Friday, March 16, 2018

Fly models of kidney disease: Drosophila nephrocytes "represent a novel and easy-to-use alternative in experimental nephrology"

Helmstädter M, Simons M. Using Drosophila nephrocytes in genetic kidney disease. Cell Tissue Res. 2017 Jul;369(1):119-126. PMID: 28401308.

The abstract: "Renal diseases are a growing health burden, and innovative models to study their pathomechanisms are greatly needed. Here, we highlight how the fruit fly Drosophila melanogaster can be used to model kidney diseases. We focus on the nephrocyte that has recently been shown to exhibit podocyte and proximal tubular cell features. These cells can be manipulated with precise genetic tools to dissect filtration and reabsorption mechanisms. Thus, they represent a novel and easy-to-use alternative in experimental nephrology."

Wednesday, February 28, 2018

Fly studies contribute to identification pathogenic variant in individuals with lethargy, acidosis, aciduria, hyperammonemia

Oláhová M, Yoon WH, Thompson K, Jangam S, Fernandez L, Davidson JM, Kyle JE, Grove ME, Fisk DG, Kohler JN, Holmes M, Dries AM, Huang Y, Zhao C, Contrepois K, Zappala Z, Frésard L, Waggott D, Zink EM, Kim YM, Heyman HM, Stratton KG, Webb-Robertson BM; Undiagnosed Diseases Network, Snyder M, Merker JD, Montgomery SB, Fisher PG, Feichtinger RG, Mayr JA, Hall J, Barbosa IA, Simpson MA, Deshpande C, Waters KM, Koeller DM, Metz TO, Morris AA, Schelley S, Cowan T, Friederich MW, McFarland R, Van Hove JLK, Enns GM, Yamamoto S, Ashley EA, Wangler MF, Taylor RW, Bellen HJ, Bernstein JA, Wheeler MT. Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder. Am J Hum Genet. 2018 Feb 16. pii: S0002-9297(18)30042-9. PMID: 29478781.

From the abstract: "... Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. ... Knockdown of Drosophila ATPsynδ, the ATP5F1D homolog, in developing eyes and brains caused a near complete loss of the fly head, a phenotype that was fully rescued by wild-type human ATP5F1D. In contrast, expression of the ATP5F1D c.245C>T and c.317T>G variants rescued the head-size phenotype but recapitulated the eye and antennae defects seen in other genetic models of mitochondrial oxidative phosphorylation deficiency. Our data establish c.245C>T (p.Pro82Leu) and c.317T>G (p.Val106Gly) in ATP5F1D as pathogenic variants leading to a Mendelian mitochondrial disease featuring episodic metabolic decompensation."

Friday, February 16, 2018

Review discusses re-think of pathogenesis underlying Ehlers-Danlos syndrome based on results of fly study

Xiao G, Zhou B. ZIP13: A Study of Drosophila Offers an Alternative Explanation for the Corresponding Human Disease. Front Genet. 2018 Jan 31;8:234. PMID: 29445391; PubMed Central PMCID: PMC5797780.

The abstract: "The fruit fly Drosophila melanogaster has become an important model organism to investigate metal homeostasis and human diseases. Previously we identified dZIP13 (CG7816), a member of the ZIP transporter family (SLC39A) and presumably a zinc importer, is in fact physiologically primarily responsible to move iron from the cytosol into the secretory compartments in the fly. This review will discuss the implication of this finding for the etiology of Spondylocheirodysplasia-Ehlers-Danlos Syndrome (SCD-EDS), a human disease defective in ZIP13. We propose an entirely different model in that lack of iron in the secretory compartment may underlie SCD-EDS. Altogether three different working models are discussed, supported by relevant findings made in different studies, with uncertainties, and questions remained to be solved. We speculate that the distinct ZIP13 sequence features, different from those of all other ZIP family members, may confer it special transport properties."

Tuesday, February 6, 2018

Drosophila experiments help inform study of Menkes disease

Zlatic SA, Vrailas-Mortimer A, Gokhale A, Carey LJ, Scott E, Burch R, McCall MM, Rudin-Rush S, Davis JB, Hartwig C, Werner E, Li L, Petris M, Faundez V. Rare Disease Mechanisms Identified by Genealogical Proteomics of Copper Homeostasis Mutant Pedigrees. Cell Syst. 2018 Jan 30. pii: S2405-4712(18)30008-5. PMID: 29397366.

From the abstract: "Rare neurological diseases shed light onto universal neurobiological processes. However, molecular mechanisms connecting genetic defects to their disease phenotypes are elusive. Here, we obtain mechanistic information by comparing proteomes of cells from individuals with rare disorders with proteomes from their disease-free consanguineous relatives. ... We found connections between copper dyshomeostasis and the UCHL1/PARK5 pathway of Parkinson disease, which we validated with mitochondrial respiration and Drosophila genetics assays. We propose that our genealogical "omics" strategy can be broadly applied to identify mechanisms linking a genomic locus to its phenotypes."

Saturday, January 27, 2018

Preprint describes contribution of Drosophila double-knockdown assay to understanding 16p11.2 deletion syndrome

Pervasive epistasis in cell proliferation pathways modulates neurodevelopmental defects of autism-associated 16p11.2 deletion

Janani Iyer, Mayanglambam Dhruba Singh, Matthew Jensen, Payal Patel, Lucilla Pizzo, Emily Huber, Haley Koerselman, Alexis T. Weiner, Paola Lepanto, Komal Vadodaria, Alexis Kubina, Qingyu Wang, Abigail Talbert, Sneha Yennawar, Jose Badano, J. Robert Manak, Melissa M. Rolls, Arjun Krishnan, Santhosh Girirajan

From the abstract: "We used RNA interference in Drosophila melanogaster to evaluate the phenotype, function, and interactions of conserved 16p11.2 homologs ... Leveraging the Drosophila eye for studying gene interactions, we performed 561 pairwise knockdowns of gene expression, and identified 24 interactions between 16p11.2 homologs ... and 62 interactions with other neurodevelopmental genes ... Overall, these results point towards a new model for pathogenicity of rare CNVs, where CNV genes interact with each other in conserved pathways to modulate expression of the neurodevelopmental phenotype."

Tuesday, January 23, 2018

Methods report--using the fly eye to study Tau toxicity

Dourlen P. Identification of Tau Toxicity Modifiers in the Drosophila Eye. Methods Mol Biol. 2017;1523:375-389 PMID: 27975266.

The abstract: "Drosophila is a powerful model to study human diseases thanks to its genetic tools and ease of screening. Human genes can be expressed in targeted organs and their toxicity assessed on easily scorable external phenotypes that can be used as readout to perform genetic screen of toxicity modifiers. In this chapter, I describe how to express human Tau protein in the Drosophila eye, assess protein expression by western blot, assess Tau toxicity by quantifying the size of the Tau-induced rough eye, and perform a genetic screen of modifiers of Tau toxicity in the Drosophila eye."

Drosophila contributes to platform for identification of "tumor calibrated inhibitors"

Sonoshita M, Scopton AP, Ung PMU, Murray MA, Silber L, Maldonado AY, Real A, Schlessinger A, Cagan RL, Dar AC. A whole-animal platform to advance a clinical kinase inhibitor into new disease space. Nat Chem Biol. 2018 Jan 22. PMID: 29355849.

From the abstract: "Synthetic tailoring of approved drugs for new indications is often difficult ... Here, we report a multidisciplinary approach for accessing novel target and chemical space starting from an FDA-approved kinase inhibitor. By combining chemical and genetic modifier screening with computational modeling, we identify distinct kinases that strongly enhance ('pro-targets') or limit ('anti-targets') whole-animal activity of the clinical kinase inhibitor sorafenib in a Drosophila medullary thyroid carcinoma (MTC) model. ... Through progressive synthetic refinement, we report a new class of 'tumor calibrated inhibitors' with unique polypharmacology and strongly improved therapeutic index in fly and human MTC xenograft models. This platform provides a rational approach to creating new high-efficacy and low-toxicity drugs."