The interplay between obesity and cancer: a fly view

Accumulating epidemiological evidence indicates a strong clinical association between obesity and an increased risk of cancer. The global pandemic of obesity indicates a public health trend towards a substantial increase in cancer incidence and mortality. However, the mechanisms that link obesity to cancer remain incompletely understood. The fruit fly Drosophila melanogaster has been increasingly used to model an expanding spectrum of human diseases. Fly models provide a genetically simpler system that is ideal for use as a first step towards dissecting disease interactions. Recently, the combining of fly models of diet-induced obesity with models of cancer has provided a novel model system in which to study the biological mechanisms that underlie the connections between obesity and cancer. In this Review, I summarize recent advances, made using Drosophila, in our understanding of the interplay between diet, obesity, insulin resistance and cancer. I also discuss how the biological mechanisms and therapeutic targets that have been identified in fly studies could be utilized to develop preventative interventions and treatment strategies for obesityassociated cancers

A fruitful fly forward : the role of the fly in drug discovery for neurodegeneration

AD, Alzheimer’s disease; APP, amyloid precursor protein; BBB, blood brain barrier; GFP, green fluorescent protein; HTS, high-throughput screening; HD, Huntington’s disease; LB, Lewy bodies; PD, Parkinson’s disease; PolyQ, Polyglutamine; RNAi, RNA interference; SNCA, α-synuclein gene; UAS, Upstream Activating Sequence.peer-reviewe

Microguards and micromessengers of the genome

The regulation of gene expression is of fundamental importance to maintain organismal function and integrity and requires a multifaceted and highly ordered sequence of events. The cyclic nature of gene expression is known as ‘transcription dynamics’. Disruption or perturbation of these dynamics can result in significant fitness costs arising from genome instability, accelerated ageing and disease. We review recent research that supports the idea that an important new role for small RNAs, particularly microRNAs (miRNAs), is in protecting the genome against short-term transcriptional fluctuations, in a process we term ‘microguarding’. An additional emerging role for miRNAs is as ‘micromessengers’—through alteration of gene expression in target cells to which they are trafficked within microvesicles. We describe the scant but emerging evidence that miRNAs can be moved between different cells, individuals and even species, to exert biologically significant responses. With these two new roles, miRNAs have the potential to protect against deleterious gene expression variation from perturbation and to themselves perturb the expression of genes in target cells. These interactions between cells will frequently be subject to conflicts of interest when they occur between unrelated cells that lack a coincidence of fitness interests. Hence, there is the potential for miRNAs to represent both a means to resolve conflicts of interest, as well as instigate them. We conclude by exploring this conflict hypothesis, by describing some of the initial evidence consistent with it and proposing new ideas for future research into this exciting topic

Investigation into the effect of LRRK2-Rab10 protein interactions on the Proboscis Extension Response of the fruit fly Drosophila melanogaster

Parkinson’s Disease (PD) is a debilitating disease which affects 1% of the population worldwide and is characterised by stiffness, tremor and bradykinesia. PD is a complex disease with many suspected genetic and environmental causes, and it is critical to understand all the pathways involved in disease progression to develop effective therapies for PD, which currently has no cure. A kinasecoding gene, LRRK2 has emerged as a focal point for much PD research, particularly PD-associated SNP LRRK2-G2019S, which leads to LRRK2 overactivity. Rab proteins, a series of small GTPases, have been identified among the proteins phosphorylated by LRRK2. These interactions may be modelled in the fruit fly Drosophila melanogaster. Using optogenetics in the fly, this project investigates the relationship between the LRRK2-G2019S and Rab10 interaction, and the speed and degree of tremor of Proboscis Extension Response (PER) by triggering a PER in fly lines of different genotypes. Significant bradykinesia in Rab10 null flies which was not recreated in flies with dopaminergic neuron Rab10RNAi suggests that the bradykinesia PER phenotype is caused by off-target effect of Rab10-KO in another tissue of the fly than the dopaminergic neurons. Over-expression of Rab10 in dopaminergic neurons of flies also expressing LRRK2-G2019S produced resting tremor and inability to fully extend the proboscis

Signalogs: Orthology-Based Identification of Novel Signaling Pathway Components in Three Metazoans

BACKGROUND: Uncovering novel components of signal transduction pathways and their interactions within species is a central task in current biological research. Orthology alignment and functional genomics approaches allow the effective identification of signaling proteins by cross-species data integration. Recently, functional annotation of orthologs was transferred across organisms to predict novel roles for proteins. Despite the wide use of these methods, annotation of complete signaling pathways has not yet been transferred systematically between species. PRINCIPAL FINDINGS: Here we introduce the concept of 'signalog' to describe potential novel signaling function of a protein on the basis of the known signaling role(s) of its ortholog(s). To identify signalogs on genomic scale, we systematically transferred signaling pathway annotations among three animal species, the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and humans. Using orthology data from InParanoid and signaling pathway information from the SignaLink database, we predict 88 worm, 92 fly, and 73 human novel signaling components. Furthermore, we developed an on-line tool and an interactive orthology network viewer to allow users to predict and visualize components of orthologous pathways. We verified the novelty of the predicted signalogs by literature search and comparison to known pathway annotations. In C. elegans, 6 out of the predicted novel Notch pathway members were validated experimentally. Our approach predicts signaling roles for 19 human orthodisease proteins and 5 known drug targets, and suggests 14 novel drug target candidates. CONCLUSIONS: Orthology-based pathway membership prediction between species enables the identification of novel signaling pathway components that we referred to as signalogs. Signalogs can be used to build a comprehensive signaling network in a given species. Such networks may increase the biomedical utilization of C. elegans and D. melanogaster. In humans, signalogs may identify novel drug targets and new signaling mechanisms for approved drugs

Response of the mosquito protein interaction network to dengue infection

<p>Abstract</p> <p>Background</p> <p>Two fifths of the world's population is at risk from dengue. The absence of effective drugs and vaccines leaves vector control as the primary intervention tool. Understanding dengue virus (DENV) host interactions is essential for the development of novel control strategies. The availability of genome sequences for both human and mosquito host greatly facilitates genome-wide studies of DENV-host interactions.</p> <p>Results</p> <p>We developed the first draft of the mosquito protein interaction network using a computational approach. The weighted network includes 4,214 <it>Aedes aegypti </it>proteins with 10,209 interactions, among which 3,500 proteins are connected into an interconnected scale-free network. We demonstrated the application of this network for the further annotation of mosquito proteins and dissection of pathway crosstalk. Using three datasets based on physical interaction assays, genome-wide RNA interference (RNAi) screens and microarray assays, we identified 714 putative DENV-associated mosquito proteins. An integrated analysis of these proteins in the network highlighted four regions consisting of highly interconnected proteins with closely related functions in each of replication/transcription/translation (RTT), immunity, transport and metabolism. Putative DENV-associated proteins were further selected for validation by RNAi-mediated gene silencing, and dengue viral titer in mosquito midguts was significantly reduced for five out of ten (50.0%) randomly selected genes.</p> <p>Conclusions</p> <p>Our results indicate the presence of common host requirements for DENV in mosquitoes and humans. We discuss the significance of our findings for pharmacological intervention and genetic modification of mosquitoes for blocking dengue transmission.</p

NEUROTOXICOLOGICAL EFFECTS OF CHLORPYRIFOS AND DELTAMETHRIN ON DOPAMINE AND ACETYLCHOLINE SYSTEMS IN DROSOPHILA MELANOGASTER

Emerging evidence suggests a positive association between pesticide exposure and sporadic Parkinson\u27s disease (PD) development. The molecular mechanisms of PD and other neurodegenerative diseases are not fully understood, which hinders the development of therapeutic agents to cure or prevent the development of such diseases. Drosophila has been widely used as a model organism to study various neurodegenerative diseases and to screen for promising therapeutic agents. The aims of this study were: (i) investigating the toxic effect of 24 hours exposure to chlorpyrifos (CPF) and deltamethrin (DLM) on the dopaminergic system and AChE activity in Drosophila melanogaster; (ii) comparing different methodologies to test negative geotaxis behavior in D. melanogaster; and (iii) investigating the combined neuroprotective effects of ferulic acid (FA), and Thymoquinone (TQ) natural compounds on DLM induced neurotoxicity. Adult male wild-type flies were exposed to either CPF, DLM, for 24 hours, or concomitantly exposed to DLM and individual neuroprotective agents, or their mix for 72 hours in 10% sucrose on a cotton swab. CPF/DLM-treated flies climbed shorter distances in the negative geotaxis assay as well as had a higher incidence of mortality when compared to the control group. Evidently, CPF/DLM exposure caused a disturbance in the expression of DA-related genes. The DLM exposure for 72 hours caused a higher incidence of mortality and severe locomotor defects. Co-treatment with neuroprotective agents offered protection against these toxic effects of DLM after 72 hours. DLM caused significant inhibition of AChE which was ameliorated with the concomitant exposure with FA. Our results suggest that FA and TQ were effective in reducing the toxicity induced by DLM in D. melanogaster as well as confirm the utility of this model to investigate potential therapeutic strategies on movement disorders, including PD. The present study indicates that a single molecule can interact and affect multiple systems that are not related to their main mechanism of action. Data gathered in the present study may be important for the assessment of the safety of insecticides that humans are at risk of daily exposure to them. Moreover, this study presents a potential natural compound that can ameliorate and protect against the neurotoxicity that is caused by these insecticides

Behavioral phenotype of Vang6 mutant Drosophila melanogaster pertaining to the Olfactory System

There are many proteins that aid in the development of the olfactory system, specifically Wnt pathway and planar cell polarity (PCP) pathway proteins. It has been shown that Vang6 mutant flies have distinct olfactory abnormalities, as do Wnt5 mutant flies. In addition, Drosophila melanogaster (Drosophila) Wnt5 mutants have an improper olfactory response compared to wildtype Drosophila. After using a T-maze to explore the behavioral tendencies of Vang6 mutant Drosophila and wildtype WT1118 flies, it was shown that there is no significance between wildtype and Vang6 mutant Drosophila selecting air (control component) or Carbon Dioxide (CO2) (test component)