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PREFACE xiii
LIST OF CONTRIBUTORS xvii
1 Lysosomes: An Introduction 1Frederick R. Maxfield
1.1 Historical Background, 2
References, 4
2 Lysosome Biogenesis and Autophagy 7Fulvio 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 33Emily 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 51Dominik 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 63Rajesh 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 87Frederick 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 101Graciana 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 115UrSka 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 137Ralph 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 181Marja 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 209Edward 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 239Adriana 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 279Xiaohong 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? 315Shuyan 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 357Robert 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 383Philip 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 409Michelle 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 423Nadia 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 445Shuyan 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 487James 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
There has been a resurgence in interest in lysosomes based on exciting new discoveries over the past decade. Lysosomal function was observed microscopically in the late 19th century, and lysosomes were purified in the 1950s by the group of Christian De Duve [1]. During the same period, accumulation of undigested material in cells was observed in pathological examination of tissues from patients with a variety of diseases [2-4]. With the biochemical and morphological characterization of lysosomes, the linkage of the accumulated material with these organelles led to significant insights into the functional importance of lysosomes.
In the second half of the 20th century, there were groundbreaking studies of the biology and biochemistry of lysosomes [5-9]. These studies were linked closely with rapid developments in understanding fundamental cellular biological processes such as secretion and endocytosis. As a result, an increasingly detailed picture emerged of the biogenesis of lysosomes and their functional role in digesting internalized cargo [10, 11]. As understanding of lysosomal function increased, mechanism-based strategies for treating lysosomal diseases emerged. These included substrate reduction therapies (e.g., for Gaucher disease) [12, 13] and enzyme replacement therapies [14].
While there continued to be advances in basic cell biology and biochemistry, as well as in new therapeutic modalities, many investigators had a sense that the exciting era of discovery in lysosome biology was ending in the early 2000s. As an example, the Gordon Conference on "Lysosomes," which for many years was one of the premier meetings on membrane traffic, changed its name to "Lysosomes and Endocytosis" in 2004.
Several related areas of investigation have blossomed over the past decade, and these have brought lysosomes back into the forefront of basic cell biology and biochemistry. One of these areas is autophagy. This process for lysosomal digestion of cytoplasmic organelles had been known for decades, but there were few handles on how to study it. With genetic studies leading to identification of key molecular components in the formation of autophagosomes and their subsequent fusion with lysosomes, it became possible to analyze this process in detail. As a result, autophagy is now recognized as playing a key role in processes including maintenance of organelle integrity, catabolism of lipid droplets, and responses to stress [15, 16]. Additionally, autophagy is essential for the survival and proliferation of some cancer cells, making it a novel target for development of therapies [17, 18]. Furthermore, genetic and molecular biological data accentuate the broad importance of the lysosome in aging and age-related diseases, including cardiovascular and neurodegenerative diseases, which make improving lysosome function an attractive target.
One of the most exciting recent developments has been the recognition that lysosomes are key regulators of signaling processes that regulate metabolism. The elucidation of the mTOR signaling pathways has shown that hydrolytic activity in lysosomes is used by the cell to sense nutrient status [19]. Among other activities, mTOR regulates autophagy to enhance the availability of new molecular building blocks when lysosomal production of catabolites is reduced. In another related area, it was recognized a few years ago that there is a coordinated transcriptional regulation of the genes involved in lysosome biogenesis [20, 21].
Along with these basic science developments, there have been important advances in the understanding of lysosomal storage disorders and in new methods for treatment. In some cases, this is beginning to turn these devastating diseases into conditions that can be managed. At the same time, there is increasing recognition that drugs used for various purposes can interact with lysosomal processes. A dramatic example of this is the discovery of mTOR as a mechanistic target for the immunosuppressive drug rapamycin [22]. Many pharmacological drugs in widespread use can affect lysosomal function [23-26], and it is important to understand the impact of these effects.
With all of these interrelated advances in understanding of lysosome biology, it seemed worthwhile to assemble an updated and integrated book on lysosomes. There are several notable earlier books on lysosomes, and a few of them will be cited here with apologies to the authors whose contributions may have been overlooked. Eric Holtzman [27] wrote a classic monograph that is still worth reading for its historical background and insights into the role of lysosomes in biology. This was followed a few years later by a book by Brian Storrie and Robert Murphy [28]. A book by Paul Saftig [29] focused on the basic biology and function of lysosomes. There have been several excellent books on lysosomal storage disorders, including one by Fran Platt and Steven Walkley [30]. More recently, there was a book emphasizing methods for the study of lysosomes [31].
The current book is intended for a broad audience of researchers interested in multiple facets of lysosome biology. Chapters 1-7 and 12 cover fundamental roles of lysosomes in physiological processes; Chapters 8-11 discusses involvement of lysosomes in various pathological conditions; Chapters 13-20 focus on the contribution of lysosomes in various aspects of drug development, including the lysosomal pathway as a target for drug discovery, toxicity, and special pharmacokinetics attributed to lysosomal accumulation and sequestration
We thank all contributors who provided their chapters despite other pressing responsibilities. We also thank our editors for their diligent effort and David B. Iaea for the cover illustration.
We hope that the broad scope, which includes both basic science and clinical applications, can promote a productive interchange among scientists working across the spectrum of lysosomal studies and nurture drug development efforts targeting lysosome pathways. Ultimately, discovery of new drugs that could improve lysosomal function will benefit multiple therapeutics areas.
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