Editorial

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Open AccessEditorial

Role of Drosophila in Human Disease Research 2.0

by Masamitsu Yamaguchi and Shinya Yamamoto

Int. J. Mol. Sci. 2022, 23(8), 4203; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084203 - 11 Apr 2022

Cited by 4 | Viewed by 1747

The fruit fly Drosophila melanogaster is a highly tractable animal model to study various human diseases [...] Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 2.0)

Research

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16 pages, 19512 KiB

Open AccessArticle

Functional Inactivation of Drosophila GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2

by Elisa Mascolo, Francesco Liguori, Lorenzo Stufera Mecarelli, Noemi Amoroso, Chiara Merigliano, Susanna Amadio, Cinzia Volonté, Roberto Contestabile, Angela Tramonti and Fiammetta Vernì

Int. J. Mol. Sci. 2021, 22(2), 918; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020918 - 18 Jan 2021

Cited by 5 | Viewed by 2877

Abstract

Maturity-onset diabetes of the young (MODY) type 2 is caused by heterozygous inactivating mutations in the gene encoding glucokinase (GCK), a pivotal enzyme for glucose homeostasis. In the pancreas GCK regulates insulin secretion, while in the liver it promotes glucose utilization and storage. [...] Read more.

Maturity-onset diabetes of the young (MODY) type 2 is caused by heterozygous inactivating mutations in the gene encoding glucokinase (GCK), a pivotal enzyme for glucose homeostasis. In the pancreas GCK regulates insulin secretion, while in the liver it promotes glucose utilization and storage. We showed that silencing the DrosophilaGCK orthologs Hex-A and Hex-C results in a MODY-2-like hyperglycemia. Targeted knock-down revealed that Hex-A is expressed in insulin producing cells (IPCs) whereas Hex-C is specifically expressed in the fat body. We showed that Hex-A is essential for insulin secretion and it is required for Hex-C expression. Reduced levels of either Hex-A or Hex-C resulted in chromosome aberrations (CABs), together with an increased production of advanced glycation end-products (AGEs) and reactive oxygen species (ROS). This result suggests that CABs, in GCK depleted cells, are likely due to hyperglycemia, which produces oxidative stress through AGE metabolism. In agreement with this hypothesis, treating GCK-depleted larvae with the antioxidant vitamin B6 rescued CABs, whereas the treatment with a B6 inhibitor enhanced genomic instability. Although MODY-2 rarely produces complications, our data revealed the possibility that MODY-2 impacts genome integrity. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 2.0)

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20 pages, 1920 KiB

Open AccessArticle

MicroRNA-31 Regulates Expression of Wntless in Both Drosophila melanogaster and Human Oral Cancer Cells

by Ji Eun Jung, Joo Young Lee, In Ryoung Kim, Sang Mee Park, Ji Wan Kang, Yun Hak Kim, Hae Ryoun Park and Ji Hye Lee

Int. J. Mol. Sci. 2020, 21(19), 7232; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197232 - 30 Sep 2020

Cited by 7 | Viewed by 2908

Abstract

Recent comparative studies have indicated distinct expression profiles of short, non-coding microRNAs (miRNAs) in various types of cancer, including oral squamous cell carcinoma (OSCC). In this study, we employed a hybrid approach using Drosophila melanogaster as well as OSCC cell lines to validate [...] Read more.

Recent comparative studies have indicated distinct expression profiles of short, non-coding microRNAs (miRNAs) in various types of cancer, including oral squamous cell carcinoma (OSCC). In this study, we employed a hybrid approach using Drosophila melanogaster as well as OSCC cell lines to validate putative targets of oral cancer-related miRNAs both in vivo and in vitro. Following overexpression of Drosophila miR-31, we found a significant decrease in the size of the imaginal wing discs and downregulation of a subset of putative targets, including wntless (wls), an important regulator of the Wnt signaling pathway. Parallel experiments performed in OSCC cells have also confirmed a similar miR-31-dependent regulation of human WLS that was not initially predicted as targets of human miR-31. Furthermore, we found subsequent downregulation of cyclin D1 and c-MYC, two of the main transcriptional targets of Wnt signaling, suggesting a potential role of miR-31 in regulating the cell cycle and proliferation of OSCC cells. Taken together, our Drosophila-based in vivo system in conjunction with the human in vitro platform will thus provide a novel insight into a mammal-to-Drosophila-to-mammal approach to validate putative targets of human miRNA and to better understand the miRNA-target relationships that play an important role in the pathophysiology of oral cancer. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 2.0)

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11 pages, 1699 KiB

Open AccessArticle

Functional Characterization of Gomisin N in High-Fat-Induced Drosophila Obesity Models

by Joo Young Lee, Ji Hye Lee and Chong Kun Cheon

Int. J. Mol. Sci. 2020, 21(19), 7209; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197209 - 29 Sep 2020

Cited by 8 | Viewed by 3233

Abstract

Gomisin N (GN) is lignin derived from Schisandra chinensis that has been reported to exhibit hepato-protective, anti-cancer, and anti-inflammatory effects. However, its role in whole-body energetic homeostasis remains unclear. In this study, we employed Drosophila melanogaster as a diet-induced obese model to elucidate [...] Read more.

Gomisin N (GN) is lignin derived from Schisandra chinensis that has been reported to exhibit hepato-protective, anti-cancer, and anti-inflammatory effects. However, its role in whole-body energetic homeostasis remains unclear. In this study, we employed Drosophila melanogaster as a diet-induced obese model to elucidate the effects of GN on lipid and glucose metabolism by measuring climbing activity, triglyceride levels, and lifespan under a rearing condition of a high-fat diet (HFD) containing 20% coconut oil, with or without GN. Constant exposure of flies to an HFD resulted in increased body weight and decreased climbing activity, along with a shortened life span. Importantly, the administration of GN to HFD groups lowered their body weight and induced a specific upregulation of lipid storage droplet (Lsd)-2 and hormone-sensitive lipase (Hsl), in addition to improved lifespan. Importantly, GN in HFD groups appeared to downregulate heat shock protein Hsp90 family member (dGRP94), a key regulator of the endoplasmic reticulum stress response, which may also contribute to improved life span in the presence of GN. Taken together, these in vivo findings suggest that GN could serve as a useful agent for the prevention and treatment of obesity. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 2.0)

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Review

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18 pages, 354 KiB

Open AccessReview

Roles of α-Synuclein and Disease-Associated Factors in Drosophila Models of Parkinson’s Disease

by Mari Suzuki, Kazunori Sango and Yoshitaka Nagai

Int. J. Mol. Sci. 2022, 23(3), 1519; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031519 - 28 Jan 2022

Cited by 7 | Viewed by 3283

Abstract

α-Synuclein (αSyn) plays a major role in the pathogenesis of Parkinson’s disease (PD), which is the second most common neurodegenerative disease after Alzheimer’s disease. The accumulation of αSyn is a pathological hallmark of PD, and mutations in the SNCA gene encoding αSyn cause [...] Read more.

α-Synuclein (αSyn) plays a major role in the pathogenesis of Parkinson’s disease (PD), which is the second most common neurodegenerative disease after Alzheimer’s disease. The accumulation of αSyn is a pathological hallmark of PD, and mutations in the SNCA gene encoding αSyn cause familial forms of PD. Moreover, the ectopic expression of αSyn has been demonstrated to mimic several key aspects of PD in experimental model systems. Among the various model systems, Drosophila melanogaster has several advantages for modeling human neurodegenerative diseases. Drosophila has a well-defined nervous system, and numerous tools have been established for its genetic analyses. The rapid generation cycle and short lifespan of Drosophila renders them suitable for high-throughput analyses. PD model flies expressing αSyn have contributed to our understanding of the roles of various disease-associated factors, including genetic and nongenetic factors, in the pathogenesis of PD. In this review, we summarize the molecular pathomechanisms revealed to date using αSyn-expressing Drosophila models of PD, and discuss the possibilities of using these models to demonstrate the biological significance of disease-associated factors. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 2.0)

24 pages, 2614 KiB

Open AccessReview

Human Hazard Assessment Using Drosophila Wing Spot Test as an Alternative In Vivo Model for Genotoxicity Testing—A Review

by Pornsiri Pitchakarn, Woorawee Inthachat, Jirarat Karinchai and Piya Temviriyanukul

Int. J. Mol. Sci. 2021, 22(18), 9932; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189932 - 14 Sep 2021

Cited by 14 | Viewed by 3498

Abstract

Genomic instability, one of cancer’s hallmarks, is induced by genotoxins from endogenous and exogenous sources, including reactive oxygen species (ROS), diet, and environmental pollutants. A sensitive in vivo genotoxicity test is required for the identification of human hazards to reduce the potential health [...] Read more.

Genomic instability, one of cancer’s hallmarks, is induced by genotoxins from endogenous and exogenous sources, including reactive oxygen species (ROS), diet, and environmental pollutants. A sensitive in vivo genotoxicity test is required for the identification of human hazards to reduce the potential health risk. The somatic mutation and recombination test (SMART) or wing spot test is a genotoxicity assay involving Drosophila melanogaster (fruit fly) as a classical, alternative human model. This review describes the principle of the SMART assay in conjunction with its advantages and disadvantages and discusses applications of the assay covering all segments of health-related industries, including food, dietary supplements, drug industries, pesticides, and herbicides, as well as nanoparticles. Chemopreventive strategies are outlined as a global health trend for the anti-genotoxicity of interesting herbal extract compounds determined by SMART assay. The successful application of Drosophila for high-throughput screening of mutagens is also discussed as a future perspective. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 2.0)

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42 pages, 4432 KiB

Open AccessReview

Drosophila as a Model for Infectious Diseases

by J. Michael Harnish, Nichole Link and Shinya Yamamoto

Int. J. Mol. Sci. 2021, 22(5), 2724; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052724 - 08 Mar 2021

Cited by 34 | Viewed by 7765

Abstract

The fruit fly, Drosophila melanogaster, has been used to understand fundamental principles of genetics and biology for over a century. Drosophila is now also considered an essential tool to study mechanisms underlying numerous human genetic diseases. In this review, we will discuss [...] Read more.

The fruit fly, Drosophila melanogaster, has been used to understand fundamental principles of genetics and biology for over a century. Drosophila is now also considered an essential tool to study mechanisms underlying numerous human genetic diseases. In this review, we will discuss how flies can be used to deepen our knowledge of infectious disease mechanisms in vivo. Flies make effective and applicable models for studying host-pathogen interactions thanks to their highly conserved innate immune systems and cellular processes commonly hijacked by pathogens. Drosophila researchers also possess the most powerful, rapid, and versatile tools for genetic manipulation in multicellular organisms. This allows for robust experiments in which specific pathogenic proteins can be expressed either one at a time or in conjunction with each other to dissect the molecular functions of each virulent factor in a cell-type-specific manner. Well documented phenotypes allow large genetic and pharmacological screens to be performed with relative ease using huge collections of mutant and transgenic strains that are publicly available. These factors combine to make Drosophila a powerful tool for dissecting out host-pathogen interactions as well as a tool to better understand how we can treat infectious diseases that pose risks to public health, including COVID-19, caused by SARS-CoV-2. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 2.0)

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19 pages, 400 KiB

Open AccessReview

Epigenetic Regulation of ALS and CMT: A Lesson from Drosophila Models

by Masamitsu Yamaguchi, Kentaro Omori, Satoshi Asada and Hideki Yoshida

Int. J. Mol. Sci. 2021, 22(2), 491; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020491 - 06 Jan 2021

Cited by 8 | Viewed by 3742

Abstract

Amyotrophic lateral sclerosis (ALS) is the third most common neurodegenerative disorder and is sometimes associated with frontotemporal dementia. Charcot–Marie–Tooth disease (CMT) is one of the most commonly inherited peripheral neuropathies causing the slow progression of sensory and distal muscle defects. Of note, the [...] Read more.

Amyotrophic lateral sclerosis (ALS) is the third most common neurodegenerative disorder and is sometimes associated with frontotemporal dementia. Charcot–Marie–Tooth disease (CMT) is one of the most commonly inherited peripheral neuropathies causing the slow progression of sensory and distal muscle defects. Of note, the severity and progression of CMT symptoms markedly vary. The phenotypic heterogeneity of ALS and CMT suggests the existence of modifiers that determine disease characteristics. Epigenetic regulation of biological functions via gene expression without alterations in the DNA sequence may be an important factor. The methylation of DNA, noncoding RNA, and post-translational modification of histones are the major epigenetic mechanisms. Currently, Drosophila is emerging as a useful ALS and CMT model. In this review, we summarize recent studies linking ALS and CMT to epigenetic regulation with a strong emphasis on approaches using Drosophila models. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 2.0)

19 pages, 620 KiB

Open AccessReview

Recent Advances in Drosophila Models of Charcot-Marie-Tooth Disease

by Fukiko Kitani-Morii and Yu-ichi Noto

Int. J. Mol. Sci. 2020, 21(19), 7419; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197419 - 08 Oct 2020

Cited by 7 | Viewed by 8104

Abstract

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited peripheral neuropathies. CMT patients typically show slowly progressive muscle weakness and sensory loss in a distal dominant pattern in childhood. The diagnosis of CMT is based on clinical symptoms, electrophysiological examinations, and genetic [...] Read more.

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited peripheral neuropathies. CMT patients typically show slowly progressive muscle weakness and sensory loss in a distal dominant pattern in childhood. The diagnosis of CMT is based on clinical symptoms, electrophysiological examinations, and genetic testing. Advances in genetic testing technology have revealed the genetic heterogeneity of CMT; more than 100 genes containing the disease causative mutations have been identified. Because a single genetic alteration in CMT leads to progressive neurodegeneration, studies of CMT patients and their respective models revealed the genotype-phenotype relationships of targeted genes. Conventionally, rodents and cell lines have often been used to study the pathogenesis of CMT. Recently, Drosophila has also attracted attention as a CMT model. In this review, we outline the clinical characteristics of CMT, describe the advantages and disadvantages of using Drosophila in CMT studies, and introduce recent advances in CMT research that successfully applied the use of Drosophila, in areas such as molecules associated with mitochondria, endosomes/lysosomes, transfer RNA, axonal transport, and glucose metabolism. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 2.0)

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