Fly model with high uric acid levels established for study of this key risk factor for multiple diseases

Lang S, Hilsabeck TA, Wilson KA, Sharma A, Bose N, Brackman DJ, Beck JN, Chen L, Watson MA, Killilea DW, Ho S, Kahn A, Giacomini K, Stoller ML, Chi T, Kapahi P. A conserved role of the insulin-like signaling pathway in diet-dependent uric acid pathologies in Drosophila melanogaster. PLoS Genet. 2019 Aug 15;15(8):e1008318. PubMed PMID: 31415568; PubMed Central PMCID: PMC6695094.

From the abstract: "Elevated uric acid (UA) is a key risk factor for many disorders, including metabolic syndrome, gout and kidney stones. ... In humans, elevated UA levels resulted from the loss of the of the urate oxidase (Uro) gene ... we established a Drosophila melanogaster model with reduced expression of the orthologous Uro gene to study the pathogenesis arising from elevated UA. Reduced Uro expression in Drosophila resulted in elevated UA levels, accumulation of concretions in the excretory system, and shortening of lifespan ..."

Drosophila as model for studying genotype influence on response to high sugar consumption

Branch A, Zhang Y, Shen P. Genetic and Neurobiological Analyses of the Noradrenergic-like System in Vulnerability to Sugar Overconsumption Using a Drosophila Model. Sci Rep. 2017 Dec 15;7(1):17642. PubMed PMID: 29247240; PubMed Central PMCID: PMC5732301.

From the abstract: "Regular overconsumption of sugar is associated with obesity and type-2 diabetes, but how genetic factors contribute to variable sugar preferences and intake levels remains mostly unclear. Here we provide evidence for the usefulness of a Drosophila larva model to investigate genetic influence on vulnerability to sugar overconsumption. ..."

Methods report -- Drosophila and the study of Fragile X Syndrome

Kong HE, Lim J, Jin P. Application of Drosophila Model Toward Understanding the Molecular Basis of Fragile X Syndrome. Methods Mol Biol. 2019;1942:141-153. PubMed PMID: 30900182.

Flies used in international effort to identify mutations associated with a recessive form of ataxia or spastic paraplegia

Seong E, Insolera R, Dulovic M, Kamsteeg EJ, Trinh J, Brüggemann N, Sandford E, Li S, Ozel AB, Li JZ, Jewett T, Kievit AJA, Münchau A, Shakkottai V, Klein C, Collins CA, Lohmann K, van de Warrenburg BP, Burmeister M. Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects. Ann Neurol. 2018 Jun;83(6):1075-1088. PubMed PMID: 29604224; PubMed Central PMCID: PMC6105379.

From the abstract: "To identify novel causes of recessive ataxias, including spinocerebellar ataxia with saccadic intrusions, spastic ataxias, and spastic paraplegia. ... In an international collaboration, we independently performed exome sequencing in 7 families with recessive ataxia and/or spastic paraplegia. To evaluate the role of VPS13D mutations, we evaluated a Drosophila knockout model and investigated mitochondrial function in patient-derived fibroblast cultures. ... Our study demonstrates that compound heterozygous mutations in VPS13D cause movement disorders along the ataxia-spasticity spectrum, making VPS13D the fourth VPS13 paralog involved in neurological disorders."

See also:

Fogel BL. Collaborative science unites researchers and a novel spastic ataxia gene. Ann Neurol. 2018 Jun;83(6):1072-1074. PubMed PMID: 29908061; PubMed Central PMCID: PMC6105536.

Several new studies and a review related to Alzheimer's disease and other neurodegenerative and age-related disorders

Goldberg J, Currais A, Prior M, Fischer W, Chiruta C, Ratliff E, Daugherty D, Dargusch R, Finley K, Esparza-Moltó PB, Cuezva JM, Maher P, Petrascheck M, Schubert D. The mitochondrial ATP synthase is a shared drug target for aging and dementia. Aging Cell. 2018 Apr;17(2). PubMed PMID: 29316249; PubMed Central PMCID: PMC5847861.

Ojelade SA, Lee TV, Giagtzoglou N, Yu L, Ugur B, Li Y, Duraine L, Zuo Z, Petyuk V, De Jager PL, Bennett DA, Arenkiel BR, Bellen HJ, Shulman JM. cindr, the Drosophila Homolog of the CD2AP Alzheimer's Disease Risk Gene, Is Required for Synaptic Transmission and Proteostasis. Cell Rep. 2019 Aug 13;28(7):1799-1813.e5. PubMed PMID: 31412248; PubMed Central PMCID:
PMC6703184.

Yang L, Cao Y, Zhao J, Fang Y, Liu N, Zhang Y. Multidimensional proteomics identifies declines in protein homeostasis and mitochondria as early signals for normal aging and age-associated disease in Drosophila. Mol Cell Proteomics. 2019 Aug 21. pii: mcp.RA119.001621. PubMed PMID: 31434710.

Park SY, Seo J, Chun YS. Targeted Downregulation of kdm4a Ameliorates Tau-engendered Defects in Drosophila melanogaster. J Korean Med Sci. 2019 Aug 26;34(33):e225. doi: 10.3346/jkms.2019.34.e225. PubMed PMID: 31436053; PubMed Central PMCID: PMC6706347.

Sun M, Zhao Y, Han M, Zhang B, Zhang X, Zhang Q, Lim NK, Wang WA, Huang FD. TTC7 and Hyccin Regulate Neuronal Aβ42 Accumulation and its Associated Neural Deficits in Aβ42-Expressing Drosophila. J Alzheimers Dis. 2018;65(3):1001-1010. PubMed PMID: 30103315.

Passarella D, Goedert M. Beta-sheet assembly of Tau and neurodegeneration in Drosophila melanogaster. Neurobiol Aging. 2018 Dec;72:98-105. PubMed PMID: 30240946;
PubMed Central PMCID: PMC6327151.

Gusareva ES, Twizere JC, Sleegers K, Dourlen P, Abisambra JF, Meier S, Cloyd R, Weiss B, Dermaut B, Bessonov K, et al. Male-specific epistasis between WWC1 and TLN2 genes is associated with Alzheimer's disease. Neurobiol Aging. 2018 Dec;72:188.e3-188.e12. PubMed PMID: 30201328.

Jantrapirom S, Lo Piccolo L, Yamaguchi M. Non-Proteasomal UbL-UbA Family of Proteins in Neurodegeneration. Int J Mol Sci. 2019 Apr 17;20(8). pii: E1893. Review. PubMed PMID: 30999567; PubMed Central PMCID: PMC6514573.

Bajracharya R, Youngson NA, Ballard JWO. Dietary Macronutrient Management to Treat Mitochondrial Dysfunction in Parkinson's Disease. Int J Mol Sci. 2019 Apr 15;20(8). pii: E1850. doi: 10.3390/ijms20081850. Review. PubMed PMID: 30991634; PubMed Central PMCID: PMC6514887.

Drosophila used in study of receptor for entry into cells of disease-causing viruses

Zhang R, Earnest JT, Kim AS, Winkler ES, Desai P, Adams LJ, Hu G, Bullock C, Gold B, Cherry S, Diamond MS. Expression of the Mxra8 Receptor Promotes Alphavirus Infection and Pathogenesis in Mice and Drosophila. Cell Rep. 2019 Sep 3;28(10):2647-2658.e5. doi: 10.1016/j.celrep.2019.07.105. PubMed PMID: 31484075; PubMed Central PMCID: PMC6745702.

From the abstract: "Mxra8 is a recently described receptor for multiple alphaviruses, including Chikungunya (CHIKV), Mayaro (MAYV), Ross River (RRV), and O'nyong nyong (ONNV) viruses. ... Ectopic Mxra8 expression is sufficient to enhance CHIKV infection and lethality in transgenic flies. ... targeting this protein may mitigate disease in humans."

Drosophila protein crystal structure proves useful in study of PURA syndrome

Reijnders MRF, Janowski R, Alvi M, Self JE, van Essen TJ, Vreeburg M, Rouhl RPW, Stevens SJC, Stegmann APA, Schieving J, et al. PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature. J Med Genet. 2018 Feb;55(2):104-113. PubMed PMID: 29097605; PubMed Central PMCID: PMC5800346.

From the abstract: "De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. ... We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. ... "

Review highlights Drosophila research contribution to understanding mTOR and tuberous sclerosis

Franz DN, Krueger DA. mTOR inhibitor therapy as a disease modifying therapy for tuberous sclerosis complex. Am J Med Genet C Semin Med Genet. 2018 Sep;178(3):365-373. doi: 10.1002/ajmg.c.31655. Review. PubMed PMID: 30307123.

Abstract: "Between 1993 and 2003, through experiments involving Drosophila sp., cancer biologists identified the protein kinase known as the mammalian target of rapamycin, its pathway, and its relationship to the genes responsible for tuberous sclerosis. Thereafter, clinical research has resulted in regulatory approval of mTOR inhibitors for four distinct manifestations of the disease: giant cell astrocytoma, angiomyolipoma, lymphangioleiomyomatosis, and epilepsy. These developments are summarized and the practical use of mTOR inhibitors to improve the lives of patients with tuberous sclerosis reviewed."

Fly model of Alzheimers disease used in study of potential therapeutic treatment

Viswanathan GK, Shwartz D, Losev Y, Arad E, Shemesh C, Pichinuk E, Engel H, Raveh A, Jelinek R, Cooper I, Gosselet F, Gazit E, Segal D. Purpurin modulates Tau-derived VQIVYK fibrillization and ameliorates Alzheimer's disease-like symptoms in animal model. Cell Mol Life Sci. 2019 Sep 27. PubMed PMID: 31562564.

Abstract: "Neurofibrillary tangles of the Tau protein and plaques of the amyloid β peptide are hallmarks of Alzheimer's disease (AD), which is characterized by the conversion of monomeric proteins/peptides into misfolded β-sheet rich fibrils. Halting the fibrillation process and disrupting the existing aggregates are key challenges for AD drug development. Previously, we performed in vitro high-throughput screening for the identification of potent inhibitors of Tau aggregation using a proxy model, a highly aggregation-prone hexapeptide fragment 306VQIVYK311 (termed PHF6) derived from Tau. Here we have characterized a hit molecule from that screen as a modulator of Tau aggregation using in vitro, in silico, and in vivo techniques. This molecule, an anthraquinone derivative named Purpurin, inhibited ~ 50% of PHF6 fibrillization in vitro at equimolar concentration and disassembled pre-formed PHF6 fibrils. In silico studies showed that Purpurin interacted with key residues of PHF6, which are responsible for maintaining its β-sheets conformation. Isothermal titration calorimetry and surface plasmon resonance experiments with PHF6 and full-length Tau (FL-Tau), respectively, indicated that Purpurin interacted with PHF6 predominantly via hydrophobic contacts and displayed a dose-dependent complexation with FL-Tau. Purpurin was non-toxic when fed to Drosophila and it significantly ameliorated the AD-related neurotoxic symptoms of transgenic flies expressing WT-FL human Tau (hTau) plausibly by inhibiting Tau accumulation and reducing Tau phosphorylation. Purpurin also reduced hTau accumulation in cell culture overexpressing hTau. Importantly, Purpurin efficiently crossed an in vitro human blood-brain barrier model. Our findings suggest that Purpurin could be a potential lead molecule for AD therapeutics."

New fly study relevant to Alzheimers disease

Higham JP, Hidalgo S, Buhl E, Hodge JJL. Restoration of Olfactory Memory in Drosophila Overexpressing Human Alzheimer's Disease Associated Tau by Manipulation of L-Type Ca(2+) Channels. Front Cell Neurosci. 2019 Sep 10;13:409. PubMed PMID: 31551716; PubMed Central PMCID: PMC6746915.

Abstract: "The cellular underpinnings of memory deficits in Alzheimer's disease (AD) are poorly understood. We utilized the tractable neural circuits sub-serving memory in Drosophila to investigate the role of impaired Ca2+ handling in memory deficits caused by expression of human 0N4R isoform of tau which is associated with AD. Expression of tau in mushroom body neuropils, or a subset of mushroom body output neurons, led to impaired memory. By using the Ca2+ reporter GCaMP6f, we observed changes in Ca2+ signaling when tau was expressed in these neurons, an effect that could be blocked by the L-type Ca2+ channel antagonist nimodipine or reversed by RNAi knock-down of the L-type channel gene. The L-type Ca2+ channel itself is required for memory formation, however, RNAi knock-down of the L-type Ca2+ channel in neurons overexpressing human tau resulted in flies whose memory is restored to levels equivalent to wild-type. Expression data suggest that Drosophila L-type Ca2+ channel mRNA levels are increased upon tau expression in neurons, thus contributing to the effects observed on memory and intracellular Ca2+ homeostasis. Together, our Ca2+ imaging and memory experiments suggest that expression of the 0N4R isoform of human tau increases the number of L-type Ca2+ channels in the membrane resulting in changes in neuronal excitability that can be ameliorated by RNAi knockdown or pharmacological blockade of L-type Ca2+ channels. This highlights a role for L-type Ca2+ channels in tauopathy and their potential as a therapeutic target for AD."

Fly model of Werner syndrome

Cassidy D, Epiney D, Salameh C, Zhou LT, Salomon RN, Schirmer AE, McVey M, Bolterstein E. Evidence for premature aging in a Drosophila model of Werner syndrome. Exp Gerontol. 2019 Sep 10:110733. doi: 10.1016/j.exger.2019.110733. PMID: 31518666.

Abstract: "Werner syndrome (WS) is an autosomal recessive progeroid disease characterized by patients' early onset of aging, increased risk of cancer and other age-related pathologies. WS is caused by mutations in WRN, a RecQ helicase that has essential roles responding to DNA damage and preventing genomic instability. While human WRN has both an exonuclease and helicase domain, Drosophila WRNexo has high genetic and functional homology to only the exonuclease domain of WRN. Like WRN-deficient human cells, Drosophila WRNexo null mutants (WRNexoΔ) are sensitive to replication stress, demonstrating mechanistic similarities between these two models. Compared to age-matched wild-type controls, WRNexoΔ flies exhibit increased physiological signs of aging, such as shorter lifespans, higher tumor incidence, muscle degeneration, reduced climbing ability, altered behavior, and reduced locomotor activity. Interestingly, these effects are more pronounced in females suggesting sex-specific differences in the role of WRNexo in aging. This and future mechanistic studies will contribute to our knowledge in linking faulty DNA repair mechanisms with the process of aging."

Video protocols published -- on bioinformatics and experimental approaches to using flies to study human gene variants

Wang J, Liu Z, Bellen HJ, Yamamoto S. Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information. J Vis Exp. 2019 Aug 15;(150). doi: 10.3791/59542. PubMed PMID: 31475990.

From the abstract: "Through whole-exome/genome sequencing, human geneticists identify rare variants that segregate with disease phenotypes. To assess if a specific variant is pathogenic, one must query many databases ... MARRVEL (Model organism Aggregated Resources for Rare Variant ExpLoration) is a one-stop data collection tool for human genes and variants and their orthologous genes in seven model organisms including in mouse, rat, zebrafish, fruit fly, nematode worm, fission yeast, and budding yeast. In this Protocol, we provide an overview of what MARRVEL can be used for and discuss how different datasets can be used to assess whether a variant of unknown significance (VUS) in a known disease-causing gene or a variant in a gene of uncertain significance (GUS) may be pathogenic. ... MARRVEL is an easily accessible open access website designed for both clinical and basic researchers and serves as a starting point to design experiments for functional studies."

Harnish JM, Deal SL, Chao HT, Wangler MF, Yamamoto S. In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila. J Vis Exp. 2019 Aug 20;(150). doi: 10.3791/59658. PubMed PMID: 31498321.

From the abstract: "... In the Undiagnosed Diseases Network (UDN) and other rare disease research consortia, model organisms (MO) including Drosophila, C. elegans, zebrafish, and mice are actively used to assess the function of putative human disease-causing variants. This protocol describes a method for the functional assessment of rare human variants ... The workflow begins with gathering human and MO information from multiple public databases, using the MARRVEL web resource ... Next, genetic tools ... are generated to assess the functions of variants of interest in Drosophila. ... This protocol allows rapid, in vivo assessments of putative human disease-causing variants of genes with known and unknown functions."

Drosophila used to define a "priority list" of genes associated with albuminuria

Teumer A, et al. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. Nat Commun. 2019 Sep 11;10(1):4130. PMID: 31511532.

Abstract: "Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria."

Advanced Review on the use of Drosophila in drug screening

Su TT. Drug screening in Drosophila; why, when, and when not? Wiley Interdiscip Rev Dev Biol. 2019 May 5:e346. doi: 10.1002/wdev.346. PubMed PMID: 31056843.

Abstract: "The best global seller among oncology drugs in 2018 is lenalidomide, an analog of thalidomide. It took 53 years and a circuitous route from the discovery of thalidomide to approval of an analog for use in treatment of cancer. We understand now a lot more about the genetic and molecular basis of diseases than we did in 1953 when thalidomide was discovered. We have also no shortage of chemical libraries with hundreds of thousands of compounds, both synthetic and natural. What we need are better ways to search among these rich resources for compounds with the potential to do what we want them to do. This review summarizes examples from the literature that make Drosophila melanogaster a good model to screen for drugs, and discusses knowledge gaps and technical challenges that make Drosophila models not as widely used as they could or should be."

Whole-animal fly system facilitates study relevant to cancer metastasis

Mishra-Gorur K, Li D, Ma X, Yarman Y, Xue L, Xu T. Spz/Toll-6 signal guides organotropic metastasis in Drosophila. Dis Model Mech. 2019 Sep 2. pii: dmm.039727. doi: 10.1242/dmm.039727. PubMed PMID: 31477571.

Abstract: "Targeted cell migration plays important roles in developmental biology and disease processes including metastasis. Drosophila tumors exhibit traits characteristic of human cancers, providing a powerful model to study developmental and cancer biology. We now find that cells derived from Drosophila eye disc tumors also display organ specific metastasis to invade receptive organs but not wing disc. Toll receptors are known to affect innate immunity and tumor inflammatory microenvironment by modulating the NF-κB pathway. Our RNAi screen and genetic analyses show that Toll-6 is required for migration and invasion of the tumor cells. Further, receptive organs express Toll-ligands, Spz family molecules, and ectopic Spz expression renders wing disc receptive to metastasis. Finally, Toll-6 promotes metastasis by activating JNK signaling, a key regulator of cell migration. Hence, we report Toll-6 and Spätzle as a new pair of guidance molecules mediating organ-specific metastasis behavior and highlight a novel signaling mechanism for Toll family receptors."