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Role of Drosophila in Human Disease Research 3.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 22154

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Dr. Masamitsu Yamaguchi

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Guest Editor

Department of Applied Biology, Kyoto Institute of Technology, Kyoto 606-8585, Japan
Interests: Drosophila model for human disease; epigenetics; DNA replication gene; autism spectrum disorder
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Dr. Sue Cotterill

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Guest Editor

Molecular and Clinical Sciences Research Institute, St George’s University of London, London SW17 0RE, UK
Interests: Drosophila models
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Dear Colleagues,

For over a century, Drosophila melanogaster has been widely used in classical and modern genetics. Many biological functions are highly conserved between humans and Drosophila, and nearly 85% of human-disease-causing genes have functional homologues in Drosophila. Because of this, Drosophila has been used as a highly tractable animal model for studying human diseases with notable success in the study of various neurodegenerative diseases, metabolic syndromes, and cancer. The similarities between the mammalian and Drosophila systems have also allowed Drosophila to play a role in the evaluation of candidate substances for the treatment of these human diseases.

More recently, based on similarities in the pathways involved in DNA replication, DNA repair pathways, physical and neurological properties, Drosophila models have also started to be used to study more complex psychiatric disorders, aging, and other rare intractable human genetic diseases. However, it is always important to keep in mind both the benefits and limitations of fly models, by comparing them to other animal models, such as mouse, zebra fish, and nematode worm. For this Special Issue, we welcome original research and up-to-date review articles that provide novel insights into how Drosophila models (especially models of DNA replication and repair genes) have progressed the understanding of human disease.

Dr. Masamitsu Yamaguchi
Dr. Sue Cotterill
Guest Editors

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Keywords

Drosophila melanogaster
human disease model
cancer
neurodegeneration
psychiatric disorder
mental retardation
metabolic syndrome
infectious disease
aging
epigenetic dysregulation
mitochondrial disorder
DNA replication or repair defects

Related Special Issues

Role of Drosophila in Human Disease Research in International Journal of Molecular Sciences (12 articles)
Role of Drosophila in Human Disease Research 2.0 in International Journal of Molecular Sciences (9 articles)

Published Papers (11 papers)

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Editorial

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4 pages, 179 KiB

Open AccessEditorial

Role of Drosophila in Human Disease Research 3.0

by Sue Cotterill and Masamitsu Yamaguchi

Int. J. Mol. Sci. 2024, 25(1), 292; https://doi.org/10.3390/ijms25010292 - 25 Dec 2023

Viewed by 885

Abstract

Drosophila melanogaster has become a commonly used animal model for biomedical research in a variety of areas [...] Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 3.0)

Research

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14 pages, 4400 KiB

Open AccessArticle

Effects of Fructose and Palmitic Acid on Gene Expression in Drosophila melanogaster Larvae: Implications for Neurodegenerative Diseases

by Luis Felipe Santos-Cruz, Santiago Cristobal Sigrist-Flores, Laura Castañeda-Partida, María Eugenia Heres-Pulido, Irma Elena Dueñas-García, Elías Piedra-Ibarra, Alberto Ponciano-Gómez, Rafael Jiménez-Flores and Myriam Campos-Aguilar

Int. J. Mol. Sci. 2023, 24(12), 10279; https://doi.org/10.3390/ijms241210279 - 17 Jun 2023

Cited by 1 | Viewed by 1607

Abstract

One of the largest health problems worldwide is the development of chronic noncommunicable diseases due to the consumption of hypercaloric diets. Among the most common alterations are cardiovascular diseases, and a high correlation between overnutrition and neurodegenerative diseases has also been found. The urgency in the study of specific damage to tissues such as the brain and intestine led us to use Drosophila melanogaster to study the metabolic effects caused by the consumption of fructose and palmitic acid in specific tissues. Thus, third instar larvae (96 ± 4 h) of the wild Canton-S strain of D. melanogaster were used to perform transcriptomic profiling in brain and midgut tissues to test for the potential metabolic effects of a diet supplemented with fructose and palmitic acid. Our data infer that this diet can alter the biosynthesis of proteins at the mRNA level that participate in the synthesis of amino acids, as well as fundamental enzymes for the dopaminergic and GABAergic systems in the midgut and brain. These also demonstrated alterations in the tissues of flies that may help explain the development of various reported human diseases associated with the consumption of fructose and palmitic acid in humans. These studies will not only help to better understand the mechanisms by which the consumption of these alimentary products is related to the development of neuronal diseases but may also contribute to the prevention of these conditions. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 3.0)

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13 pages, 1760 KiB

Open AccessArticle

NSD Overexpression in the Fat Body Increases Antimicrobial Peptide Production by the Immune Deficiency Pathway in Drosophila

by Chihyun Won, Kyungju Nam, Donghee Ko, Byungjun Kang and Im-Soon Lee

Int. J. Mol. Sci. 2023, 24(9), 8443; https://doi.org/10.3390/ijms24098443 - 8 May 2023

Cited by 1 | Viewed by 1486

Abstract

Nuclear receptor-binding SET domain-containing protein 1 (NSD1) inactivation in tumor cells contributes to an immune-cold phenotype, indicating its potential association with immune disturbances. Drosophila NSD is a homolog of the human NSD1. Thus, in this study, we investigated the effect of NSD overexpression in the fat body, the central organ involved in Drosophila immune responses. Upon ectopic expression of NSD in the fat body, the mRNA levels of antimicrobial peptides increased. Using reporter constructs containing deletions of various NF-κB sites in the Attacin-A (AttA) promoter, we found that transcriptional activation by NSD is mainly mediated via the IMD pathway by activating Relish. Since the IMD pathway is required to resist Gram-negative bacterial infections, we further examined the effect of fat body-specific NSD overexpression on Drosophila immune defenses. Upon oral ingestion of Gram-negative Pseudomonas entomophila, the survival rate of the NSD-overexpressing larvae was higher than that of the wild type, suggesting a positive role of NSD in immune responses. Taken together, these results suggest the association of NSD with the IMD pathway and is thus expected to contribute to the elucidation of the molecular mechanisms of immune malfunction in various NSD1-associated human diseases. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 3.0)

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16 pages, 1797 KiB

Open AccessArticle

Inositol in Disease and Development: Roles of Catabolism via myo-Inositol Oxygenase in Drosophila melanogaster

by Altagracia Contreras, Melissa K. Jones, Elizabeth D. Eldon and Lisa S. Klig

Int. J. Mol. Sci. 2023, 24(4), 4185; https://doi.org/10.3390/ijms24044185 - 20 Feb 2023

Cited by 2 | Viewed by 1746

Abstract

Inositol depletion has been associated with diabetes and related complications. Increased inositol catabolism, via myo-inositol oxygenase (MIOX), has been implicated in decreased renal function. This study demonstrates that the fruit fly Drosophila melanogaster catabolizes myo-inositol via MIOX. The levels of mRNA encoding MIOX and MIOX specific activity are increased when fruit flies are grown on a diet with inositol as the sole sugar. Inositol as the sole dietary sugar can support D. melanogaster survival, indicating that there is sufficient catabolism for basic energy requirements, allowing for adaptation to various environments. The elimination of MIOX activity, via a piggyBac WH-element inserted into the MIOX gene, results in developmental defects including pupal lethality and pharate flies without proboscises. In contrast, RNAi strains with reduced levels of mRNA encoding MIOX and reduced MIOX specific activity develop to become phenotypically wild-type-appearing adult flies. myo-Inositol levels in larval tissues are highest in the strain with this most extreme loss of myo-inositol catabolism. Larval tissues from the RNAi strains have inositol levels higher than wild-type larval tissues but lower levels than the piggyBac WH-element insertion strain. myo-Inositol supplementation of the diet further increases the myo-inositol levels in the larval tissues of all the strains, without any noticeable effects on development. Obesity and blood (hemolymph) glucose, two hallmarks of diabetes, were reduced in the RNAi strains and further reduced in the piggyBac WH-element insertion strain. Collectively, these data suggest that moderately increased myo-inositol levels do not cause developmental defects and directly correspond to reduced larval obesity and blood (hemolymph) glucose. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 3.0)

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32 pages, 2574 KiB

Open AccessArticle

Sleep Modulates Alcohol Toxicity in Drosophila

by Aliza K. De Nobrega, Eric J. Noakes, Natalie A. Storch, Alana P. Mellers and Lisa C. Lyons

Int. J. Mol. Sci. 2022, 23(20), 12091; https://doi.org/10.3390/ijms232012091 - 11 Oct 2022

Cited by 3 | Viewed by 2459

Abstract

Alcohol abuse is a significant public health problem. While considerable research has shown that alcohol use affects sleep, little is known about the role of sleep deprivation in alcohol toxicity. We investigated sleep as a factor modulating alcohol toxicity using Drosophila melanogaster, a model for studies of sleep, alcohol, and aging. Following 24 h of sleep deprivation using a paradigm that similarly affects males and females and induces rebound sleep, flies were given binge-like alcohol exposures. Sleep deprivation increased mortality, with no sex-dependent differences. Sleep deprivation also abolished functional tolerance measured at 24 h after the initial alcohol exposure, although there was no effect on alcohol absorbance or clearance. We investigated the effect of chronic sleep deprivation using mutants with decreased sleep, insomniac and insulin-like peptide 2, finding increased alcohol mortality. Furthermore, we investigated whether pharmacologically inducing sleep prior to alcohol exposure using the GABA_A-receptor agonist 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) mitigated the effects of alcohol toxicity on middle-aged flies, flies with environmentally disrupted circadian clocks, and flies with short sleep. Pharmacologically increasing sleep prior to alcohol exposure decreased alcohol-induced mortality. Thus, sleep prior to binge-like alcohol exposure affects alcohol-induced mortality, even in vulnerable groups such as aging flies and those with circadian dysfunction. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 3.0)

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17 pages, 2822 KiB

Open AccessArticle

Roles of ZnT86D in Neurodevelopment and Pathogenesis of Alzheimer Disease in a Drosophila melanogaster Model

by Banseok Lee, Byoungyun Choi, Youngjae Park, Seokhui Jang, Chunyu Yuan, Chaejin Lim, Jang Ho Lee, Gyun Jee Song and Kyoung Sang Cho

Int. J. Mol. Sci. 2022, 23(19), 11832; https://doi.org/10.3390/ijms231911832 - 5 Oct 2022

Cited by 4 | Viewed by 2035

Abstract

Zinc is a fundamental trace element essential for numerous biological processes, and zinc homeostasis is regulated by the Zrt-/Irt-like protein (ZIP) and zinc transporter (ZnT) families. ZnT7 is mainly localized in the Golgi apparatus and endoplasmic reticulum (ER) and transports zinc into these organelles. Although previous studies have reported the role of zinc in animal physiology, little is known about the importance of zinc in the Golgi apparatus and ER in animal development and neurodegenerative diseases. In this study, we demonstrated that ZnT86D, a Drosophila ortholog of ZnT7, plays a pivotal role in the neurodevelopment and pathogenesis of Alzheimer disease (AD). When ZnT86D was silenced in neurons, the embryo-to-adult survival rate, locomotor activity, and lifespan were dramatically reduced. The toxic phenotypes were accompanied by abnormal neurogenesis and neuronal cell death. Furthermore, knockdown of ZnT86D in the neurons of a Drosophila AD model increased apoptosis and exacerbated neurodegeneration without significant changes in the deposition of amyloid beta plaques and susceptibility to oxidative stress. Taken together, our results suggest that an appropriate distribution of zinc in the Golgi apparatus and ER is important for neuronal development and neuroprotection and that ZnT7 is a potential protective factor against AD. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 3.0)

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17 pages, 2209 KiB

Open AccessArticle

Peppers in Diet: Genome-Wide Transcriptome and Metabolome Changes in Drosophila melanogaster

by Carlos Lopez-Ortiz, Mary Edwards, Purushothaman Natarajan, Armando Pacheco-Valenciana, Padma Nimmakayala, Donald A. Adjeroh, Cristian Sirbu and Umesh K. Reddy

Int. J. Mol. Sci. 2022, 23(17), 9924; https://doi.org/10.3390/ijms23179924 - 1 Sep 2022

Cited by 4 | Viewed by 2402

Abstract

The habanero pepper (Capsicum chinense) is an increasingly important spice and vegetable crop worldwide because of its high capsaicin content and pungent flavor. Diets supplemented with the phytochemicals found in habanero peppers might cause shifts in an organism’s metabolism and gene expression. Thus, understanding how these interactions occur can reveal the potential health effects associated with such changes. We performed transcriptomic and metabolomic analyses of Drosophila melanogaster adult flies reared on a habanero pepper diet. We found 539 genes/59 metabolites that were differentially expressed/accumulated in flies fed a pepper versus control diet. Transcriptome results indicated that olfactory sensitivity and behavioral responses to the pepper diet were mediated by olfactory and nutrient-related genes including gustatory receptors (Gr63a, Gr66a, and Gr89a), odorant receptors (Or23a, Or59a, Or82a, and Orco), and odorant-binding proteins (Obp28a, Obp83a, Obp83b, Obp93a, and Obp99a). Metabolome analysis revealed that campesterol, sitosterol, and sucrose were highly upregulated and azelaic acid, ethyl phosphoric acid, and citric acid were the major metabolites downregulated in response to the habanero pepper diet. Further investigation by integration analysis between transcriptome and metabolome data at gene pathway levels revealed six unique enriched pathways, including phenylalanine metabolism; insect hormone biosynthesis; pyrimidine metabolism; glyoxylate, and dicarboxylate metabolism; glycine, serine, threonine metabolism; and glycerolipid metabolism. In view of the transcriptome and metabolome findings, our comprehensive analysis of the response to a pepper diet in Drosophila have implications for exploring the molecular mechanism of pepper consumption. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 3.0)

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Review

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19 pages, 1086 KiB

Open AccessReview

The Stage-Based Model of Addiction—Using Drosophila to Investigate Alcohol and Psychostimulant Responses

by Pearl N. Cummins-Beebee, Maggie M. Chvilicek and Adrian Rothenfluh

Int. J. Mol. Sci. 2023, 24(13), 10909; https://doi.org/10.3390/ijms241310909 - 30 Jun 2023

Cited by 2 | Viewed by 2781

Abstract

Addiction is a progressive and complex disease that encompasses a wide range of disorders and symptoms, including substance use disorder (SUD), for which there are few therapeutic treatments. SUD is the uncontrolled and chronic use of substances despite the negative consequences resulting from this use. The progressive nature of addiction is organized into a testable framework, the neurobiological stage-based model, that includes three behavioral stages: (1) binge/intoxication, (2) withdrawal/negative affect, and (3) preoccupation/anticipation. Human studies offer limited opportunities for mechanistic insights into these; therefore, model organisms, like Drosophila melanogaster, are necessary for understanding SUD. Drosophila is a powerful model organism that displays a variety of SUD-like behaviors consistent with human and mammalian substance use, making flies a great candidate to study mechanisms of behavior. Additionally, there are an abundance of genetic tools like the GAL4/UAS and CRISPR/Cas9 systems that can be used to gain insight into the molecular mechanisms underlying the endophenotypes of the three-stage model. This review uses the three-stage framework and discusses how easily testable endophenotypes have been examined with experiments using Drosophila, and it outlines their potential for investigating other endophenotypes. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 3.0)

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14 pages, 857 KiB

Open AccessReview

Association of Mutations in Replicative DNA Polymerase Genes with Human Disease: Possible Application of Drosophila Models for Studies

by Masamitsu Yamaguchi and Sue Cotterill

Int. J. Mol. Sci. 2023, 24(9), 8078; https://doi.org/10.3390/ijms24098078 - 29 Apr 2023

Cited by 2 | Viewed by 1566

Abstract

Replicative DNA polymerases, such as DNA polymerase α-primase, δ and ε, are multi-subunit complexes that are responsible for the bulk of nuclear DNA replication during the S phase. Over the last decade, extensive genome-wide association studies and expression profiling studies of the replicative DNA polymerase genes in human patients have revealed a link between the replicative DNA polymerase genes and various human diseases and disorders including cancer, intellectual disability, microcephalic primordial dwarfism and immunodeficiency. These studies suggest the importance of dissecting the mechanisms involved in the functioning of replicative DNA polymerases in understanding and treating a range of human diseases. Previous studies in Drosophila have established this organism as a useful model to understand a variety of human diseases. Here, we review the studies on Drosophila that explored the link between DNA polymerases and human disease. First, we summarize the recent studies linking replicative DNA polymerases to various human diseases and disorders. We then review studies on replicative DNA polymerases in Drosophila. Finally, we suggest the possible use of Drosophila models to study human diseases and disorders associated with replicative DNA polymerases. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 3.0)

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14 pages, 619 KiB

Open AccessReview

Drosophila as an Animal Model for Testing Plant-Based Immunomodulators

by Andre Rizky Pratomo, Emil Salim, Aki Hori and Takayuki Kuraishi

Int. J. Mol. Sci. 2022, 23(23), 14801; https://doi.org/10.3390/ijms232314801 - 26 Nov 2022

Cited by 2 | Viewed by 2464

Abstract

Allopathic medicines play a key role in the prevention and treatment of diseases. However, long-term consumption of these medicines may cause serious undesirable effects that harm human health. Plant-based medicines have emerged as alternatives to allopathic medicines because of their rare side effects. They contain several compounds that have the potential to improve health and treat diseases in humans, including their function as immunomodulators to treat immune-related diseases. Thus, the discovery of potent and safe immunomodulators from plants is gaining considerable research interest. Recently, Drosophila has gained prominence as a model organism in evaluating the efficacy of plant and plant-derived substances. Drosophila melanogaster “fruit fly” is a well-known, high-throughput model organism that has been used to study different biological aspects of development and diseases for more than 110 years. Most developmental and cell signaling pathways and 75% of human disease-related genes are conserved between humans and Drosophila. Using Drosophila, one can easily examine the pharmacological effects of plants/plant-derived components by employing a variety of tests in flies, such as survival, anti-inflammatory, antioxidant, and cell death tests. This review focused on D. melanogaster’s potential for identifying immunomodulatory features associated with plants/plant-derived components. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 3.0)

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16 pages, 1000 KiB

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Epigenetic Regulation by Polycomb Complexes from Drosophila to Human and Its Relation to Communicable Disease Pathogenesis

by Aaron Scholl and Sandip De

Int. J. Mol. Sci. 2022, 23(20), 12285; https://doi.org/10.3390/ijms232012285 - 14 Oct 2022

Cited by 2 | Viewed by 1669

Abstract

Although all cells in the human body are made of the same DNA, these cells undergo differentiation and behave differently during development, through integration of external and internal stimuli via ‘specific mechanisms.’ Epigenetics is one such mechanism that comprises DNA/RNA, histone modifications, and non-coding RNAs that regulate transcription without changing the genetic code. The discovery of the first Polycomb mutant phenotype in Drosophila started the study of epigenetics more than 80 years ago. Since then, a considerable number of Polycomb Group (PcG) genes in Drosophila have been discovered to be preserved in mammals, including humans. PcG proteins exert their influence through gene repression by acting in complexes, modifying histones, and compacting the chromatin within the nucleus. In this article, we discuss how our knowledge of the PcG repression mechanism in Drosophila translates to human communicable disease research. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 3.0)

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