Top

Amazon no longer offers textbook rentals. We do!

Lysosomes Biology, Diseases, and Therapeutics

by: Maxfield, Frederick R.; Willard, James M.; Lu, Shuyan

Lysosomes Biology, Diseases, and Therapeutics

by: Maxfield, Frederick R.; Willard, James M.; Lu, Shuyan

ISBN 13:
9781118645154
ISBN 10:
1118645154
Edition: 1st
Format: Hardcover
Copyright: 06/27/2016
Publisher: Wiley

New From $208.97

Sorry, this item is currently unavailable.

Free Shipping On Every Order

List Price $210.07 Save $1.10

New $208.97

Print on Demand: 2-4 Weeks. This item cannot be cancelled or returned.

We Buy This Book Back!

Included with your book

Free Shipping On Every Order

Add to Cart

Note: Supplemental materials are not guaranteed with Rental or Used book purchases.

Extend or Purchase Your Rental at Any Time

Need to keep your rental past your due date? At any time before your due date you can extend or purchase your rental through your account.

Lysosomes Biology, Diseases, and Therapeutics > ISBN13: 9781118645154

Summary

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

Author Biography

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.

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

Supplemental Materials

What is included with this book?

The New copy of this book will include any supplemental materials advertised. Please check the title of the book to determine if it should include any access cards, study guides, lab manuals, CDs, etc.

The Used, Rental and eBook copies of this book are not guaranteed to include any supplemental materials. Typically, only the book itself is included. This is true even if the title states it includes any access cards, study guides, lab manuals, CDs, etc.