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Role of Drosophila in Human Disease Research

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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 (31 August 2020) | Viewed by 69204

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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
Special Issues, Collections and Topics in MDPI journals

Prof. Shinya Yamamoto

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Guest Editor

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Interests: Rare and Undiagnosed Diseases; Drosophila melanogaster; Notch signaling, Dopamine Signaling
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Special Issue Information

Dear Colleagues,

For over a century, Drosophila melanogaster has been widely used in classical and modern genetics. For over a decade, Drosophila has been used as a highly tractable animal model for studying human diseases. Many biological functions, including physical and neurological properties, are highly conserved between humans and Drosophila. Moreover, nearly 75% of human-disease-causing genes have their functional homologues in Drosophila. Drosophila has been successful in the study of various neurodegenerative diseases, metabolic syndromes, and cancer. It is also playing a role in the evaluation of candidate substances for treatment of these human diseases. Currently, scientists are studying more complex psychiatric disorders, aging, and rare intractable human genetic diseases using Drosophila models. However, we always have 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 models. For this Special Issue, we welcome original research articles and up-to-date review articles that provide novel insights into the related academic fields.

Prof. Masamitsu Yamaguchi
Prof. Shinya Yamamoto
Guest Editors

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Keywords

Drosophila melanogaster
Human disease model
Cancer
Neurodegeneration
Psychiatric disorder
Intellectual disorder
Metabolic syndrome
Aging
Epigenetic dysregulation
Mitochondrial disorder
Infectious diseases

Related Special Issue

Role of Drosophila in Human Disease Research 3.0 in International Journal of Molecular Sciences (11 articles)

Published Papers (12 papers)

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Research

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20 pages, 4092 KiB

Open AccessArticle

Abnormal Social Interactions in a Drosophila Mutant of an Autism Candidate Gene: Neuroligin 3

by Ryley T. Yost, J. Wesley Robinson, Carling M. Baxter, Andrew M. Scott, Liam P. Brown, M. Sol Aletta, Ramtin Hakimjavadi, Asad Lone, Robert C. Cumming, Reuven Dukas, Brian Mozer and Anne F. Simon

Int. J. Mol. Sci. 2020, 21(13), 4601; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134601 - 29 Jun 2020

Cited by 7 | Viewed by 5002

Abstract

Social interactions are typically impaired in neuropsychiatric disorders such as autism, for which the genetic underpinnings are very complex. Social interactions can be modeled by analysis of behaviors, including social spacing, sociability, and aggression, in simpler organisms such as Drosophila melanogaster. Here, we examined the effects of mutants of the autism-related gene neuroligin 3 (nlg3) on fly social and non-social behaviors. Startled-induced negative geotaxis is affected by a loss of function nlg3 mutation. Social space and aggression are also altered in a sex- and social-experience-specific manner in nlg3 mutant flies. In light of the conserved roles that neuroligins play in social behavior, our results offer insight into the regulation of social behavior in other organisms, including humans. Full article

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

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13 pages, 1196 KiB

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Anti-Aging Effect of the Ketone Metabolite β-Hydroxybutyrate in Drosophila Intestinal Stem Cells

by Joung-Sun Park and Yung-Jin Kim

Int. J. Mol. Sci. 2020, 21(10), 3497; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103497 - 15 May 2020

Cited by 14 | Viewed by 3290

Abstract

Age-related changes in tissue-resident adult stem cells may be closely linked to tissue aging and age-related diseases, such as cancer. β-Hydroxybutyrate is emerging as an important molecule for exhibiting the anti-aging effects of caloric restriction and fasting, which are generally considered to be beneficial for stem cell maintenance and tissue regeneration. The effects of β-hydroxybutyrate on adult stem cells remain largely unknown. Therefore, this study was undertaken to investigate whether β-hydroxybutyrate supplementation exerts beneficial effects on age-related changes in intestinal stem cells that were derived from the Drosophila midgut. Our results indicate that β-hydroxybutyrate inhibits age- and oxidative stress-induced changes in midgut intestinal stem cells, including centrosome amplification (a hallmark of cancers), hyperproliferation, and DNA damage accumulation. Additionally, β-hydroxybutyrate inhibits age- and oxidative stress-induced heterochromatin instability in enterocytes, an intestinal stem cells niche cells. Our results suggest that β-hydroxybutyrate exerts both intrinsic as well as extrinsic influence in order to maintain stem cell homeostasis. Full article

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

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22 pages, 4214 KiB

Open AccessArticle

Loss of Histone Locus Bodies in the Mature Hemocytes of Larval Lymph Gland Result in Hyperplasia of the Tissue in mxc Mutants of Drosophila

by Masanori Kurihara, Kouyou Komatsu, Rie Awane and Yoshihiro H. Inoue

Int. J. Mol. Sci. 2020, 21(5), 1586; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051586 - 26 Feb 2020

Cited by 8 | Viewed by 3004

Abstract

Mutations in the multi sex combs (mxc) gene in Drosophila results in malignant hyperplasia in larval hematopoietic tissues, called lymph glands (LG). mxc encodes a component of the histone locus body (HLB) that is essential for cell cycle-dependent transcription and processing of histone mRNAs. The mammalian nuclear protein ataxia-telangiectasia (NPAT) gene, encoded by the responsible gene for ataxia telangiectasia, is a functional Mxc orthologue. However, their roles in tumorigenesis are unclear. Genetic analyses of the mxc mutants and larvae having LG-specific depletion revealed that a reduced activity of the gene resulted in the hyperplasia, which is caused by hyper-proliferation of immature LG cells. The depletion of mxc in mature hemocytes of the LG resulted in the hyperplasia. Furthermore, the inhibition of HLB formation was required for LG hyperplasia. In the mutant larvae, the total mRNA levels of the five canonical histones decreased, and abnormal forms of polyadenylated histone mRNAs, detected rarely in normal larvae, were generated. The ectopic expression of the polyadenylated mRNAs was sufficient for the reproduction of the hyperplasia. The loss of HLB function, especially 3′-end processing of histone mRNAs, is critical for malignant LG hyperplasia in this leukemia model in Drosophila. We propose that mxc is involved in the activation to induce adenosine deaminase-related growth factor A (Adgf-A), which suppresses immature cell proliferation in LG. Full article

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

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Review

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29 pages, 1182 KiB

Open AccessReview

Flying Together: Drosophila as a Tool to Understand the Genetics of Human Alcoholism

by Daniel R. Lathen, Collin B. Merrill and Adrian Rothenfluh

Int. J. Mol. Sci. 2020, 21(18), 6649; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186649 - 11 Sep 2020

Cited by 16 | Viewed by 6627

Abstract

Alcohol use disorder (AUD) exacts an immense toll on individuals, families, and society. Genetic factors determine up to 60% of an individual’s risk of developing problematic alcohol habits. Effective AUD prevention and treatment requires knowledge of the genes that predispose people to alcoholism, play a role in alcohol responses, and/or contribute to the development of addiction. As a highly tractable and translatable genetic and behavioral model organism, Drosophila melanogaster has proven valuable to uncover important genes and mechanistic pathways that have obvious orthologs in humans and that help explain the complexities of addiction. Vinegar flies exhibit remarkably strong face and mechanistic validity as a model for AUDs, permitting many advancements in the quest to understand human genetic involvement in this disease. These advancements occur via approaches that essentially fall into one of two categories: (1) discovering candidate genes via human genome-wide association studies (GWAS), transcriptomics on post-mortem tissue from AUD patients, or relevant physiological connections, then using reverse genetics in flies to validate candidate genes’ roles and investigate their molecular function in the context of alcohol. (2) Utilizing flies to discover candidate genes through unbiased screens, GWAS, quantitative trait locus analyses, transcriptomics, or single-gene studies, then validating their translational role in human genetic surveys. In this review, we highlight the utility of Drosophila as a model for alcoholism by surveying recent advances in our understanding of human AUDs that resulted from these various approaches. We summarize the genes that are conserved in alcohol-related function between humans and flies. We also provide insight into some advantages and limitations of these approaches. Overall, this review demonstrates how Drosophila have and can be used to answer important genetic questions about alcohol addiction. Full article

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

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40 pages, 1659 KiB

Open AccessReview

Investigating Developmental and Epileptic Encephalopathy Using Drosophila melanogaster

by Akari Takai, Masamitsu Yamaguchi, Hideki Yoshida and Tomohiro Chiyonobu

Int. J. Mol. Sci. 2020, 21(17), 6442; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176442 - 03 Sep 2020

Cited by 13 | Viewed by 7148

Abstract

Developmental and epileptic encephalopathies (DEEs) are the spectrum of severe epilepsies characterized by early-onset, refractory seizures occurring in the context of developmental regression or plateauing. Early infantile epileptic encephalopathy (EIEE) is one of the earliest forms of DEE, manifesting as frequent epileptic spasms and characteristic electroencephalogram findings in early infancy. In recent years, next-generation sequencing approaches have identified a number of monogenic determinants underlying DEE. In the case of EIEE, 85 genes have been registered in Online Mendelian Inheritance in Man as causative genes. Model organisms are indispensable tools for understanding the in vivo roles of the newly identified causative genes. In this review, we first present an overview of epilepsy and its genetic etiology, especially focusing on EIEE and then briefly summarize epilepsy research using animal and patient-derived induced pluripotent stem cell (iPSC) models. The Drosophila model, which is characterized by easy gene manipulation, a short generation time, low cost and fewer ethical restrictions when designing experiments, is optimal for understanding the genetics of DEE. We therefore highlight studies with Drosophila models for EIEE and discuss the future development of their practical use. Full article

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

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38 pages, 834 KiB

Open AccessReview

Drosophila Glia: Models for Human Neurodevelopmental and Neurodegenerative Disorders

by Taejoon Kim, Bokyeong Song and Im-Soon Lee

Int. J. Mol. Sci. 2020, 21(14), 4859; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144859 - 09 Jul 2020

Cited by 19 | Viewed by 9535

Abstract

Glial cells are key players in the proper formation and maintenance of the nervous system, thus contributing to neuronal health and disease in humans. However, little is known about the molecular pathways that govern glia–neuron communications in the diseased brain. Drosophila provides a useful in vivo model to explore the conserved molecular details of glial cell biology and their contributions to brain function and disease susceptibility. Herein, we review recent studies that explore glial functions in normal neuronal development, along with Drosophila models that seek to identify the pathological implications of glial defects in the context of various central nervous system disorders. Full article

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

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13 pages, 267 KiB

Open AccessReview

PRPS-Associated Disorders and the Drosophila Model of Arts Syndrome

by Keemo Delos Santos, Eunjeong Kwon and Nam-Sung Moon

Int. J. Mol. Sci. 2020, 21(14), 4824; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144824 - 08 Jul 2020

Cited by 2 | Viewed by 2475

Abstract

While a plethora of genetic techniques have been developed over the past century, modifying specific sequences of the fruit fly genome has been a difficult, if not impossible task. clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 truly redefined molecular genetics and provided new tools to model human diseases in Drosophila melanogaster. This is particularly true for genes whose protein sequences are highly conserved. Phosphoribosyl pyrophosphate synthetase (PRPS) is a rate-limiting enzyme in nucleotide metabolism whose missense mutations are found in several neurological disorders, including Arts syndrome. In addition, PRPS is deregulated in cancer, particularly those that become resistant to cancer therapy. Notably, Drosophila PRPS shares about 90% protein sequence identity with its human orthologs, making it an ideal gene to study via CRISPR/Cas9. In this review, we will summarize recent findings on PRPS mutations in human diseases including cancer and on the molecular mechanisms by which PRPS activity is regulated. We will also discuss potential applications of Drosophila CRISPR/Cas9 to model PRPS-dependent disorders and other metabolic diseases that are associated with nucleotide metabolism. Full article

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

17 pages, 1250 KiB

Open AccessReview

Pharmacological Treatment of Alzheimer’s Disease: Insights from Drosophila melanogaster

by Xingyi Cheng, Chaochun Song, Yanjiao Du, Uma Gaur and Mingyao Yang

Int. J. Mol. Sci. 2020, 21(13), 4621; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134621 - 29 Jun 2020

Cited by 15 | Viewed by 4258

Abstract

Aging is an ineluctable law of life. During the process of aging, the occurrence of neurodegenerative disorders is prevalent in the elderly population and the predominant type of dementia is Alzheimer’s disease (AD). The clinical symptoms of AD include progressive memory loss and impairment of cognitive functions that interfere with daily life activities. The predominant neuropathological features in AD are extracellular β-amyloid (Aβ) plaque deposition and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated Tau. Because of its complex pathobiology, some tangible treatment can only ameliorate the symptoms, but not prevent the disease altogether. Numerous drugs during pre-clinical or clinical studies have shown no positive effect on the disease outcome. Therefore, understanding the basic pathophysiological mechanism of AD is imperative for the rational design of drugs that can be used to prevent this disease. Drosophila melanogaster has emerged as a highly efficient model system to explore the pathogenesis and treatment of AD. In this review we have summarized recent advancements in the pharmacological research on AD using Drosophila as a model species, discussed feasible treatment strategies and provided further reference for the mechanistic study and treatment of age-related AD. Full article

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

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27 pages, 9584 KiB

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Genetic Dissection of Alzheimer’s Disease Using Drosophila Models

by Youngjae Jeon, Jae Ha Lee, Byoungyun Choi, So-Yoon Won and Kyoung Sang Cho

Int. J. Mol. Sci. 2020, 21(3), 884; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030884 - 30 Jan 2020

Cited by 24 | Viewed by 6984

Abstract

Alzheimer’s disease (AD), a main cause of dementia, is the most common neurodegenerative disease that is related to abnormal accumulation of the amyloid β (Aβ) protein. Despite decades of intensive research, the mechanisms underlying AD remain elusive, and the only available treatment remains symptomatic. Molecular understanding of the pathogenesis and progression of AD is necessary to develop disease-modifying treatment. Drosophila, as the most advanced genetic model, has been used to explore the molecular mechanisms of AD in the last few decades. Here, we introduce Drosophila AD models based on human Aβ and summarize the results of their genetic dissection. We also discuss the utility of functional genomics using the Drosophila system in the search for AD-associated molecular mechanisms in the post-genomic era. Full article

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

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13 pages, 1214 KiB

Open AccessReview

Drosophila as a Model Organism to Understand the Effects during Development of TFIIH-Related Human Diseases

by Mario Zurita and Juan Manuel Murillo-Maldonado

Int. J. Mol. Sci. 2020, 21(2), 630; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020630 - 17 Jan 2020

Cited by 3 | Viewed by 3839

Abstract

Human mutations in the transcription and nucleotide excision repair (NER) factor TFIIH are linked with three human syndromes: xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS). In particular, different mutations in the XPB, XPD and p8 subunits of TFIIH may cause one or a combination of these syndromes, and some of these mutations are also related to cancer. The participation of TFIIH in NER and transcription makes it difficult to interpret the different manifestations observed in patients, particularly since some of these phenotypes may be related to problems during development. TFIIH is present in all eukaryotic cells, and its functions in transcription and DNA repair are conserved. Therefore, Drosophila has been a useful model organism for the interpretation of different phenotypes during development as well as the understanding of the dynamics of this complex. Interestingly, phenotypes similar to those observed in humans caused by mutations in the TFIIH subunits are present in mutant flies, allowing the study of TFIIH in different developmental processes. Furthermore, studies performed in Drosophila of mutations in different subunits of TFIIH that have not been linked to any human diseases, probably because they are more deleterious, have revealed its roles in differentiation and cell death. In this review, different achievements made through studies in the fly to understand the functions of TFIIH during development and its relationship with human diseases are analysed and discussed. Full article

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

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24 pages, 2327 KiB

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Autism Spectrum Disorder-Related Syndromes: Modeling with Drosophila and Rodents

by Ibuki Ueoka, Hang Thi Nguyet Pham, Kinzo Matsumoto and Masamitsu Yamaguchi

Int. J. Mol. Sci. 2019, 20(17), 4071; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20174071 - 21 Aug 2019

Cited by 14 | Viewed by 14771 | Correction

Abstract

Whole exome analyses have identified a number of genes associated with autism spectrum disorder (ASD) and ASD-related syndromes. These genes encode key regulators of synaptogenesis, synaptic plasticity, cytoskeleton dynamics, protein synthesis and degradation, chromatin remodeling, transcription, and lipid homeostasis. Furthermore, in silico studies suggest complex regulatory networks among these genes. Drosophila is a useful genetic model system for studies of ASD and ASD-related syndromes to clarify the in vivo roles of ASD-associated genes and the complex gene regulatory networks operating in the pathogenesis of ASD and ASD-related syndromes. In this review, we discuss what we have learned from studies with vertebrate models, mostly mouse models. We then highlight studies with Drosophila models. We also discuss future developments in the related field. Full article

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

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1 pages, 147 KiB

Open AccessCorrection

Correction: Ueoka, I., et al. Autism Spectrum Disorder-Related Syndromes: Modeling with Drosophila and Rodents. Int. J. Mol. Sci. 2019, 20, 4071

by Ibuki Ueoka, Hang Thi Nguyet Pham, Kinzo Matsumoto and Masamitsu Yamaguchi

Int. J. Mol. Sci. 2020, 21(21), 8093; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218093 - 30 Oct 2020

Cited by 1 | Viewed by 1158

Abstract

The author wishes to make the following correction to this paper [...] Full article

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

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