Details

Lysosomes

Biology, Diseases, and Therapeutics
1. Aufl.

von: Frederick R. Maxfield, James M. Willard, Shuyan Lu
153,99 €
Verlag:	Wiley
Format:	PDF
Veröffentl.:	31.05.2016
ISBN/EAN:	9781118978306
Sprache:	englisch
Anzahl Seiten:	544

In den Warenkorb

Als Gutschein

DRM-geschütztes eBook, Sie benötigen z.B. Adobe Digital Editions und eine Adobe ID zum Lesen.

Beschreibungen

Titelbeschreibung

Discussing recent findings, up-to-date research, and novel strategies, the book integrates perspectives from pharmacology, toxicology, and biochemistry to illustrate the potential of lysosomes in drug discovery and development. • Explores basic principles and properties of lysosomes that allow them to act as regulators of cell metabolism, therapeutic targets, and sites for activation of drug conjugates • Discusses the role of lysosomes in metabolism, drug targeting, apoptosis, cancer, aging, inflammation, autophagy, metabolism, toxicity, and membrane repair • Introduces new pathways in therapeutic development and new mechanisms in drug development

Inhaltsverzeichnis

PREFACE xiii LIST OF CONTRIBUTORS xvii 1 Lysosomes: An Introduction 1 Frederick R. Maxfield 1.1 Historical Background, 2 References, 4 2 Lysosome Biogenesis and Autophagy 7 Fulvio Reggiori and Judith Klumperman 2.1 Introduction, 7 2.2 Pathways to the Lysosomes, 10 2.2.1 Biosynthetic Transport Routes to the Lysosome, 10 2.2.2 Endocytic Pathways to the Lysosome, 10 2.2.3 Autophagy Pathways to the Lysosome, 12 2.2.4 The ATG Proteins: The Key Regulators of Autophagy, 14 2.3 Fusion and Fission between the Endolysosomal and Autophagy Pathways, 16 2.3.1 Recycling Endosomes and Autophagosome Biogenesis, 16 2.3.2 Autophagosome Fusion with Late Endosomes and Lysosomes, 17 2.3.3 Autophagic Lysosomal Reformation, 18 2.4 Diseases, 19 2.4.1 Lysosome-Related Disorders (LSDs), 19 2.4.2 Lysosomes in Neurodegeneration and Its Links to Autophagy, 20 2.4.3 Autophagy-Related Diseases, 20 2.5 Concluding Remarks, 22 Acknowledgments, 23 References, 23 3 Multivesicular Bodies: Roles in Intracellular and Intercellular Signaling 33 Emily R. Eden, Thomas Burgoyne, and Clare E. Futter 3.1 Introduction, 33 3.2 Downregulation of Signaling by Sorting onto ILVs, 35 3.3 Upregulation of Signaling by Sorting onto ILVs, 38 3.4 Intercellular Signaling Dependent on Sorting onto ILVs, 39 3.5 Conclusion, 44 References, 45 4 Lysosomes and Mitophagy 51 Dominik Haddad and Patrik Verstreken 4.1 Summary, 51 4.2 Mitochondrial Significance, 51 4.3 History of Mitophagy, 52 4.4 Mechanisms of Mitophagy, 53 4.4.1 Mitophagy in Yeast, 54 4.4.2 Mitophagy in Mammals, 55 4.5 Conclusion, 57 Acknowledgments, 57 References, 58 5 Lysosome Exocytosis and Membrane Repair 63 Rajesh K. Singh and Abigail S. Haka 5.1 Introduction, 63 5.2 Functions of Lysosome Exocytosis, 63 5.2.1 Specialized Lysosome-Related Organelles, 64 5.2.2 Lysosome Exocytosis for Membrane Repair, 65 5.2.3 Lysosome Exocytosis as a Source of Membrane, 66 5.2.4 Lysosome Exocytosis for Extracellular Degradation, 66 5.2.5 Lysosome Exocytosis and Delivery of Proteins to the Cell Surface, 68 5.3 Mechanisms of Lysosome Exocytosis, 68 5.3.1 Maturation of Lysosomes and Lysosome-Related Organelles, 69 5.3.2 Transport of Lysosomes to the Plasma Membrane, 70 5.3.3 Tethering of Lysosomes to the Plasma Membrane, 72 5.3.4 Lysosome Fusion with the Plasma Membrane, 75 5.3.5 Calcium-Dependent Exocytosis, 76 5.4 Conclusion, 76 Acknowledgments, 77 References, 77 6 Role of Lysosomes in Lipid Metabolism 87 Frederick R. Maxfield 6.1 Introduction, 87 6.2 Endocytic Uptake of Lipoproteins, 88 6.3 Lipid Metabolism in Late Endosomes and Lysosomes, 91 6.4 Autophagy and Lysosomal Lipid Turnover, 94 6.5 Lysosomal Lipid Hydrolysis and Metabolic Regulation, 95 6.6 Summary, 96 References, 96 7 TFEB, Master Regulator of Cellular Clearance 101 Graciana Diez-Roux and Andrea Ballabio 7.1 Lysosome, 101 7.2 The Transcriptional Regulation of Lysosomal Function, 102 7.3 TFEB Subcellular Regulation is Regulated by Its Phosphorylation, 104 7.4 A Lysosome-to-Nucleus Signaling Mechanism, 105 7.5 TFEB and Cellular Clearance in Human Disease, 106 7.5.1 Lysosomal Storage Disorders, 107 7.5.2 Neurodegenerative Disorders, 109 7.5.3 Metabolic Syndrome, 110 7.5.4 Cancer, Inborn Errors of Metabolism, Immunity, and Longevity, 110 References, 111 8 Lysosomal Membrane Permeabilization in Cell Death 115 Urška Repnik and Boris Turk 8.1 Introduction, 115 8.2 Cell Death Modalities, 116 8.3 Lysosomal Membrane Permeabilization (LMP) and Cell Death, 117 8.3.1 Mechanisms of LMP, 118 8.3.2 Upstream of LMP: Direct Insult Versus Molecular Signaling, 121 8.3.3 Signaling Downstream of LMP, 124 8.4 Conclusion, 127 Acknowledgments, 127 References, 128 9 The Lysosome in Aging-Related Neurodegenerative Diseases 137 Ralph A. Nixon 9.1 Introduction, 137 9.2 Lysosome Function in Aging Organisms, 139 9.3 Lysosomes and Diseases of Late Age Onset, 142 9.3.1 Cardiovascular Disease, 142 9.4 Lysosomes in Aging-Related Neurodegenerative Diseases, 144 9.4.1 Alzheimer’s Disease (AD), 145 9.4.2 Parkinson’s Disease and Related Disorders, 150 9.4.3 Diffuse Lewy Body Disease (DLB), 155 9.4.4 Frontotemporal Lobar Degeneration (FTLD), 155 9.5 Conclusion, 158 Acknowledgments, 158 References, 159 10 Lysosome and Cancer 181 Marja Jäättelä and Tuula Kallunki 10.1 Introduction, 181 10.2 Lysosomal Function and Its Importance for Cancer Development and Progression, 181 10.3 Cancer-Induced Changes in Lysosomal Function, 182 10.3.1 Increased Activity of Lysosomal Enzymes, 182 10.3.2 Altered Lysosome Membrane Permeability, 184 10.3.3 Increased Lysosome Size, 184 10.3.4 Altered Lysosome Trafficking – Increased Lysosomal Exocytosis, 185 10.4 Cancer-Induced Changes in Lysosome Composition, 185 10.4.1 Changes in Lysosomal Hydrolases, 185 10.4.2 Changes in the Lysosomal Membrane Proteins, 192 10.5 Molecular Changes Involving Lysosomal Integrity, 193 10.5.1 Cancer-Associated Changes in Lysosomal Sphingolipid Metabolism, 193 10.5.2 Targeting Lysosomal Membrane Integrity, 195 10.6 Conclusion, 196 References, 197 11 The Genetics of Sphingolipid Hydrolases and Sphingolipid Storage Diseases 209 Edward H. Schuchman and Calogera M. Simonaro 11.1 Introduction and Overview, 209 11.2 Acid Ceramidase Deficiency: Farber Disease, 210 11.3 Acid Sphingomyelinase Deficiency: Types A and B Niemann–Pick Disease, 213 11.4 Beta-Glucocerebrosidase Deficiency: Gaucher Disease, 215 11.5 Galactocerebrosidase Deficiency: Krabbe Disease/Globoid Cell Leukodystrophy, 218 11.6 Arylsulfatase a Deficiency: Metachromatic Leukodystrophy, 219 11.7 Alpha-Galactosidase a Deficiency: Fabry Disease, 221 11.8 Beta-Galactosidase Deficiency: GM1 Gangliosidosis, 224 11.9 Hexosaminidase A and B Deficiency: GM2 Gangliosidoses, 226 11.10 Sphingolipid Activator Proteins, 229 References, 231 12 Lysosome-Related Organelles: Modifications of the Lysosome Paradigm 239 Adriana R. Mantegazza and Michael S. Marks 12.1 Differences Between LROs and Secretory Granules, 240 12.2 Physiological Functions of LROs, 240 12.3 LRO Biogenesis, 244 12.3.1 Chediak–Higashi Syndrome and Gray Platelet Syndrome, 244 12.3.2 Hermansky–Pudlak Syndrome, 246 12.3.3 Melanosome Biogenesis, 247 12.3.4 HPS and Melanosome Maturation, 248 12.3.5 HPS and the Biogenesis of Other LROs, 250 12.3.6 HPS and Neurosecretory Granule Biogenesis, 250 12.3.7 Weibel–Palade Body Biogenesis, 251 12.4 LRO Motility, Docking, and Secretion, 252 12.5 LROs and Immunity to Pathogens, 253 12.5.1 Cytolytic Granules, 253 12.5.2 Familial Hemophagocytic Lymphohistiocytosis and Cytolytic Granule Secretion, 254 12.5.3 Azurophilic Granules, 255 12.5.4 NADPH Oxidase-Containing LROs, 255 12.5.5 IRF7-Signaling LROs and Type I Interferon Induction, 256 12.5.6 MIICs: LROs or Conventional Late Endosome/Lysosomes?, 256 12.5.7 Phagosomes and Autophagosomes as New Candidate LROs, 258 12.6 Perspectives, 260 Acknowledgments, 260 References, 260 13 Autophagy Inhibition as a Strategy for Cancer Therapy 279 Xiaohong Ma, Shengfu Piao, Quentin Mcafee, and Ravi K. Amaravadi 13.1 Stages and Steps of Autophagy, 282 13.2 Induction of Autophagy, 283 13.3 Studies in Mouse Models Unravel the Dual Roles of Autophagy in Tumor Biology, 285 13.4 Clinical Studies on Autophagy’s Dual Role in Tumorigenesis, 286 13.5 Mouse Models Provide the Rationale for Autophagy Modulation in the Context of Cancer Therapy, 288 13.6 Multiple Druggable Targets in the Autophagy Pathway, 291 13.7 Overview of Preclinical Autophagy Inhibitors and Evidence Supporting Combination with Existing and New Anticancer Agents, 292 13.8 Proximal Autophagy Inhibitors, 293 13.9 Quinolines: From Antimalarials to Prototypical Distal Autophagy Inhibitors, 293 13.10 Summary for the Clinical Trials for CQ/HCQ, 295 13.11 Developing More Potent Anticancer Autophagy Inhibitors, 298 13.12 Summary, Conclusion, and Future Directions, 300 13.13 In Summary, 302 References, 302 14 Autophagy Enhancers, are we there Yet? 315 Shuyan Lu and Ralph A. Nixon 14.1 Introduction, 315 14.2 Autophagy Impairment and Diseases, 316 14.3 Autophagy Enhancer Screening, 317 14.3.1 Methods for Monitoring Autophagy, 317 14.3.2 Autophagy Enhancers Identified from Early Literature, 326 14.3.3 mTOR Inhibitors, 331 14.4 Other Agents that Boost Autophagy and Lysosomal Functions, 335 14.4.1 HDAC Inhibition, 336 14.4.2 pH Restoration, 337 14.4.3 TRP Activator, 337 14.4.4 TFEB Overexpression/Activation, 338 14.4.5 Lysosomal Efficiency, 338 14.4.6 MicroRNA, 339 14.5 Concluding Remarks, 340 References, 341 15 Pharmacological Chaperones as Potential Therapeutics for Lysosomal Storage Disorders: Preclinical Research to Clinical Studies 357 Robert E. Boyd, Elfrida R. Benjamin, Su Xu, Richie Khanna, and Kenneth J. Valenzano 15.1 Introduction, 357 15.2 Fabry Disease, 359 15.3 Gaucher Disease, 363 15.4 GM2 Gangliosidoses (Tay–Sachs/Sandhoff Diseases), 367 15.5 Pompe Disease, 368 15.6 PC-ERT Combination Therapy, 370 References, 372 16 Endosomal Escape Pathways for Delivery of Biologics 383 Philip L. Leopold 16.1 Introduction, 383 16.2 Endosome Characteristics, 384 16.3 Delivery of Nature’s Biologics: Lessons on Endosomal Escape from Pathogens, 389 16.3.1 Viruses, 390 16.3.2 Bacteria, Protozoa, and Fungi, 392 16.3.3 Toxins, 394 16.4 Endosomal Escape Using Engineered Systems, 395 16.4.1 Peptides and Polymers, 396 16.4.2 Lipids, 398 16.4.3 Other Chemical and Physical Strategies, 399 16.5 Conclusion, 399 References, 400 17 Lysosomes and Antibody–Drug Conjugates 409 Michelle Mack, Jennifer Kahler, Boris Shor, Michael Ritchie, Maureen Dougher, Matthew Sung, and Puja Sapra 17.1 Introduction, 409 17.2 Receptor Internalization, 410 17.3 Antibody–Drug Conjugates, 413 17.4 Mechanisms of Resistance to ADCs, 416 17.5 Summary, 417 References, 417 18 The Mechanisms and Therapeutic Consequences of Amine-Containing Drug Sequestration in Lysosomes 423 Nadia Hamid and Jeffrey P. Krise 18.1 Introduction, 423 18.2 Lysosomal Trapping Overview, 424 18.3 Techniques to Assess Lysosomal Trapping, 427 18.4 Influence of Lysosomotropism on Drug Activity, 429 18.5 Influence of Lysosomal Trapping on Pharmacokinetics, 435 18.6 Pharmacokinetic Drug–Drug Interactions Involving Lysosomes, 438 References, 440 19 Lysosome Dysfunction: an Emerging Mechanism of Xenobiotic-Induced Toxicity 445 Shuyan Lu, Bart Jessen, Yvonne Will, and Greg Stevens 19.1 Introduction, 445 19.2 Compounds that Impact Lysosomal Function, 446 19.2.1 Lysosomotropic Compounds, 446 19.2.2 Nonlysosomotropic Compounds, 451 19.3 Cellular Consequences, 452 19.3.1 Effect of Drugs on pH and Lysosomal Volume, 452 19.3.2 Effects on Lysosomal Enzymes, 453 19.3.3 Lysosomal Substrate Accumulation, 454 19.3.4 Lysosomal Membrane Permeabilization (LMP) and Cell Death, 454 19.3.5 Membrane Trafficking Changes, 455 19.3.6 Other Cellular Impacts, 458 19.4 Impaired Lysosomal Function as a Mechanism for Organ Toxicity, 461 19.4.1 Liver Toxicity, 462 19.4.2 Kidney Toxicity, 464 19.4.3 Retinal, 466 19.4.4 Peripheral Neuropathy, 466 19.4.5 Muscle Toxicity, 467 19.4.6 Tumorigenesis, 468 19.4.7 General Considerations for Organ Toxicity, 469 19.5 Concluding Remarks, 471 References, 472 20 Lysosomes and Phospholipidosis in Drug Development and Regulation 487 James M. Willard and Albert De Felice 20.1 Introduction, 487 20.2 FDA Involvement, 488 20.3 Autophagy and DIPL, 489 20.4 Early Experience with Lethal DIPL, 489 20.5 Clinical and Nonclinical Expressions of DIPL, 490 20.5.1 Clinical, 490 20.5.2 Nonclinical, 491 20.6 Physical Chemistry, 491 20.7 Quantitative Structure–Activity Relationship (QSAR), 492 20.8 Toxicogenomics, 493 20.9 Fluorescence, Dye, and Immunohistochemical Methods for Screening, 494 20.10 FDA Database and QSAR Modeling, 494 20.11 Linking Phospholipidosis and Overt Toxicity, 494 20.12 Phospholipidosis and QT Interval Prolongation, 496 20.13 DIPL Mechanisms, 500 20.14 Treatment, 501 20.15 Discussion, 501 20.16 Future Directions and Recommendations, 505 References, 506 INDEX 513

Autorenportrait

Frederick R. Maxfield, PhD, is Professor and Chair of the Department of Biochemistry at Weill Cornell Medical College. He has used digital imaging microscopy to characterize pH changes in endocytic organelles, to measure the kinetics of transport of molecules among organelles, and to identify new endocytic organelles such as the endocytic recycling compartment. Dr. Maxfield has published extensively on trafficking of lipids and cholesterol. James M. Willard, PhD, has been a member of the Phospholipidosis Working Group at the Center for Drug Evaluation and Research (CDER) of the Food and Drug Administration since 2005 and Co-Chair of the group since 2011. Shuyan Lu, MSc, has been an Investigative Toxicologist of Drug Research and Development at Pfizer for over 10 years. She studies the role of lysosomal pathways and physical chemical properties of compounds in drug-induced toxicity.

Back cover copy

Traditionally known as the “stomach of the cell,” lysosomes contain enzymes to break down and recycle internal and external macromolecules, like waste materials and cellular debris. The roles of lysosomes have been expanded to include much broader functions such as membrane repair and amino acid sensing. The organelles also emerge as a signalling hub for mTOR to maintain energy homeostasis. With significant implication in various pathological conditions, lysosomal pathways are evaluated as a pharmacological target for lysosomal storage diseases, cancer, and neurodegeneration. Lysosomes also involve the delivery of other biologicals and antibody drug conjugates. In addition, many drugs are found to accumulate inside lysosomes, thus allowing them to contribute to our understanding of pharmacokinetics, drug-drug interactions, and toxicity profiling. Discussing recent findings, up-to-date research, and novel strategies, Lysosomes integrates perspectives from cell biology, pharmacology, toxicology, and biochemistry to illustrate both the basic properties of lysosomes and their potential roles in drug discovery and development. With perspectives from various fields, this book illustrates the potential of lysosomes beyond their cellular function, focusing on disease and drug targeting. An opening section covers basic cell biology and functions of lysosomes – including chapters on the lysosome’s role in therapeutic pathways, cancer, cell death, and metabolism. The second section explores lysosomes in various aspects of drug development and toxicity and features discussion of autophagy intervention for cancer and neurodegeneration, ADC delivery and efficacy, and drug sequestration in lysosomes and its therapeutic and toxicological consequences. With in-depth coverage of a broad range of material, Lysosomes presents a number of key benefits to readers that include: Integration of key aspects of lysosomes to present an understanding of their roles, potential, and future prospects Discussion of lysosomes in drug targeting, apoptosis, cancer, aging, autophagy, metabolism, toxicity, and membrane repair Exploration of basic principles and properties of lysosomes that allow them to act as therapeutic targets and impact various aspects of drug development