Contents
List of Contributors
Preface/Foreword (Will come)
Chapter 1: Lysosomes an Introduction
Frederick R. Maxfield
1.1. Historical Background
References
Chapter 2: Lysosome biogenesis and autophagy
Fulvio Reggiori, Judith Klumperman
2.1. Introduction
2.2. Pathways to the lysosomes
2.3. Fusion and fission between the endo-lysosomal and autophagy pathways
2.4. Diseases
2.5. Concluding remarks
Acknowledgements
References
Chapter 3: Multivesicular bodies: roles in intracellular and intercellular signaling
Emily R. Eden, Thomas Burgoyne, Clare E. Futter
3.1. Introduction
3.2. Down regulation of signaling by sorting onto ILVs -
3.3. Up regulation of signaling by sorting onto ILVs
3.4. Intercellular signaling dependent on sorting onto ILVs
3.5. Conclusions
References
Chapter 4: Lysosomes and mitophagy
Dominik Haddad, Patrik Verstreken
4.1. Summary
4.2. Mitochondrial significance
4.3. History of mitophagy
4.4. Mechanisms of mitophagy
4.5. Conclusion
Acknowledgments
References
Chapter 5: Lysosome Exocytosis and Membrane Repair
Rajesh K. Singh, Abigail S. Haka
5.1. Introduction
5.2. Functions of Lysosome Exocytosis
5.2.1. Specialized Lysosome Related Organelles
5.2.2. Lysosome Exocytosis for Membrane Repair
5.2.3. Lysosome Exocytosis as a Source of Membrane
5.2.4. Lysosome Exocytosis for Extracellular Degradation
5.2.5. Lysosome Exocytosis and Delivery of Proteins to the Cell Surface
5.3. Mechanisms of Lysosome Exocytosis
5.3.1. Maturation of Lysosomes and Lysosome Related Organelles
5.3.2. Transport of Lysosomes to the Plasma Membrane
5.3.3. Tethering of Lysosomes to the Plasma Membrane
5.3.4. Lysosome Fusion with the Plasma Membrane
5.4. Conclusions
Acknowledgements
References
Chapter 6: Role of lysosomes in lipid metabolism
Frederick R. Maxfield
6.1. Introduction
6.2. Endocytic uptake of lipoproteins
6.3. Lipid metabolism in late endosomes and lysosomes
6.4. Autophagy and lysosomal lipid turnover
6.5. Lysosomal lipid hydrolysis and metabolic regulation
6.6. Summary
References
Chapter 7: TFEB, master regulator of cellular clearance
Graciana Diez-Roux and Andrea Ballabio
7.1. The lysosome
7.2. The transcriptional regulation of lysosomal function
7.3. TFEB subcellular regulation is regulated by its phosphorylation
7.4. A lysosome-to-nucleus signaling mechanism
7.5. TFEB and cellular clearance in human disease
References
Chapter 8: Lysosomal membrane permeabilization in cell death
Ur ka Repnik, Boris Turk
8.1. Introduction
8.2. Cell death modalities
8.3. Lysosomal membrane permeabilization (LMP) and cell death
8.4. Conclusions
Acknowledgements
References
Chapter 9: The Lysosome in Aging-Related Neurodegenerative Diseases
Ralph A. Nixon
9.1. Introduction
9.2. Lysosome function in aging organisms
9.3. Lysosomes and diseases of late age onset
9.4. Lysosomes in aging-related neurodegenerative diseases
9.5. Conclusions
Acknowledgements
References
Chapter 10: Lysosome and cancer
Marja Jäättelä and Tuula Kallunki
10.1. Introduction
10.2. Lysosomal function and its importance for cancer development and progression
10.3. Cancer-induced changes in lysosomal function
10.4. Cancer-induced changes in lysosome composition
10.5. Changes in the lysosomal membrane proteins
10.6. Molecular changes involving lysosomal integrity
10.7. Conclusion
References
Chapter 11: The Genetics Of Sphingolipid Hydrolases & Sphingolipid Storage Diseases
Edward H. Schuchman and Calogera M. Simonaro
11.1. Introduction & Overview
11.2. Acid Ceramidase Deficiency: Farber Disease
11.3. Acid Sphingomyelinase Deficiency: Types A and B Niemann-Pick Disease
11.4. Beta-Glucocerebrosidase Deficiency: Gaucher Disease
11.5. Galactocerebrosidase Deficiency: Krabbe Disease/Globoid Cell Leukodystrophy
11.6. Arylsulfatase A Deficiency: Metachromatic Leukodystrophy
11.7. Alpha Galactosidase A Deficiency: Fabry Disease
11.8. Beta Galactosidase Deficiency: GM1 Gangliosidosis
11.9. Hexosaminidase A & B Deficiency: GM2 Gangliosidoses
11.10. Sphingolipid Activator Proteins
References
Chapter 12: Lysosome-related organelles: modifications of the lysosome paradigm
Adriana R. Mantegazza and Michael S. Marks
12.1. Differences between LROs and secretory granules
12.2. Physiological functions of LROs.
12.3. LRO biogenesis
12.4. LRO motility, docking and secretion
12.5. LROs and immunity to pathogens
12.6. Perspectives
Acknowledgments
References
Chapter 13: Autophagy inhibition as a strategy for cancer therapy
Xiaohong Ma, Shengfu Piao, Quentin Mcafee, and Ravi K. Amaravadi
13.1. Stages and steps of autophagy
13.2. Induction of autophagy
13.3. Studies in mouse models unravel the dual roles of autophagy in tumor biology
13.4. Clinical Studies on autophagy's dual role in tumorigenesis
13.5. Mouse models provide the rationale for autophagy modulation in the context of cancer therapy
13.6. Multiple druggable targets in the autophagy pathway
13.7. Overview of preclinical autophagy inhibitors and evidence supporting combination with existing and new anticancer agents
13.8. Proximal autophagy inhibitors
13.9. Quinolines: From antimalarials to prototypical distal autophagy inhibitors.
13.9.1. Summary for the clinical trials for CQ/HCQ
13.9.2. Developing more potent anticancer autophagy inhibitors
13.10. Summary, Conclusion, and Future Directions
References
Chapter 14: Autophagy enhancers, are we there yet?
Shuyan Lu & Ralph A Nixon
14.1. Introduction
14.2. Autophagy impairment and diseases
14.3. Autophagy enhancer screening
14.4. Concluding Remarks
References
Chapter 15: Pharmacological Chaperones as Potential Therapeutics for Lysosomal Storage Disorders: Preclinical Research to Clinical Studies
Robert E. Boyd, Elfrida R. Benjamin, Su Xu, Richie Khanna, and Kenneth J. Valenzano
15.1. Introduction
15.2. Fabry Disease
15.3. Gaucher Disease
15.4. GM2 Gangliosidoses (Tay-Sachs/Sandhoff Diseases)
15.5. Pompe Disease
15.6. PC-ERT Combination Therapy
References
Chapter 16: Endosomal Escape Pathways for Delivery of Biologics
Philip L. Leopold
16.1. Introduction
16.2. Endosome characteristics
16.3. Delivery of nature's biologics: lessons on endosomal escape from pathogens
16.4. Endosomal escape using engineered systems
16.5. Conclusion
References
Chapter 17: Lysosomes and Antibody Drug Conjugates
Michelle Mack, Jennifer Kahler, Boris Shor, Michael Ritchie, Maureen Dougher, Matthew Sung, and Puja Sapra
17.1. Introduction
17.2. Receptor Internalization
17.3. Antibody Drug Conjugates
17.4. Mechanisms of Resistance to ADCs
17.5. Summary
References
Chapter 18: The mechanisms and therapeutic consequences of amine-containing drug sequestration in lysosomes
Nadia Hamid and Jeffrey P. Krise
18.1. Introduction
18.2. Lysosomal trapping overview
18.3. Techniques to assess lysosomal trapping
18.4. Influence of lysosomotropism on drug activity
18.5. Influence of lysosomal trapping on pharmacokinetics
18.6. Pharmacokinetic drug-drug interactions involving lysosomes
References
Chapter 19: Lysosome dysfunction: an emerging mechanism of xenobiotic-induced toxicity
Shuyan Lu, Bart Jessen, Yvonne Will & Greg Stevens
19.1. Introduction
19.2. Compounds that impact lysosomal function
19.3. Cellular consequences
19.4. Impairment lysosomal function as a mechanism for organ toxicity
19.5. Concluding Remarks
References
Chapter 20: Lysosomes and Phospholipidosis in Drug Development and Regulation
James M. Willard and Albert De Felice
20.1. Introduction
20.2. FDA involvement
20.3. Autophagy and DIPL
20.4. Early experience with lethal DIPL
20.5. Clinical and non-clinical expressions of DIPL
20.6. Physical Chemistry
20.7. Quantitative Structure-Activity Relationship(QSAR)
20.8. Toxicogenomics
20.9. Fluorescence, dye and immunohistochemical methods for screening
20.10. FDA database and QSAR modelling
20.11. Linking phospholipidosis and overt toxicity
20.12. Phospholipidosis and QT interval prolongation
20.13. DIPL Mechanisms
20.14. Treatment
20.15. Discussion
20.16. Future Directions and Recommendations
References
Index
Author Information
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.