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

https://www.biorxiv.org/content/early/2017/09/20/185355

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."

Wednesday, January 3, 2018

Drosophila model points to involvement of potassium channel in aging hearts

Klassen MP, Peters CJ, Zhou S, Williams HH, Jan LY, Jan YN. Age-dependent diastolic heart failure in an in vivo Drosophila model. Elife. 2017 Mar 22;6. pii: e20851. PMID: 28328397; PMCID: PMC5362267.

The abstract: "While the signals and complexes that coordinate the heartbeat are well established, how the heart maintains its electromechanical rhythm over a lifetime remains an open question with significant implications to human health. Reasoning that this homeostatic challenge confronts all pulsatile organs, we developed a high resolution imaging and analysis toolset for measuring cardiac function in intact, unanesthetized Drosophila melanogaster. We demonstrate that, as in humans, normal aging primarily manifests as defects in relaxation (diastole) while preserving contractile performance. Using this approach, we discovered that a pair of two-pore potassium channel (K2P) subunits, largely dispensable early in life, are necessary for terminating contraction (systole) in aged animals, where their loss culminates in fibrillatory cardiac arrest. As the pumping function of its heart is acutely dispensable for survival, Drosophila represents a uniquely accessible model for understanding the signaling networks maintaining cardiac performance during normal aging."

Drosophila gut as model for uncovering mechanisms of antimicrobial activity

Liu X, Hodgson JJ, Buchon N. Drosophila as a model for homeostatic,antibacterial, and antiviral mechanisms in the gut. PLoS Pathog. 2017 May 4;13(5):e1006277. PMID: 28472194; PMCID: PMC5417715.

This review article includes an illustrated comparison of fly and mammalian guts and their interactions with microbes such as bacteria and viruses.