Lysosomes. Biology, Diseases, and Therapeutics

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
Urška 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.