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Modeling Human Biological Pathways in Health, Aging and Disease: The Drosophila Paradigm - in Memory of Professor Suzanne Eaton (1959-2019)

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 30633

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Special Issue Editors

Dr. Athanassios D. Velentzas

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Guest Editor

Section of Cell Biology & Biophysics, Department of Biology, School of Science, National & Kapodistrian University of Athens (NKUA), Panepistimiopolis, Zografou, 15701 Athens, Greece
Interests: development; Drosophila models of human diseases; oogenesis; metabolic disorders; neurological pathologies; programmed cell death; proteasome
Special Issues, Collections and Topics in MDPI journals

Dr. Dimitrios J. Stravopodis

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Section of Cell Biology & Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens (NKUA), Panepistimiopolis, Zografou, 15701 Athens, Greece
Interests: development; cancer; chemotherapy; metastasis; programmed cell death; metabolism; Drosophila aging; brain signaling; proteasome
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Drosophila melanogaster, with its powerful transgenic technology that enables scientists to drive or silence the expression of a gene in a spatial and/or temporal manner, is now established as one of the most sophisticated model organisms for the in vivo investigation of mechanisms regulating, among others, cell differentiation, gene regulation, and aging.

Furthermore, the high level of structural and functional conservation in many fundamental biological processes between humans and flies, and the fact that approximately 75% of all known human disease genes have functional fly homologues, render Drosophila an ideal model for understanding the molecular mechanisms of human diseases, including malignancies. Hence, Drosophila has been effectively used for drug screenings and target discoveries, as well as for the study of various pathological conditions, such as metabolic disorders, neurodegenerative diseases, cardiovascular diseases, aging, and cancer.

Recent research in Drosophila gives special emphasis to the large-scale screening of candidate genes identified from patient genomic sequencing studies aiming at the identification of novel druggable targets for personalized medicine schemes.

For this Special Issue, we welcome original research articles and reviews by experts in this field, whose contribution will provide novel insights into the outlined research areas.

Dr. Athanassios D. Velentzas
Dr. Dimitrios J. Stravopodis
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Drosophila melanogaster
Human disease model
Neurodegenerative diseases
Metabolic disorders
Diabetes
Cardiovascular diseases
Inflammatory disorders
Cancer model
Epigenetic dysregulation
Aging
Stem cell maintenance
Fertility
Programmed cell death
Cell differentiation
Gene regulation

Published Papers (10 papers)

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Research

Jump to: Review

26 pages, 11710 KiB

Open AccessArticle

Genetic Targeting of dSAMTOR, A Negative dTORC1 Regulator, during Drosophila Aging: A Tissue-Specific Pathology

by Stamatia A. Katarachia, Sophia P. Markaki, Athanassios D. Velentzas and Dimitrios J. Stravopodis

Int. J. Mol. Sci. 2023, 24(11), 9676; https://doi.org/10.3390/ijms24119676 - 02 Jun 2023

Viewed by 1639

Abstract

mTORC1 regulates mammalian cell metabolism and growth in response to diverse environmental stimuli. Nutrient signals control the localization of mTORC1 onto lysosome surface scaffolds that are critically implicated in its amino acid-dependent activation. Arginine, leucine and S-adenosyl-methionine (SAM) can serve as major mTORC1-signaling activators, with SAM binding to SAMTOR (SAM + TOR), a fundamental SAM sensor, preventing the protein’s (SAMTOR’s) inhibitory action(s) against mTORC1, thereby triggering its (mTORC1) kinase activity. Given the lack of knowledge regarding the role of SAMTOR in invertebrates, we have identified the Drosophila SAMTOR homologue (dSAMTOR) in silico and have, herein, genetically targeted it through the utilization of the GAL4/UAS transgenic tool. Survival profiles and negative geotaxis patterns were examined in both control and dSAMTOR-downregulated adult flies during aging. One of the two gene-targeted schemes resulted in lethal phenotypes, whereas the other one caused rather moderate pathologies in most tissues. The screening of head-specific kinase activities, via PamGene technology application, unveiled the significant upregulation of several kinases, including the dTORC1 characteristic substrate dp70S6K, in dSAMTOR-downregulated flies, thus strongly supporting the inhibitory dSAMTOR action(s) upon the dTORC1/dp70S6K signaling axis in Drosophila brain settings. Importantly, genetic targeting of the Drosophila BHMT bioinformatics counterpart (dBHMT), an enzyme that catabolizes betaine to produce methionine (the SAM precursor), led to severe compromises in terms of fly longevity, with glia-, motor neuron- and muscle-specific dBHMT downregulations exhibiting the strongest effects. Abnormalities in wing vein architectures were also detected in dBHMT-targeted flies, thereby justifying their notably reduced negative geotaxis capacities herein observed mainly in the brain–(mid)gut axis. In vivo adult fly exposure to clinically relevant doses of methionine revealed the mechanistic synergism of decreased dSAMTOR and increased methionine levels in pathogenic longevity, thus rendering (d)SAMTOR an important component in methionine-associated disorders, including homocystinuria(s). Full article

(This article belongs to the Special Issue Modeling Human Biological Pathways in Health, Aging and Disease: The Drosophila Paradigm - in Memory of Professor Suzanne Eaton (1959-2019))

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10 pages, 3907 KiB

Open AccessCommunication

Optimization and Technical Considerations for the Dye-Exclusion Protocol Used to Assess Blood–Brain Barrier Integrity in Adult Drosophila melanogaster

by Kesshni Bhasiin, Olivia Heintz and Kenneth J. Colodner

Int. J. Mol. Sci. 2023, 24(3), 1886; https://doi.org/10.3390/ijms24031886 - 18 Jan 2023

Cited by 1 | Viewed by 1819

Abstract

The blood–brain barrier (BBB) is a multicellular construct that regulates the diffusion and transport of metabolites, ions, toxins, and inflammatory mediators into and out of the central nervous system (CNS). Its integrity is essential for proper brain physiology, and its breakdown has been shown to contribute to neurological dysfunction. The BBB in vertebrates exists primarily through the coordination between endothelial cells, pericytes, and astrocytes, while invertebrates, which lack a vascularized circulatory system, typically have a barrier composed of glial cells that separate the CNS from humoral fluids. Notably, the invertebrate barrier is molecularly and functionally analogous to the vertebrate BBB, and the fruit fly, Drosophila melanogaster, is increasingly recognized as a useful model system in which to investigate barrier function. The most widely used technique to assess barrier function in the fly is the dye-exclusion assay, which involves monitoring the infiltration of a fluorescent-coupled dextran into the brain. In this study, we explore analytical and technical considerations of this procedure that yield a more reliable assessment of barrier function, and we validate our findings using a traumatic injury model. Together, we have identified parameters that optimize the dye-exclusion assay and provide an alternative framework for future studies examining barrier function in Drosophila. Full article

(This article belongs to the Special Issue Modeling Human Biological Pathways in Health, Aging and Disease: The Drosophila Paradigm - in Memory of Professor Suzanne Eaton (1959-2019))

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Graphical abstract

19 pages, 4395 KiB

Open AccessArticle

Using Drosophila melanogaster to Analyse the Human Paralogs of the ESCRT-III Core Component Shrub/CHMP4/Snf7 and Its Interactions with Members of the LGD/CC2D1 Family

by Miriam Baeumers, Katharina Schulz and Thomas Klein

Int. J. Mol. Sci. 2022, 23(14), 7507; https://doi.org/10.3390/ijms23147507 - 06 Jul 2022

Cited by 3 | Viewed by 1411

Abstract

The evolutionary conserved ESCRT-III complex is a device for membrane remodelling in various cellular processes, such as the formation of intraluminal vesicles (ILVs), cytokinesis, and membrane repair. The common theme of all these processes is the abscission of membrane away from the cytosol. At its heart in Drosophila is Shrub, CHMP4 in humans, which dynamically polymerises into filaments through electrostatic interactions among the protomers. For the full activity, Shrub/CHMP4 requires physical interaction with members of the Lgd protein family. This interaction is mediated by the odd-numbered DM14 domains of Lgd, which bind to the negative interaction surface of Shrub. While only one Lgd and one Shrub exist in the genome of Drosophila, mammals have two Lgd orthologs, LGD1/CC2D1B and LGD2/CC2D1A, as well as three CHMP4s in their genomes, CHMP4A, CHMP4B, and CHMP4C. The rationale for the diversification of the ESCRT components is not understood. We here use Drosophila as a model system to analyse the activity of the human orthologs of Shrub and Lgd at an organismal level. This enabled us to use the plethora of available techniques available for Drosophila. We present evidence that CHMP4B is the true ortholog of Shrub, while CHMP4A and CHMP4C have diverging activities. Nevertheless, CHMP4A and CHMP4C can enhance the activity of CHMP4B, raising the possibility that they can form heteropolymers in vivo. Our structure-function analysis of the LGD1 and LGD2 indicates that the C2 domain of the LGD proteins has a specific function beyond protein stability and subcellular localisation. Moreover, our data specify that CHMP4B interacts more efficiently with LGD1 than with LGD2. Full article

(This article belongs to the Special Issue Modeling Human Biological Pathways in Health, Aging and Disease: The Drosophila Paradigm - in Memory of Professor Suzanne Eaton (1959-2019))

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Review

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36 pages, 2492 KiB

Open AccessReview

Genetic, Environmental, and Stochastic Components of Lifespan Variability: The Drosophila Paradigm

by Oleg V. Bylino, Anna A. Ogienko, Mikhail A. Batin, Pavel G. Georgiev and Evgeniya S. Omelina

Int. J. Mol. Sci. 2024, 25(8), 4482; https://doi.org/10.3390/ijms25084482 - 19 Apr 2024

Viewed by 652

Abstract

Lifespan is a complex quantitative trait involving genetic and non-genetic factors as well as the peculiarities of ontogenesis. As with all quantitative traits, lifespan shows considerable variation within populations and between individuals. Drosophila, a favourite object of geneticists, has greatly advanced our understanding of how different forms of variability affect lifespan. This review considers the role of heritable genetic variability, phenotypic plasticity and stochastic variability in controlling lifespan in Drosophila melanogaster. We discuss the major historical milestones in the development of the genetic approach to study lifespan, the breeding of long-lived lines, advances in lifespan QTL mapping, the environmental factors that have the greatest influence on lifespan in laboratory maintained flies, and the mechanisms, by which individual development affects longevity. The interplay between approaches to study ageing and lifespan limitation will also be discussed. Particular attention will be paid to the interaction of different types of variability in the control of lifespan. Full article

(This article belongs to the Special Issue Modeling Human Biological Pathways in Health, Aging and Disease: The Drosophila Paradigm - in Memory of Professor Suzanne Eaton (1959-2019))

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11 pages, 1061 KiB

Open AccessReview

Regenerative Strategies for Retinal Neurons: Novel Insights in Non-Mammalian Model Organisms

by Elisabetta Catalani, Agnese Cherubini, Simona Del Quondam and Davide Cervia

Int. J. Mol. Sci. 2022, 23(15), 8180; https://doi.org/10.3390/ijms23158180 - 25 Jul 2022

Cited by 1 | Viewed by 1628

Abstract

A detailed knowledge of the status of the retina in neurodegenerative conditions is a crucial point for the development of therapeutics in retinal pathologies and to translate eye research to CNS disease. In this context, manipulating signaling pathways that lead to neuronal regeneration offers an excellent opportunity to substitute damaged cells and, thus, restore the tissue functionality. Alternative systems and methods are increasingly being considered to replace/reduce in vivo approaches in the study of retina pathophysiology. Herein, we present recent data obtained from the zebrafish (Danio rerio) and the fruit fly Drosophila melanogaster that bring promising advantages into studying and modeling, at a preclinical level, neurodegeneration and regenerative approaches in retinal diseases. Indeed, the regenerative ability of vertebrate model zebrafish is particularly appealing. In addition, the fruit fly is ideal for regenerative studies due to its high degree of conservation with vertebrates and the broad spectrum of genetic variants achievable. Furthermore, a large part of the drosophila brain is dedicated to sight, thus offering the possibility of studying common mechanisms of the visual system and the brain at once. The knowledge acquired from these alternative models may help to investigate specific well-conserved factors of interest in human neuroregeneration after injuries or during pathologies. Full article

(This article belongs to the Special Issue Modeling Human Biological Pathways in Health, Aging and Disease: The Drosophila Paradigm - in Memory of Professor Suzanne Eaton (1959-2019))

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16 pages, 1205 KiB

Open AccessReview

Peeling Back the Layers of Lymph Gland Structure and Regulation

by Bayan Kharrat, Gábor Csordás and Viktor Honti

Int. J. Mol. Sci. 2022, 23(14), 7767; https://doi.org/10.3390/ijms23147767 - 14 Jul 2022

Cited by 5 | Viewed by 2551

Abstract

During the past 60 years, the fruit fly, Drosophila melanogaster, has proven to be an excellent model to study the regulation of hematopoiesis. This is not only due to the evolutionarily conserved signalling pathways and transcription factors contributing to blood cell fate, but also to convergent evolution that led to functional similarities in distinct species. An example of convergence is the compartmentalization of blood cells, which ensures the quiescence of hematopoietic stem cells and allows for the rapid reaction of the immune system upon challenges. The lymph gland, a widely studied hematopoietic organ of the Drosophila larva, represents a microenvironment with similar features and functions to classical hematopoietic stem cell niches of vertebrates. Lymph gland studies were effectively supported by the unparalleled toolkit developed in Drosophila, which enabled the high-resolution investigation of the cellular composition and regulatory interaction networks of the lymph gland. In this review, we summarize how our understanding of lymph gland structure and hematopoietic cell-to-cell communication evolved during the past decades and compare their analogous features to those of the vertebrate hematopoietic stem cell niche. Full article

(This article belongs to the Special Issue Modeling Human Biological Pathways in Health, Aging and Disease: The Drosophila Paradigm - in Memory of Professor Suzanne Eaton (1959-2019))

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24 pages, 1549 KiB

Open AccessReview

Drosophila as a Model System for Studying of the Evolution and Functional Specialization of the Y Chromosome

by Alexei A. Kotov, Sergei S. Bazylev, Vladimir E. Adashev, Aleksei S. Shatskikh and Ludmila V. Olenina

Int. J. Mol. Sci. 2022, 23(8), 4184; https://doi.org/10.3390/ijms23084184 - 10 Apr 2022

Cited by 3 | Viewed by 3334

Abstract

The Y chromosome is one of the sex chromosomes found in males of animals of different taxa, including insects and mammals. Among all chromosomes, the Y chromosome is characterized by a unique chromatin landscape undergoing dynamic evolutionary change. Being entirely heterochromatic, the Y chromosome as a rule preserves few functional genes, but is enriched in tandem repeats and transposons. Due to difficulties in the assembly of the highly repetitive Y chromosome sequence, deep analyses of Y chromosome evolution, structure, and functions are limited to a few species, one of them being Drosophila melanogaster. Despite Y chromosomes exhibiting high structural divergence between even closely related species, Y-linked genes have evolved convergently and are mainly associated with spermatogenesis-related activities. This indicates that male-specific selection is a dominant force shaping evolution of Y chromosomes across species. This review presents our analysis of current knowledge concerning Y chromosome functions, focusing on recent findings in Drosophila. Here we dissect the experimental and bioinformatics data about the Y chromosome accumulated to date in Drosophila species, providing comparative analysis with mammals, and discussing the relevance of our analysis to a wide range of eukaryotic organisms, including humans. Full article

(This article belongs to the Special Issue Modeling Human Biological Pathways in Health, Aging and Disease: The Drosophila Paradigm - in Memory of Professor Suzanne Eaton (1959-2019))

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37 pages, 1310 KiB

Open AccessReview

Inter-Species Rescue of Mutant Phenotype—The Standard for Genetic Analysis of Human Genetic Disorders in Drosophila melanogaster Model

by Alexandru Al. Ecovoiu, Attila Cristian Ratiu, Miruna Mihaela Micheu and Mariana Carmen Chifiriuc

Int. J. Mol. Sci. 2022, 23(5), 2613; https://doi.org/10.3390/ijms23052613 - 27 Feb 2022

Cited by 3 | Viewed by 6787

Abstract

Drosophila melanogaster (the fruit fly) is arguably a superstar of genetics, an astonishing versatile experimental model which fueled no less than six Nobel prizes in medicine. Nowadays, an evolving research endeavor is to simulate and investigate human genetic diseases in the powerful D. melanogaster platform. Such a translational experimental strategy is expected to allow scientists not only to understand the molecular mechanisms of the respective disorders but also to alleviate or even cure them. In this regard, functional gene orthology should be initially confirmed in vivo by transferring human or vertebrate orthologous transgenes in specific mutant backgrounds of D. melanogaster. If such a transgene rescues, at least partially, the mutant phenotype, then it qualifies as a strong candidate for modeling the respective genetic disorder in the fruit fly. Herein, we review various examples of inter-species rescue of relevant mutant phenotypes of the fruit fly and discuss how these results recommend several human genes as candidates to study and validate genetic variants associated with human diseases. We also consider that a wider implementation of this evolutionist exploratory approach as a standard for the medicine of genetic disorders would allow this particular field of human health to advance at a faster pace. Full article

(This article belongs to the Special Issue Modeling Human Biological Pathways in Health, Aging and Disease: The Drosophila Paradigm - in Memory of Professor Suzanne Eaton (1959-2019))

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14 pages, 1057 KiB

Open AccessReview

Drosophila Trachea as a Novel Model of COPD

by Aaron Scholl, Istri Ndoja and Lan Jiang

Int. J. Mol. Sci. 2021, 22(23), 12730; https://doi.org/10.3390/ijms222312730 - 25 Nov 2021

Cited by 5 | Viewed by 3642

Abstract

COPD, a chronic obstructive pulmonary disease, is one of the leading causes of death worldwide. Clinical studies and research in rodent models demonstrated that failure of repair mechanisms to cope with increased ROS and inflammation in the lung leads to COPD. Despite this progress, the molecular mechanisms underlying the development of COPD remain poorly understood, resulting in a lack of effective treatments. Thus, an informative, simple model is highly valued and desired. Recently, the cigarette smoke-induced Drosophila COPD model showed a complex set of pathological phenotypes that resemble those seen in human COPD patients. The Drosophila trachea has been used as a premier model to reveal the mechanisms of tube morphogenesis. The association of these mechanisms to structural changes in COPD can be analyzed by using Drosophila trachea. Additionally, the timeline of structural damage, ROS, and inflammation can be studied in live organisms using fluorescently-tagged proteins. The related function of human COPD genes identified by GWAS can be screened using respective fly homologs. Finally, the Drosophila trachea can be used as a high-throughput drug screening platform to identify novel treatments for COPD. Therefore, Drosophila trachea is an excellent model that is complementary to rodent COPD models. Full article

(This article belongs to the Special Issue Modeling Human Biological Pathways in Health, Aging and Disease: The Drosophila Paradigm - in Memory of Professor Suzanne Eaton (1959-2019))

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19 pages, 1240 KiB

Open AccessReview

Drosophila melanogaster as a Model Organism to Study Lithium and Boron Bioactivity

by Katharina Jans, Kai Lüersen and Gerald Rimbach

Int. J. Mol. Sci. 2021, 22(21), 11710; https://doi.org/10.3390/ijms222111710 - 28 Oct 2021

Cited by 7 | Viewed by 5596

Abstract

The fruit fly Drosophila melanogaster has become a valuable model organism in nutritional science, which can be applied to elucidate the physiology and the biological function of nutrients, including trace elements. Importantly, the application of chemically defined diets enables the supply of trace elements for nutritional studies under highly standardized dietary conditions. Thus, the bioavailability and bioactivity of trace elements can be systematically monitored in D. melanogaster. Numerous studies have already revealed that central aspects of trace element homeostasis are evolutionary conserved among the fruit fly and mammalian species. While there is sufficient evidence of vital functions of boron (B) in plants, there is also evidence regarding its bioactivity in animals and humans. Lithium (Li) is well known for its role in the therapy of bipolar disorder. Furthermore, recent findings suggest beneficial effects of Li regarding neuroprotection as well as healthy ageing and longevity in D. melanogaster. However, no specific essential function in the animal kingdom has been found for either of the two elements so far. Here, we summarize the current knowledge of Li and B bioactivity in D. melanogaster in the context of health and disease prevention. Full article

(This article belongs to the Special Issue Modeling Human Biological Pathways in Health, Aging and Disease: The Drosophila Paradigm - in Memory of Professor Suzanne Eaton (1959-2019))

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