.6;8.6 Transcriptional Regulation of the Metabolic Programs;179
3.8.7;8.7 Inappropriate S-Nitrosylation Contributes to Neurodegenerative Disorders;181
3.8.8;8.8 The Electron Transport Chain Can Generate Reactive Oxygen Species;183
3.8.9;Further Reading;185
4;Part II: Cancer;189
4.1;The Cell Cycle;190
4.1.1;9.1 The Cell Cycle Has Four Phases;193
4.1.2;9.2 Ubiquitin-Mediated Proteolysis Is a Key Part of the Cell Cycle Machinery;194
4.1.3;9.3 Several Families of Activators and Inhibitors Are Part of the Cell Cycle Engine;195
4.1.4;9.4 The Retinoblastoma Proteins and E2F Transcription Factors Are Downstream Cell Cycle Effectors at the G1/S Transition;196
4.1.5;9.5 Cell Cycle Effectors at the G2/M Transition;198
4.1.6;9.6 The SCF and APC/C Are Large Multisubunit Complexes;199
4.1.7;9.7 Mathematical Modeling Is an Essential Tool in Understanding Signaling Pathways and Networks;200
4.1.8;9.8 The Goldbeter Model of Entry and Exit from Mitosis;203
4.1.9;9.9 Multiple Positive and Negative Feedback Regulate the Progression Through the Cell Cycle;205
4.1.10;9.10 Multisite Phosphorylation Helps Ensure the Correct Ordering of Events;207
4.1.11;9.11 Traversing the Cell Cycle with the APC and SCF;207
4.1.12;Further Reading;208
4.2;Cell Cycle Checkpoints and DNA Damage Repair;212
4.2.1;10.1 The G1/S Checkpoint Pathway;213
4.2.2;10.2 Formation of IRIFs and Activation of ATM;214
4.2.3;10.3 Mediators Amplify the ATM Signal;216
4.2.4;10.4 Intra-S Phase and G2/M Checkpoints;217
4.2.5;10.5 Formation of SDSCs and Activation of ATR;218
4.2.6;10.6 Structure and Posttranslational Modifications of Checkpoint Proteins;219
4.2.7;10.7 p53 Structure and Function;221
4.2.8;10.8 Restoration of p53 Function by Second-Site Suppressors;223
4.2.9;10.9 Special Domains Mediate Protein-Protein Interactions and Chromatin Binding by Proteins that Function at the Apex of the Checkpoint and Repair Pathways;224
4.2.10;10.10 Base Excision Repair;225
4.2.11;10.11 Nucleotide Excision Repair;227
4.2.12;10.12 Mismatch Repair;227
4.2.13;10.13 Repair Proteins Diffuse Laterally in One-Dimension Along DNA;228
4.2.14;10.14 There Are Two Double-StrandBreak Repair Systems;229
4.2.15;10.15 The Mre11-Rad50-Nbs1 (MRN) Complex Is Involved in DNA Damage Sensing, Signaling, and Repair;231
4.2.16;10.16 Completing the Repair and Terminating the Checkpoint;232
4.2.17;Further Reading;233
4.3;Apoptosis and Senescence;237
4.3.1;11.1 Pathways to Apoptosis - Extrinsic and Intrinsic;238
4.3.2;11.2 Bcl2 Proteins Mediate the Apoptotic Balance;240
4.3.3;11.3 Sequestration and Release of Cytochrome c;242
4.3.4;11.4 Damage-Induced Apoptosis via p53 Transcription and Mitochondrial Actions;243
4.3.5;11.5 Cells That Are Healthy Do Not Have an Unlimited Capacity to Divide;244
4.3.6;11.6 Telomere Structure and Capping Proteins;244
4.3.7;11.7 Cancer Cells Increase Their Production of Telomerase, an Enzyme That Immortalizes the Cells;245
4.3.8;11.8 Regulation of Replicative Senescence by p53 and pRb;246
4.3.9;11.9 DNA Damage and Oncogene-Induced Senescence;247
4.3.10;11.10 A Model or Two of Oncogene-Induced Stress;248
4.3.11;11.11 p53 Undergoes Posttranslational Modifications Including Phosphorylation, Acetylation, and Ubiquitination at Multiple Sites;250
4.3.12;11.12 Heterochromatin Formation Provides a Route to Oncogene-Induced Senescence;251
4.3.13;11.13 The Retinoblastoma Protein Helps Establish the Senescent State by Mediating Heterochromatin Formation;253
4.3.14;Further Reading;254
4.4;Epigenetics;259
4.4.1;12.1 Nucleosomes and Chromatin Structure;260
4.4.2;12.2 Epigenetic Marks;261
4.4.3;12.3 DNA Methylation;263
4.4.4;12.4 Polycomb and Trithorax Group Proteins;264
4.4.5;12.5 Histone Acetylation and Deacetylation;264
4.4.6;12.6 Histone Methylation and Demethylation;265
4.4.7;12.7 Reading Out Histone Marks by Recognition Modules;266
4.4.8;12.8 Cooperative Actions by Histone Modification Enzymes and DNA Methyltransferases Can Silence Genes and Lead to Cancer;269
4.4.9;12.9 Recently Discovered Small Noncoding RNAs (ncRNAs) Regulate Gene Expression;270
4.4.10;12.10 Atomic-Level Studies of Dicer and Slicer Provide Crucial Insights into ncRNA Function;272
4.4.11;12.11 MicroRNAs and Cancer;274
4.4.12;12.12 Induced Pluripotent Stem Cells;276
4.4.13;Further Reading;277
4.5;Tumor Growth;281
4.5.1;13.1 Growth and Survival Signaling Pathways;281
4.5.2;13.2 Receptor Activation Leads to Recruitment of Molecular Adaptors to Docking Sites;283
4.5.3;13.3 Ras and Other Small GTPases Link Adaptors to Downstream Signaling Elements;285
4.5.4;13.4 Many of the Growth Signaling Proteins Function as Oncogenes;286
4.5.5;13.5 MAP Kinase Signaling Modules;288
4.5.6;13.6 The MAP Kinase Modules and Their Substrates Function as Dynamical Circuits;290
4.5.7;13.7 Active and Inactive Conformations of Protein Kinases;291
4.5.8;13.8 Oncogene Addiction;292
4.5.9;13.9 Target-Based Anticancer Therapies;293
4.5.10;13.10 Myc Protein Structure and Function;294
4.5.11;13.11 Phosphorylation and Polyubiquitination Sculpt Myc-Mediated Gene Transcription;295
4.5.12;13.12 Regulation of Cellular Growth by Ras, Erk, and Myc;296
4.5.13;13.13 Regulation of Cellular Proliferation by Myc;297
4.5.14;Further Reading;298
4.6;Tumor Metabolism;301
4.6.1;14.1 The Central Growth Network of the Cell Is Organized About the mTOR Cassette;302
4.6.2;14.2 AMPK Supplies a Gating Signal Indicative of Energy Balance;303
4.6.3;14.3 Cells Halt Growth in Response to Hypoxia and Other Cellular Stresses;303
4.6.4;14.4 Regulation of Cell Growth by Amino Acid Starvation Signaling to mTOR;305
4.6.5;14.5 Regulation of the Translation Initiation Complex by mTOR;306
4.6.6;14.6 Starvation and Autophagy;308
4.6.7;14.7 p53 Modulation of Metabolism Is One of Its Barrier Functions;310
4.6.8;14.8 The PTEN Tumor Suppressor Acts at the Plasma Membrane and in the Nucleus;312
4.6.9;14.9 Mutations and Disturbed Redox Balance Deactivate PTEN;313
4.6.10;14.10 HIF Transcription Factors Sense and Respond to Low Oxygen Conditions;314
4.6.11;14.11 HIFs Regulate Cellular Metabolism and Drive the Glycolytic Shift;316
4.6.12;14.12 Hexokinase II and Akt Drive the Glycolytic Shift and Prevent Apoptosis in Tumors;317
4.6.13;Further Reading;319
4.7;Metastasis;323
4.7.1;15.1 Tumor Growth and Metastasis Are Community Affairs;324
4.7.2;15.2 Macrophages and Fibroblasts Direct Invasion and Intravasation;326
4.7.3;15.3 The SDF-1/CXCR4 Axis Is a Central Participant in Metastasis;327
4.7.4;15.4 Focal Adhesions and Metastasic Migration;328
4.7.5;15.5 Receptor Cooperativity and Src Signaling;330
4.7.6;15.6 The Transforming Growth Factor-beta Pathway;332
4.7.7;15.7 TGF-beta Promotes Cytostasis;335
4.7.8;15.8 The Wnt Pathway;336
4.7.9;15.9 The Epithelial to Mesenchymal Transition;337
4.7.10;15.10 MicroRNAs and Transcription Repressors Jointly Regulate E-Cadherin Expression;339
4.7.11;15.11 MicroRNAs Act as Metastasis Repressors and Activators;341
4.7.12;15.12 Stem Cells and Cancer Stem Cells;341
4.7.13;15.13 Changing Views About Metastatic Spread;342
4.7.14;15.14 The Notch Pathway;343
4.7.15;15.15 The Hedgehog Pathway in Drosophila;345
4.7.16;15.16 The Hedgehog Pathway in Mammals;346
4.7.17;15.17 Bone Metastasis Is a Seed-and-Soil Exemplar;348
4.7.18;Further Reading;349
5;Part III: Neurodegeneration;353
5.1;Protein Folding, Misfolding, and Aggregation;354
5.1.1;16.1 Proteins Spontaneously Fold into Their Native State Based Solely on Their Primary Amino Acid Sequence;357
5.1.2;16.2 Protein Folding Can Be Described in Terms of an Energy Landscape Dominated by a Folding Funnel;358
5.1.3;16.3 Some Landscapes Are Smooth While Others Are Rugged;360
5.1.4;16.4 Proteins, Especially Those Involved in Signaling, Often Fold into Nonglobular, Extended Conformations;361
5.1.5;16.5 Dialysis-Related Amyloidosis Is Brought on by Partial Unfolding and Aggregation of beta-2 Microglobulin;363
5.1.6;16.6 beta Cell Failure and Amyloid Formation in Type 2 Diabetes Is Brought on by Amylin Misfolding and Aggregation;366
5.1.7;16.7 Some Proteins Have Native States That Are Metastable and Not at a Global Minimum in the Free Energy;366
5.1.8;16.8 beta-Sheet Conformational Variations Underlie the Prion Strains and Disease Potential;367
5.1.9;16.9 Strains and Transmissibility;370
5.1.10;16.10 General Observations on How Proteins Fold into Alternative Disease-Causing Structures Characterized by Cross-beta-Sheets;371
5.1.11;Further Reading;373
5.2;Alzheimer’s Disease;377
5.2.1;17.1 Generation of the Amyloid beta Protein;378
5.2.2;17.2 Removal Through Degradation and Clearance;381
5.2.3;17.3 Folding Physics, Metal Homeostasis, and Redox Chemistry;383
5.2.4;17.4 Normal Physiological Function of the Abeta Protein at the Synapse;384
5.2.5;17.5 Action of the Abeta Oligomers at the Synapse - Aberrant LTD;385
5.2.6;17.6 The Local Microenvironment Contains Neurons, Astrocytes, and Microglia;387
5.2.7;17.7 Microglia Respond to Amyloid Plaque Buildup by Mounting an Inflammatory Response;388
5.2.8;17.8 Inflammatory and Synaptic Cytokines Are Released by Microglia and Astrocytes;390
5.2.9;17.9 Tau Hyperphosphorylation and Formation of the Tangles;392
5.2.10;Further Reading;395
5.3;Chaperones, Endoplasmic Reticulum Stress, and the Unfolded Protein Response;398
5.3.1;18.1 The Cellular Complement of Molecular Chaperones;399
5.3.2;18.2 Hsp70 Structure and Function;400
5.3.3;18.3 Hsp90 Structure and Function;401
5.3.4;18.4 Heat Shock Factor 1 Is a Master Regulator of Protein Homeostasis;403
5.3.5;18.5 Folding, Processing, and Maturation of Membrane and Secreted Proteins;404
5.3.6;18.6 N-Linked Glycan Processing;406
5.3.7;18.7 The Unfolded Protein Response;408
5.3.8;18.8 ERAD and the Sec61 Translocon;411
5.3.9;18.9 The p97 Motor Protein Is a Molecular Chaperone Required for ERAD;412
5.3.10;Further Reading;414
5.4;Parkinson’s Disease;418
5.4.1;19.1 alpha-Synuclein Is a Presynaptic Protein;421
5.4.2;19.2 Abnormalities and Toxicity Result from alpha-Synuclein Misfolding and Aggregation;421
5.4.3;19.3 Oxidative Damage Is a Cause of alpha-Synuclein Aggregation and PD;422
5.4.4;19.4 Parkin Is an E3 Ubiquitin Ligase;423
5.4.5;19.5 Protein Carbonylation and UCH-L1;424
5.4.6;19.6 PINK1 Is a Neuroprotective Serine/Threonine Kinase;424
5.4.7;19.7 DJ-1 Protects Against Oxidative Stress;425
5.4.8;19.8 LRRK2 Is a ROCO Family Member and Mutations in This Protein Are Most Strongly Associated with PD;426
5.4.9;19.9 HtrA2/Omi Removes Misfolded Proteins;427
5.4.10;19.10 The Pathway Is Illuminated;428
5.4.11;19.11 Proteasome Organization;429
5.4.12;19.12 Cellular Garbage Collection and the Aggresomal - Autophagic Railway;431
5.4.13;19.13 Histone Deacetylase 6 Mediates Transport Along the Disposal Railway;432
5.4.14;Further Reading;433
5.5;Huntington’s Disease and Amyotrophic Lateral Sclerosis;438
5.5.1;20.1 Huntington’s Disease Is an Expanded PolyQ Repeat Disorder;439
5.5.2;20.2 The Structure of the Huntingtin Protein Is That of a Multipurpose Signaling Organizer;441
5.5.3;20.3 Synaptic Terminal Interactions Occur;441
5.5.4;20.4 Impaired Fast Axonal Transport Happens;443
5.5.5;20.5 Zippers, Aggregation, Fibrils, Inclusion Body Formation, and Toxicity;443
5.5.6;20.6 The Ubiquitin-Proteasome System Regulates Synaptic Transmission and This Function Is Impaired by Mutant Htt;445
5.5.7;20.7 Impaired Transcription: CBP and PGC-1 - and Mitochondrial Dysfunction;446
5.5.8;20.8 Structure and Folding of the Superoxide Dismutase Protein SOD1;447
5.5.9;20.9 SOD1 Mutations and Aggregation;448
5.5.10;20.10 Impaired Fast Axonal Transport and Retraction of Axons from Synapses;449
5.5.11;20.11 A Model for Amyotrophic Lateral Sclerosis;450
5.5.12;20.12 Acceleration of ALS Through Interactions Between Neurons and Other Cellular Residents of Its Microenvironment;451
5.5.13;20.13 PolyQs, Mutant SOD1, and Impaired ERAD;453
5.5.14;20.14 Mutations in Genes Other Than That for SOD1 Can Cause fALS;454
5.5.15;20.15 Interlocking Signaling Networks Underlie Health and Disease;456
5.5.16;Further Reading;457
6;Index;462