Front Cover

Fly Models of Human Diseases

Copyright

Contents

Contributors

Preface

References

Chapter One: Fly Models of Human Diseases: Drosophila as a Model for Understanding Human Mitochondrial Mutations and Disease

1. Mitochondria Play Diverse Roles

2. Mitochondrial Diseases-Causes and Effects

3. How Can Studying Drosophila Contribute to Our Understanding of Human Mitochondrial Diseases?

4. Mitochondrial Diseases Caused by mtDNA Mutations

5. Disease-Causing Point Mutations Are Most Prevalent in mt:tRNAs-Conservation Between Human and Drosophila

6. Drosophila Models of mtDNA-Induced Disease: Untapped Future Potential

7. Mitochondrial Inheritance and Quality Control Checkpoints

8. Concluding Remarks: Loss of Mitochondrial Function Broadly Impacts Human Disease

Acknowledgments

References

Chapter Two: Drosophila as a Model for Human Diseases-Focus on Innate Immunity in Barrier Epithelia

1. Introduction

2. Evolutionary Conservation of Innate Immunity

2.1. The Innate Immune System of Drosophila

2.2. The Discovery of Antimicrobial Peptides

2.3. The Role of Drosophila Toll and IMD Pathways in Innate Immunity

2.4. Pattern Recognition Receptors

2.5. The Role of Other Evolutionarily Conserved Signaling Pathways in Immunity

3. Innate Immunity in Barrier Epithelia

3.1. Epithelia as Physical and Chemical Barriers

3.2. Impact and Relevance of Innate Epithelial Infections in Humans

3.2.1. Bacterial Infections and Immunity

3.2.2. Fungal Infections and Immunity

3.2.3. Human Microbial Pathogens and Virulence Mechanisms Studied in Drosophila

4. Epithelial Immunity in the Gastrointestinal Tract of Humans and Drosophila

4.1. Similarities and Differences in Human and Fly Gut Structure and Immune Systems

4.2. The Importance of the Gut Commensal Microbiota in Health and Disease

4.2.1. Microbial Metabolites and Regulation of the Immune Responses

4.3. Recognition of Microbes in Human and Drosophila Gut

4.4. Innate Immune Responses in the Human and Drosophila Gut-Effector Molecules

4.5. Dual Roles for ROS in the Intestinal Epithelium

4.6. Autophagy as an Effector Mechanism

4.7. The Intestinal Barrier and Aging-Examples from Human and Drosophila

4.8. Gut Regeneration and Microbiota Interactions in Inflammation and Cancer

5. Drosophila as a Model for Human Respiratory Organ Diseases Linked to Infection and Inflammation

5.1. Human Lung Responses to Infection

5.2. Drosophila Tracheal Responses to Infection

5.3. Drosophila as a Model of Specific Lung Infections and Diseases

5.3.1. Asthma and Chronic Obstructive Pulmonary Diseases (COPD)

5.3.2. Hypercapnia

5.3.3. Cystic Fibrosis

5.3.4. Tuberculosis

5.3.5. Fungal Lung Infections

5.4. The Role of Intestinal Microbiota in Lung Diseases

6. Drosophila as a Model of Human Skin Infections and Wound Healing

6.1. Expression and Regulation of AMPs in Skin/Epidermis

6.2. Skin Microbiota

6.3. Wound Healing and Immunity

7. Concluding Remarks

Acknowledgments

References

Chapter Three: Drosophila Melanogaster as a Model of Muscle Degeneration Disorders

1. Introduction

2. Drosophila Models for Muscular Dystrophies

2.1. Duchenne Muscular Dystrophy

2.2. Congenital Muscular Dystrophies

3. Muscle Disease Models Related to Motor Neuron Disorders

3.1. DMD: Hyperthermic Seizures

3.2. Amyotrophic Lateral Sclerosis

3.3. Spinal Muscular Atrophy

4. Drosophila Models of Cachexia-Like Wasting

4.1. Modeling Muscle Wasting in Drosophila

4.2. Muscle-Wasting Phenotypes

4.3. Signaling Pathways Altered in Wasting Muscles

5. Therapeutic Potential of Identified in Drosophila Screens Factors

5.1. Sphingosine-1-Phosphate Pathway

5.2. miRNAs in Muscular Dystrophies

6. Conclusions

References

Chapter Four: Amyotrophic Lateral Sclerosis Pathogenesis Converges on Defects in Protein Homeostasis Associated with TDP ...

1. Introduction

2. Current Challenges in ALS Research

3. RNA Processing, Splicing, RNA Foci, and Protein Aggregation

3.1. TDP-43

3.2. FUS

3.3. C9orf72

4. Proteostasis Deficiency in ALS

4.1. VCP

4.2. UBQLN2

4.3. VAPB

5. SOD-1 and Proteinopathy in ALS

6. Prion-Like Protein Toxicity and ALS

7. Conclusion and Future Perspective

Acknowledgments

References

Chapter Five: Mechanisms of Parkinson´s Disease: Lessons from Drosophila

1. Introduction

2. Drosophila as a Model System for PD

3. Dominant Traits

3.1. α-Synuclein Models

3.2. LRRK2

3.3. Vps35

3.4. GBA

4. Recessive Traits

4.1. parkin

4.2. DJ-1

4.3. PINK1

4.4. PLA2G6

4.5. FBXO7

5. Functions of the PINK1/Parkin Pathway

5.1. Mitochondrial Dynamics

5.2. Mitophagy

5.3. Complex I

6. Convergent Therapeutic Approaches

7. Concluding Remarks

Acknowledgments

References

Chapter Six: Neurotoxicity Pathways in Drosophila Models of the Polyglutamine Disorders

1. Introduction

2. Transcriptional and Nuclear Dysfunction

3. Genetic and Pharmacological Screens for Suppressors of PolyQ Pathology

4. Mitochondrial Dysfunction

5. Autophagy Defects

6. Conclusion

References

Chapter Seven: AxGxE: Using Flies to Interrogate the Complex Etiology of Neurodegenerative Disease

1. Age, Environmental Insult and Genetic Risk in Human Neurodegenerative Disease

2. Challenges in Interrogating Contributions from Aging, Genetic Risk Factors and Environmental Insult to Human Neurodeg ...

2.1. Age

2.2. Genetics

2.3. Environment

2.4. Noncell Autonomous Interactions

2.5. Clinical Considerations

3. Drosophila as a Versatile Model for Investigating Aging, Genetics and Environmental Factors Involved in Neurodegeneration

3.1. Aging

3.2. Genetics

3.3. Environmental Exposure

3.4. Noncell Autonomous Interactions

3.5. Selective Advantages and Drawbacks of Drosophila

4. The Relevance of Drosophila in a Drug Discovery Pipeline

References

Chapter Eight: Unraveling the Neurobiology of Sleep and Sleep Disorders Using Drosophila

1. What is Sleep, and What Controls Sleep?

1.1. Defining Sleep in Drosophila: Behavioral and Electrophysiological Correlates

1.2. Factors Regulating Sleep-Wake States in Drosophila

1.2.1. Ion Channels

1.2.2. Neurotransmitter Systems

1.2.3. Intracellular Signaling Molecules

1.2.4. Circadian Outputs

1.3. Brain Regions Involved in Regulating Sleep

2. Modeling Sleep in Health and Disease Using Drosophila

2.1. Sleep and Brain Development

2.2. Functions of Sleep in the Adult Brain

2.3. Drosophila Studies of Primary Sleep Disorders

2.4. The Role of Sleep in Neurodevelopmental Disorders

2.4.1. Single Gene Disorders and Autism Spectrum Disorder

2.4.2. Attention Deficit Hyperactivity Disorder

2.5. Sleep and Psychiatric Illness

2.6. Sleep in Normal Aging and Neurodegenerative Disease

3. Conclusions

Acknowledgments

References

Chapter Nine: Modeling Human Cancers in Drosophila

1. Introduction

2. Fly Cancer Models

2.1. Neoplasia

2.1.1. Cell Polarity

2.1.2. Inducible Expression of Cancer Genes

2.1.3. Ras

2.2. Fly Models for Invasion and Metastasis

2.2.1. Ras-Based Models

2.2.2. Src-Based Models

2.2.3. Ras/Src Models and the Importance of Diet

2.2.4. Brain Tumor Models

2.2.5. Medullary Thyroid Cancer Models

2.3. Microenvironment

2.4. Cachexia

3. Drug Discovery

3.1. Flies as a Therapeutics Screening Platform

3.2. Drosophila and the Case for Polypharmacology

4. Conclusion

Acknowledgments

References

Chapter Ten: Stem-Cell-Based Tumorigenesis in Adult Drosophila

1. Cancer Stem Cells

2. Stem-Cell-Based Tumorigenesis in the Adult Drosophila Midgut

2.1. Intestinal Stem Cells in the Adult Drosophila Posterior Midgut

2.2. Spontaneous Somatic Mutations of N Lead to Neoplasias in Aged Flies

2.3. Niche Appropriation Drives ISC Tumor Progression

2.3.1. Tumor Initiation

2.3.2. Tumor Progression

3. Tumorigenesis Through Stem-Cell Competition in Testis

3.1. Tumorigenesis Through Stem-Cell Competition in Mammals

3.2. Stem Cells in the Adult Drosophila Testis

3.3. Madm Regulates Stem-Cell Competition in the Adult Drosophila Testis

3.4. JAK-STAT Signaling Regulates the Madm-Directed Stem-Cell Competition

3.4. p53 and Madm Regulate Stem-Cell Competition

4. Differences Between Normal and CSCs

4.1. The Stem Cells in MTs

4.2. Ras-Transformed RNSCs

4.3. Ras-TSCs Exhibit Hallmarks of Cancer

4.4. Signaling Downstream of Ras Regulates RNSC Transformation

4.5. New Genes That Mediate Ras' Regulation of RNSC Transformation

5. Potential Biology Behind the Therapy Resistance of CSCs

5.1. Therapy Resistance of CSCs in Mammals

5.2. Therapy Resistance of Normal and TSCs in Drosophila

5.2.1. Female GSCs Use a ``Dying Daughters Protect Their Mother´´ Strategy to Protect GSCs from IR-Induced Death in Dros ...

5.2.2. ISCs Are Internally Resistant to Apoptosis but Sensitive to Lipolysis Disruption in Drosophila

6. Summary and Perspectives

References

Chapter Eleven: The Drosophila Accessory Gland as a Model for Prostate Cancer and Other Pathologies

1. Introduction

1.1. Modeling Adenocarcinoma

2. The Prostate

2.1. The Human Prostate

2.2. Human Prostate Cancer

2.3. Mouse Models of Prostate Biology and Cancer

3. The Drosophila Accessory Gland-A Key Gland in the Male Reproductive System

3.1. Sex Peptide-An Essential Component of the Accessory Gland Secretome

3.2. Sex Peptide Signaling in Females

3.3. Other Main Cell-Derived Peptides Have Effects on Female Behavior

4. Molecular and Functional Parallels Between Seminal Fluid Proteins in Flies and Humans

4.1. Proteases and Their Inhibitors Have Multiple Functions in Seminal Fluid

4.2. Rapid Evolution of Seminal Fluid Proteins

4.3. Males Strategically Allocate Seminal Fluid Proteins in Reproduction

5. Development and Cellular Organization of the Accessory Gland

5.1. Early Development of the Accessory Gland

5.2. Developmental Regulation of Secondary Cells

5.3. Abd-B-Regulated Genes Control Secondary Cell Functions

6. Functions of the Adult Secondary Cell

6.1. Aging Adult Secondary Cells Continue to Grow

6.2. BMP Signaling Controls Adult Secondary Cell Growth and Migration

6.3. BMP Signaling in the Human Prostate

6.4. Secretion by Adult Secondary Cells

6.5. Secondary Cells Secrete Exosomes That Inhibit Female Receptivity

6.6. Secondary Cell Exosomes and Prostasomes in Fertility and Sexual Conflict

7. Modeling Prostate Cancer Biology in Secondary Cells

7.1. Studying Exosome Regulation and Functions in Flies

7.2. Signaling and Exosome Biogenesis

7.3. Growth and Exosome Biogenesis

7.4. Steroid Signaling in the Male Reproductive System

7.5. The Secondary Cell as a General Model for Exosome Biology

Acknowledgments

References

Chapter Twelve: Drosophila melanogaster Models of Galactosemia

1. Galactose Metabolism via the Leloir Pathway

1.1. Alternate Pathways of Galactose Metabolism

1.2. Three Types of Galactosemias

1.2.1. Type I, or Classic Galactosemia

1.2.2. Type II, or GALK-Deficiency Galactosemia

1.2.3. Type III, or Epimerase (GALE) Deficiency Galactosemia

1.3. Galactose Metabolism in Drosophila melanogaster

2. A D. melanogaster Model of Classic Galactosemia

2.1. Creating GALT-Null Drosophila

2.2. Characterizing the Galactose Sensitivity of GALT-Null Larvae

2.3. A Motor Defect in Adult GALT-Null Drosophila

2.4. Mediators of Long-Term Outcome Severity in GALT-Null Drosophila

2.5. Oxidative Stress and GALT Deficiency

2.6. Potential Impact of GALT Deficiency on Synaptic Architecture and Synaptomatrix Glycosylation at the Neuromuscular J ...

3. A D. melanogaster Model of Epimerase Deficiency Galactosemia

3.1. Creation of GALE-Deficient Drosophila

3.2. Characterizing the Phenotype of GALE Deficiency in Drosophila

3.2.1. dGALE Is Required Throughout Development

3.2.2. GALE Activity Is Required in Specific Tissues in Drosophila

3.2.3. Galactose Sensitivity of dGALE Hypomorphs

3.2.4. GALE-Deficient Drosophila Accumulate a High Level of Gal-1P

3.3. Using Drosophila to Dissect the Differential Roles of GALE in Development

3.3.1. Uncoupling the Two Activities of GALE in Drosophila

3.3.2. Both GALE Activities Play Essential Roles During Development

3.3.3. GALE Activity Toward UDPgal/UDPglc Is Required for Normal Life Span of Adult Drosophila Exposed to Dietary Galactose

3.3.4. The Two GALE Activities Impact Galactose Metabolite Levels Differently

4. A D. melanogaster Model of Kinase Deficiency Galactosemia

5. Conclusions

Acknowledgments

References

Chapter Thirteen: Drosophila as a Model for Diabetes and Diseases of Insulin Resistance

1. Introduction

2. Sugar Metabolism in Drosophila and Humans

3. Drosophila Models of Type 1 Diabetes

4. Modeling Insulin-Dependent Sugar Uptake and Insulin Release in Drosophila

5. Drosophila as a Model for Insulin Resistance and Type 2 Diabetes

6. Are Glucose and Trehalose Metabolism Regulated Independently in Drosophila?

7. Drosophila as a Model for Obesity-Related Heart Disease

8. Drosophila as a Model for Metabolic Syndrome

9. From Correlation to Causation: Drosophila as a Model to Study Gene Function in Metabolism

10. Concluding Remarks

Acknowledgments

References

Index

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