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Special Issue "Drosophila Model and Human Disease"

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 2018)

Special Issue Editor

Guest Editor
Prof. Dr. Beat Suter

Institute of Cell Biology, University of Bern, Baltzerstrasse 4, 3012 Bern, Switzerland
Website | E-Mail
Interests: drosophila model; development; cell cycle control; microtubule transport; mRNA localization; multifunctional proteins; human disease; cancer

Special Issue Information

Dear Colleagues,

Many molecular and cellular mechanisms that drive the physiological functions of cells or control the development of an animal are well conserved between vertebrates and insects. This conservation made the genetically and experimentally tractable Drosophila a valuable model to study human development and diseases. The high similarity of these processes is illustrated by the fact that close to two out of three human disease genes have Drosophila counterparts that are thought to be functional homologs.

The availability of extensive resources and sophisticated genetic tools allows researchers to efficiently generate Drosophila disease models for numerous disorders with the goal of identifying the etiology of these human diseases. The knowledge about the disease pathway often points to novel possible therapeutic targets and whole organism screening for compounds that interact with the pathway. Because Drosophila allows the researchers to adjust the genetic background, whole organism Drosophila disease models will play an important role in the future of personalized medicine. For this Special Issue, we welcome original research articles and reviews that provide novel insights into the outlined research areas.

Prof. Dr. Beat Suter
Guest Editor

Manuscript Submission Information

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Keywords

  • Drosophila melanogaster
  • human disease model
  • neurodegeneration
  • cancer model
  • developmental defects
  • defects in physiology
  • experimental genetics model
  • whole organism model
  • disease etiology

Published Papers (17 papers)

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Editorial

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Open AccessEditorial
Useful Flies
Int. J. Mol. Sci. 2019, 20(4), 871; https://doi.org/10.3390/ijms20040871
Received: 1 February 2019 / Accepted: 14 February 2019 / Published: 18 February 2019
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Abstract
Many molecular and cellular mechanisms that drive the physiological functions of cells or control the development of an animal are well conserved between vertebrates and insects [...] Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)

Research

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Open AccessArticle
Dme-Hsa Disease Database (DHDD): Conserved Human Disease-Related miRNA and Their Targeting Genes in Drosophila melanogaster
Int. J. Mol. Sci. 2018, 19(9), 2642; https://doi.org/10.3390/ijms19092642
Received: 31 May 2018 / Revised: 29 August 2018 / Accepted: 31 August 2018 / Published: 6 September 2018
Cited by 2 | PDF Full-text (1585 KB) | HTML Full-text | XML Full-text
Abstract
Abnormal expressions of microRNA (miRNA) can result in human diseases such as cancer and neurodegenerative diseases. MiRNA mainly exert their biological functions via repressing the expression of their target genes. Drosophila melanogaster (D. melanogaster) is an ideal model for studying the [...] Read more.
Abnormal expressions of microRNA (miRNA) can result in human diseases such as cancer and neurodegenerative diseases. MiRNA mainly exert their biological functions via repressing the expression of their target genes. Drosophila melanogaster (D. melanogaster) is an ideal model for studying the molecular mechanisms behind biological phenotypes, including human diseases. In this study, we collected human and D. melanogaster miRNA as well as known human disease-related genes. In total, we identified 136 human disease-related miRNA that are orthologous to 83 D. melanogaster miRNA by mapping “seed sequence”, and 677 human disease-related genes that are orthologous to 734 D. melanogaster genes using the DRSC Integrative Ortholog Prediction Tool Furthermore, we revealed the target relationship between genes and miRNA using miRTarBase database and target prediction software, including miRanda and TargetScan. In addition, we visualized interaction networks and signalling pathways for these filtered miRNA and target genes. Finally, we compiled all the above data and information to generate a database designated DHDD This is the first comprehensive collection of human disease-related miRNA and their targeting genes conserved in a D. melanogaster database. The DHDD provides a resource for easily searching human disease-related miRNA and their disease-related target genes as well as their orthologs in D. melanogaster, and conveniently identifying the regulatory relationships among them in the form of a visual network. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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Open AccessArticle
Src Cooperates with Oncogenic Ras in Tumourigenesis via the JNK and PI3K Pathways in Drosophila epithelial Tissue
Int. J. Mol. Sci. 2018, 19(6), 1585; https://doi.org/10.3390/ijms19061585
Received: 19 April 2018 / Revised: 15 May 2018 / Accepted: 23 May 2018 / Published: 27 May 2018
Cited by 3 | PDF Full-text (3770 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The Ras oncogene (Rat Sarcoma oncogene, a small GTPase) is a key driver of human cancer, however alone it is insufficient to produce malignancy, due to the induction of cell cycle arrest or senescence. In a Drosophila melanogaster genetic screen for genes that [...] Read more.
The Ras oncogene (Rat Sarcoma oncogene, a small GTPase) is a key driver of human cancer, however alone it is insufficient to produce malignancy, due to the induction of cell cycle arrest or senescence. In a Drosophila melanogaster genetic screen for genes that cooperate with oncogenic Ras (bearing the RasV12 mutation, or RasACT), we identified the Drosophila Src (Sarcoma virus oncogene) family non-receptor tyrosine protein kinase genes, Src42A and Src64B, as promoting increased hyperplasia in a whole epithelial tissue context in the Drosophila eye. Moreover, overexpression of Src cooperated with RasACT in epithelial cell clones to drive neoplastic tumourigenesis. We found that Src overexpression alone activated the Jun N-terminal Kinase (JNK) signalling pathway to promote actin cytoskeletal and cell polarity defects and drive apoptosis, whereas, in cooperation with RasACT, JNK led to a loss of differentiation and an invasive phenotype. Src + RasACT cooperative tumourigenesis was dependent on JNK as well as Phosphoinositide 3-Kinase (PI3K) signalling, suggesting that targeting these pathways might provide novel therapeutic opportunities in cancers dependent on Src and Ras signalling. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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Open AccessArticle
Loss of ISWI Function in Drosophila Nuclear Bodies Drives Cytoplasmic Redistribution of Drosophila TDP-43
Int. J. Mol. Sci. 2018, 19(4), 1082; https://doi.org/10.3390/ijms19041082
Received: 8 January 2018 / Revised: 27 March 2018 / Accepted: 3 April 2018 / Published: 4 April 2018
Cited by 4 | PDF Full-text (17175 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Over the past decade, evidence has identified a link between protein aggregation, RNA biology, and a subset of degenerative diseases. An important feature of these disorders is the cytoplasmic or nuclear aggregation of RNA-binding proteins (RBPs). Redistribution of RBPs, such as the human [...] Read more.
Over the past decade, evidence has identified a link between protein aggregation, RNA biology, and a subset of degenerative diseases. An important feature of these disorders is the cytoplasmic or nuclear aggregation of RNA-binding proteins (RBPs). Redistribution of RBPs, such as the human TAR DNA-binding 43 protein (TDP-43) from the nucleus to cytoplasmic inclusions is a pathological feature of several diseases. Indeed, sporadic and familial forms of amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration share as hallmarks ubiquitin-positive inclusions. Recently, the wide spectrum of neurodegenerative diseases characterized by RBPs functions’ alteration and loss was collectively named proteinopathies. Here, we show that TBPH (TAR DNA-binding protein-43 homolog), the Drosophila ortholog of human TDP-43 TAR DNA-binding protein-43, interacts with the arcRNA hsrω and with hsrω-associated hnRNPs. Additionally, we found that the loss of the omega speckles remodeler ISWI (Imitation SWI) changes the TBPH sub-cellular localization to drive a TBPH cytoplasmic accumulation. Our results, hence, identify TBPH as a new component of omega speckles and highlight a role of chromatin remodelers in hnRNPs nuclear compartmentalization. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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Review

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Open AccessReview
Using Mouse and Drosophila Models to Investigate the Mechanistic Links between Diet, Obesity, Type II Diabetes, and Cancer
Int. J. Mol. Sci. 2018, 19(12), 4110; https://doi.org/10.3390/ijms19124110
Received: 23 November 2018 / Revised: 12 December 2018 / Accepted: 14 December 2018 / Published: 18 December 2018
Cited by 3 | PDF Full-text (1964 KB) | HTML Full-text | XML Full-text
Abstract
Many of the links between diet and cancer are controversial and over simplified. To date, human epidemiological studies consistently reveal that patients who suffer diet-related obesity and/or type II diabetes have an increased risk of cancer, suffer more aggressive cancers, and respond poorly [...] Read more.
Many of the links between diet and cancer are controversial and over simplified. To date, human epidemiological studies consistently reveal that patients who suffer diet-related obesity and/or type II diabetes have an increased risk of cancer, suffer more aggressive cancers, and respond poorly to current therapies. However, the underlying molecular mechanisms that increase cancer risk and decrease the response to cancer therapies in these patients remain largely unknown. Here, we review studies in mouse cancer models in which either dietary or genetic manipulation has been used to model obesity and/or type II diabetes. These studies demonstrate an emerging role for the conserved insulin and insulin-like growth factor signaling pathways as links between diet and cancer progression. However, these models are time consuming to develop and expensive to maintain. As the world faces an epidemic of obesity and type II diabetes we argue that the development of novel animal models is urgently required. We make the case for Drosophila as providing an unparalleled opportunity to combine dietary manipulation with models of human metabolic disease and cancer. Thus, combining diet and cancer models in Drosophila can rapidly and significantly advance our understanding of the conserved molecular mechanisms that link diet and diet-related metabolic disorders to poor cancer patient prognosis. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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Open AccessReview
Dissecting Pathogenetic Mechanisms and Therapeutic Strategies in Drosophila Models of Myotonic Dystrophy Type 1
Int. J. Mol. Sci. 2018, 19(12), 4104; https://doi.org/10.3390/ijms19124104
Received: 11 November 2018 / Revised: 8 December 2018 / Accepted: 13 December 2018 / Published: 18 December 2018
Cited by 1 | PDF Full-text (751 KB) | HTML Full-text | XML Full-text
Abstract
Myotonic dystrophy type 1 (DM1), the most common cause of adult-onset muscular dystrophy, is autosomal dominant, multisystemic disease with characteristic symptoms including myotonia, heart defects, cataracts and testicular atrophy. DM1 disease is being successfully modelled in Drosophila allowing to identify and validate new [...] Read more.
Myotonic dystrophy type 1 (DM1), the most common cause of adult-onset muscular dystrophy, is autosomal dominant, multisystemic disease with characteristic symptoms including myotonia, heart defects, cataracts and testicular atrophy. DM1 disease is being successfully modelled in Drosophila allowing to identify and validate new pathogenic mechanisms and potential therapeutic strategies. Here we provide an overview of insights gained from fruit fly DM1 models, either: (i) fundamental with particular focus on newly identified gene deregulations and their link with DM1 symptoms; or (ii) applied via genetic modifiers and drug screens to identify promising therapeutic targets. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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Open AccessReview
Drosophila Jak/STAT Signaling: Regulation and Relevance in Human Cancer and Metastasis
Int. J. Mol. Sci. 2018, 19(12), 4056; https://doi.org/10.3390/ijms19124056
Received: 8 November 2018 / Revised: 8 December 2018 / Accepted: 11 December 2018 / Published: 14 December 2018
Cited by 2 | PDF Full-text (3574 KB) | HTML Full-text | XML Full-text
Abstract
Over the past three-decades, Janus kinase (Jak) and signal transducer and activator of transcription (STAT) signaling has emerged as a paradigm to understand the involvement of signal transduction in development and disease pathology. At the molecular level, cytokines and interleukins steer Jak/STAT signaling [...] Read more.
Over the past three-decades, Janus kinase (Jak) and signal transducer and activator of transcription (STAT) signaling has emerged as a paradigm to understand the involvement of signal transduction in development and disease pathology. At the molecular level, cytokines and interleukins steer Jak/STAT signaling to transcriptional regulation of target genes, which are involved in cell differentiation, migration, and proliferation. Jak/STAT signaling is involved in various types of blood cell disorders and cancers in humans, and its activation is associated with carcinomas that are more invasive or likely to become metastatic. Despite immense information regarding Jak/STAT regulation, the signaling network has numerous missing links, which is slowing the progress towards developing drug therapies. In mammals, many components act in this cascade, with substantial cross-talk with other signaling pathways. In Drosophila, there are fewer pathway components, which has enabled significant discoveries regarding well-conserved regulatory mechanisms. Work across species illustrates the relevance of these regulators in humans. In this review, we showcase fundamental Jak/STAT regulation mechanisms in blood cells, stem cells, and cell motility. We examine the functional relevance of key conserved regulators from Drosophila to human cancer stem cells and metastasis. Finally, we spotlight less characterized regulators of Drosophila Jak/STAT signaling, which stand as promising candidates to be investigated in cancer biology. These comparisons illustrate the value of using Drosophila as a model for uncovering the roles of Jak/STAT signaling and the molecular means by which the pathway is controlled. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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Open AccessReview
Drosophila as a Model to Study Brain Innate Immunity in Health and Disease
Int. J. Mol. Sci. 2018, 19(12), 3922; https://doi.org/10.3390/ijms19123922
Received: 19 November 2018 / Revised: 5 December 2018 / Accepted: 5 December 2018 / Published: 7 December 2018
Cited by 1 | PDF Full-text (694 KB) | HTML Full-text | XML Full-text
Abstract
Innate immunity is the first line of defense against invading pathogens and plays an essential role in defending the brain against infection, injury, and disease. It is currently well recognized that central nervous system (CNS) infections can result in long-lasting neurological sequelae and [...] Read more.
Innate immunity is the first line of defense against invading pathogens and plays an essential role in defending the brain against infection, injury, and disease. It is currently well recognized that central nervous system (CNS) infections can result in long-lasting neurological sequelae and that innate immune and inflammatory reactions are highly implicated in the pathogenesis of neurodegeneration. Due to the conservation of the mechanisms that govern neural development and innate immune activation from flies to mammals, the lack of a classical adaptive immune system and the availability of numerous genetic and genomic tools, the fruit fly Drosophila melanogaster presents opportunities to investigate the cellular and molecular mechanisms associated with immune function in brain tissue and how they relate to infection, injury and neurodegenerative diseases. Here, we present an overview of currently identified innate immune mechanisms specific to the adult Drosophila brain. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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Open AccessReview
Drosophila Gut—A Nexus Between Dietary Restriction and Lifespan
Int. J. Mol. Sci. 2018, 19(12), 3810; https://doi.org/10.3390/ijms19123810
Received: 29 October 2018 / Revised: 26 November 2018 / Accepted: 26 November 2018 / Published: 29 November 2018
Cited by 1 | PDF Full-text (900 KB) | HTML Full-text | XML Full-text
Abstract
Aging is often defined as the accumulation of damage at the molecular and cellular levels which, over time, results in marked physiological impairments throughout the organism. Dietary restriction (DR) has been recognized as one of the strongest lifespan extending therapies observed in a [...] Read more.
Aging is often defined as the accumulation of damage at the molecular and cellular levels which, over time, results in marked physiological impairments throughout the organism. Dietary restriction (DR) has been recognized as one of the strongest lifespan extending therapies observed in a wide array of organisms. Recent studies aimed at elucidating how DR promotes healthy aging have demonstrated a vital role of the digestive tract in mediating the beneficial effects of DR. Here, we review how dietary restriction influences gut metabolic homeostasis and immune function. Our discussion is focused on studies of the Drosophila digestive tract, where we describe in detail the potential mechanisms in which DR enhances maintenance of the intestinal epithelial barrier, up-regulates lipid metabolic processes, and improves the ability of the gut to deal with damage or stress. We also examine evidence of a tissue-tissue crosstalk between gut and neighboring organs including brain and fat body. Taken together, we argue that the Drosophila gut plays a critical role in DR-mediated lifespan extension. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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Open AccessReview
Drosophila Models of Sporadic Parkinson’s Disease
Int. J. Mol. Sci. 2018, 19(11), 3343; https://doi.org/10.3390/ijms19113343
Received: 6 September 2018 / Revised: 22 October 2018 / Accepted: 23 October 2018 / Published: 26 October 2018
Cited by 4 | PDF Full-text (539 KB) | HTML Full-text | XML Full-text
Abstract
Parkinson’s disease (PD) is the most common cause of movement disorders and is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. It is increasingly recognized as a complex group of disorders presenting widely heterogeneous symptoms and pathology. With the [...] Read more.
Parkinson’s disease (PD) is the most common cause of movement disorders and is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. It is increasingly recognized as a complex group of disorders presenting widely heterogeneous symptoms and pathology. With the exception of the rare monogenic forms, the majority of PD cases result from an interaction between multiple genetic and environmental risk factors. The search for these risk factors and the development of preclinical animal models are in progress, aiming to provide mechanistic insights into the pathogenesis of PD. This review summarizes the studies that capitalize on modeling sporadic (i.e., nonfamilial) PD using Drosophila melanogaster and discusses their methodologies, new findings, and future perspectives. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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Open AccessReview
The Tiny Drosophila Melanogaster for the Biggest Answers in Huntington’s Disease
Int. J. Mol. Sci. 2018, 19(8), 2398; https://doi.org/10.3390/ijms19082398
Received: 2 July 2018 / Revised: 8 August 2018 / Accepted: 9 August 2018 / Published: 14 August 2018
Cited by 1 | PDF Full-text (3346 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The average life expectancy for humans has increased over the last years. However, the quality of the later stages of life is low and is considered a public health issue of global importance. Late adulthood and the transition into the later stage of [...] Read more.
The average life expectancy for humans has increased over the last years. However, the quality of the later stages of life is low and is considered a public health issue of global importance. Late adulthood and the transition into the later stage of life occasionally leads to neurodegenerative diseases that selectively affect different types of neurons and brain regions, producing motor dysfunctions, cognitive impairment, and psychiatric disorders that are progressive, irreversible, without remission periods, and incurable. Huntington’s disease (HD) is a common neurodegenerative disorder. In the 25 years since the mutation of the huntingtin (HTT) gene was identified as the molecule responsible for this neural disorder, a variety of animal models, including the fruit fly, have been used to study the disease. Here, we review recent research that used Drosophila as an experimental tool for improving knowledge about the molecular and cellular mechanisms underpinning HD. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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Open AccessReview
The Air Sac Primordium of Drosophila: A Model for Invasive Development
Int. J. Mol. Sci. 2018, 19(7), 2074; https://doi.org/10.3390/ijms19072074
Received: 13 June 2018 / Revised: 11 July 2018 / Accepted: 12 July 2018 / Published: 17 July 2018
Cited by 2 | PDF Full-text (1870 KB) | HTML Full-text | XML Full-text
Abstract
The acquisition of invasive properties preceding tumor metastasis is critical for cancer progression. This phenomenon may result from mutagenic disruption of typical cell function, but recent evidence suggests that cancer cells frequently co-opt normal developmental programs to facilitate invasion as well. The signaling [...] Read more.
The acquisition of invasive properties preceding tumor metastasis is critical for cancer progression. This phenomenon may result from mutagenic disruption of typical cell function, but recent evidence suggests that cancer cells frequently co-opt normal developmental programs to facilitate invasion as well. The signaling cascades that have been implicated present an obstacle to identifying effective therapeutic targets because of their complex nature and modulatory capacity through crosstalk with other pathways. Substantial efforts have been made to study invasive behavior during organogenesis in several organisms, but another model found in Drosophilamelanogaster has not been thoroughly explored. The air sac primordium (ASP) appears to be a suitable candidate for investigating the genes and morphogens required for invasion due to the distinct overlap in the events that occur during its normal growth and the development of metastatic tumor cells. Among these events are the conversion of larval cells in the trachea into a population of mitotically active cells, reduced cell–cell contact along the leading edge of the ASP, and remodeling of the extracellular matrix (ECM) that surrounds the structure. Here, we summarize the development of ASPs and invasive behavior observed therein. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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Open AccessReview
Recent Developments in Using Drosophila as a Model for Human Genetic Disease
Int. J. Mol. Sci. 2018, 19(7), 2041; https://doi.org/10.3390/ijms19072041
Received: 12 June 2018 / Revised: 9 July 2018 / Accepted: 10 July 2018 / Published: 13 July 2018
Cited by 1 | PDF Full-text (751 KB) | HTML Full-text | XML Full-text
Abstract
Many insights into human disease have been built on experimental results in Drosophila, and research in fruit flies is often justified on the basis of its predictive value for questions related to human health. Additionally, there is now a growing recognition of [...] Read more.
Many insights into human disease have been built on experimental results in Drosophila, and research in fruit flies is often justified on the basis of its predictive value for questions related to human health. Additionally, there is now a growing recognition of the value of Drosophila for the study of rare human genetic diseases, either as a means of validating the causative nature of a candidate genetic variant found in patients, or as a means of obtaining functional information about a novel disease-linked gene when there is little known about it. For these reasons, funders in the US, Europe, and Canada have launched targeted programs to link human geneticists working on discovering new rare disease loci with researchers who work on the counterpart genes in Drosophila and other model organisms. Several of these initiatives are described here, as are a number of output publications that validate this new approach. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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Open AccessReview
Impact of Drosophila Models in the Study and Treatment of Friedreich’s Ataxia
Int. J. Mol. Sci. 2018, 19(7), 1989; https://doi.org/10.3390/ijms19071989
Received: 28 May 2018 / Revised: 26 June 2018 / Accepted: 3 July 2018 / Published: 7 July 2018
Cited by 3 | PDF Full-text (2435 KB) | HTML Full-text | XML Full-text
Abstract
Drosophila melanogaster has been for over a century the model of choice of several neurobiologists to decipher the formation and development of the nervous system as well as to mirror the pathophysiological conditions of many human neurodegenerative diseases. The rare disease Friedreich’s ataxia [...] Read more.
Drosophila melanogaster has been for over a century the model of choice of several neurobiologists to decipher the formation and development of the nervous system as well as to mirror the pathophysiological conditions of many human neurodegenerative diseases. The rare disease Friedreich’s ataxia (FRDA) is not an exception. Since the isolation of the responsible gene more than two decades ago, the analysis of the fly orthologue has proven to be an excellent avenue to understand the development and progression of the disease, to unravel pivotal mechanisms underpinning the pathology and to identify genes and molecules that might well be either disease biomarkers or promising targets for therapeutic interventions. In this review, we aim to summarize the collection of findings provided by the Drosophila models but also to go one step beyond and propose the implications of these discoveries for the study and cure of this disorder. We will present the physiological, cellular and molecular phenotypes described in the fly, highlighting those that have given insight into the pathology and we will show how the ability of Drosophila to perform genetic and pharmacological screens has provided valuable information that is not easily within reach of other cellular or mammalian models. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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Open AccessReview
Obesity and Aging in the Drosophila Model
Int. J. Mol. Sci. 2018, 19(7), 1896; https://doi.org/10.3390/ijms19071896
Received: 19 May 2018 / Revised: 19 June 2018 / Accepted: 25 June 2018 / Published: 27 June 2018
Cited by 4 | PDF Full-text (1459 KB) | HTML Full-text | XML Full-text
Abstract
Being overweight increases the risk of many metabolic disorders, but how it affects lifespan is not completely clear. Not all obese people become ill, and the exact mechanism that turns excessive fat storage into a health-threatening state remains unknown. Drosophila melanogaster has served [...] Read more.
Being overweight increases the risk of many metabolic disorders, but how it affects lifespan is not completely clear. Not all obese people become ill, and the exact mechanism that turns excessive fat storage into a health-threatening state remains unknown. Drosophila melanogaster has served as an excellent model for many diseases, including obesity, diabetes, and hyperglycemia-associated disorders, such as cardiomyopathy or nephropathy. Here, we review the connections between fat storage and aging in different types of fly obesity. Whereas obesity induced by high-fat or high-sugar diet is associated with hyperglycemia, cardiomyopathy, and in some cases, shortening of lifespan, there are also examples in which obesity correlates with longevity. Transgenic lines with downregulations of the insulin/insulin-like growth factor (IIS) and target of rapamycin (TOR) signaling pathways, flies reared under dietary restriction, and even certain longevity selection lines are obese, yet long-lived. The mechanisms that underlie the differential lifespans in distinct types of obesity remain to be elucidated, but fat turnover, inflammatory pathways, and dysregulations of glucose metabolism may play key roles. Altogether, Drosophila is an excellent model to study the physiology of adiposity in both health and disease. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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Open AccessReview
Big Lessons from Tiny Flies: Drosophila melanogaster as a Model to Explore Dysfunction of Dopaminergic and Serotonergic Neurotransmitter Systems
Int. J. Mol. Sci. 2018, 19(6), 1788; https://doi.org/10.3390/ijms19061788
Received: 22 May 2018 / Revised: 11 June 2018 / Accepted: 13 June 2018 / Published: 16 June 2018
Cited by 4 | PDF Full-text (1093 KB) | HTML Full-text | XML Full-text
Abstract
The brain of Drosophila melanogaster is comprised of some 100,000 neurons, 127 and 80 of which are dopaminergic and serotonergic, respectively. Their activity regulates behavioral functions equivalent to those in mammals, e.g., motor activity, reward and aversion, memory formation, feeding, sexual appetite, etc. [...] Read more.
The brain of Drosophila melanogaster is comprised of some 100,000 neurons, 127 and 80 of which are dopaminergic and serotonergic, respectively. Their activity regulates behavioral functions equivalent to those in mammals, e.g., motor activity, reward and aversion, memory formation, feeding, sexual appetite, etc. Mammalian dopaminergic and serotonergic neurons are known to be heterogeneous. They differ in their projections and in their gene expression profile. A sophisticated genetic tool box is available, which allows for targeting virtually any gene with amazing precision in Drosophila melanogaster. Similarly, Drosophila genes can be replaced by their human orthologs including disease-associated alleles. Finally, genetic manipulation can be restricted to single fly neurons. This has allowed for addressing the role of individual neurons in circuits, which determine attraction and aversion, sleep and arousal, odor preference, etc. Flies harboring mutated human orthologs provide models which can be interrogated to understand the effect of the mutant protein on cell fate and neuronal connectivity. These models are also useful for proof-of-concept studies to examine the corrective action of therapeutic strategies. Finally, experiments in Drosophila can be readily scaled up to an extent, which allows for drug screening with reasonably high throughput. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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Open AccessReview
Molecular Genetics of Frontotemporal Dementia Elucidated by Drosophila Models—Defects in Endosomal–Lysosomal Pathway
Int. J. Mol. Sci. 2018, 19(6), 1714; https://doi.org/10.3390/ijms19061714
Received: 19 May 2018 / Revised: 6 June 2018 / Accepted: 7 June 2018 / Published: 9 June 2018
Cited by 2 | PDF Full-text (768 KB) | HTML Full-text | XML Full-text
Abstract
Frontotemporal dementia (FTD) is the second most common senile neurodegenerative disease. FTD is a heterogeneous disease that can be classified into several subtypes. A mutation in CHMP2B locus (CHMP2Bintron5), which encodes a component of endosomal sorting complex required for transport-III [...] Read more.
Frontotemporal dementia (FTD) is the second most common senile neurodegenerative disease. FTD is a heterogeneous disease that can be classified into several subtypes. A mutation in CHMP2B locus (CHMP2Bintron5), which encodes a component of endosomal sorting complex required for transport-III (ESCRT-III), is associated with a rare hereditary subtype of FTD linked to chromosome 3 (FTD-3). ESCRT is involved in critical cellular processes such as multivesicular body (MVB) formation during endosomal–lysosomal pathway and autophagy. ESCRT mutants causes diverse physiological defects primarily due to accumulation of endosomes and defective MVBs resulting in misregulation of signaling pathways. Charged multivesicular body protein 2B (CHMP2B) is important for neuronal physiology which especially rely on precise regulation of protein homeostasis due to their post-mitotic status. Drosophila has proven to be an excellent model for charaterization of mechanistic underpinning of neurodegenerative disorders including FTD. In this review, current understanding of various FTD-related mutations is discussed with a focus on Drosophila models of CHMP2Bintron5-associated FTD. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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