Tuesday, January 24, 2017

Results of a study in Drosophila suggest the possible relevance of neuronal aneuploidy to Tau-associated neurodegeneration

Malmanche N, Dourlen P, Gistelinck M, Demiautte F, Link N, Dupont C, Vanden Broeck L, Werkmeister E, Amouyel P, Bongiovanni A, Bauderlique H, Moechars D, Royou A, Bellen HJ, Lafont F, Callaerts P, Lambert JC, Dermaut B. Developmental Expression of 4-Repeat-Tau Induces Neuronal Aneuploidy in Drosophila Tauopathy Models. Sci Rep. 2017 Jan 23;7:40764. PMID: 28112163.

From the abstract: "Tau-mediated neurodegeneration in Alzheimer's disease and tauopathies is generally assumed to start in a normally developed brain. However, several lines of evidence suggest that impaired Tau isoform expression during development could affect mitosis and ploidy in post-mitotic differentiated tissue. ... Here, we used genetic and cellular tools to study the link between 3R and 4R-Tau isoform expression, mitotic progression in neuronal progenitors and post-mitotic neuronal survival. Our results illustrated that the severity of Tau-induced adult phenotypes depends on 4R-Tau isoform expression during development. ... we found a high level of aneuploidy in post-mitotic differentiated tissue. ... our results suggested that neurodegeneration could be in part linked to neuronal aneuploidy caused by 4R-Tau expression during brain development."

Monday, January 23, 2017

Using flies to functionally validate candidate heart disease-related genes

Zhu JY, Fu Y, Nettleton M, Richman A, Han Z. High throughput in vivo functional validation of candidate congenital heart disease genes in Drosophila. Elife. 2017 Jan 13;6. pii: e22617. PMID: 28084990.

From the abstract: "... We developed a Drosophila-based functional system to screen candidate disease genes identified from Congenital Heart Disease (CHD) patients. 134 genes were tested in the Drosophila heart using RNAi-based gene silencing. Quantitative analyses of multiple cardiac phenotypes demonstrated essential structural, functional, and developmental roles for more than 70 genes ... We also demonstrated the use of Drosophila to evaluate cardiac phenotypes resulting from specific, patient-derived alleles of candidate disease genes. ... This approach has the potential to facilitate development of precision medicine approaches for CHD and other diseases associated with genetic factors."

Review of drug discovery using model organisms including Drosophila

Strange K. Drug Discovery in Fish, Flies, and Worms. ILAR J. 2016 Dec;57(2):133-143. PMID: 28053067.

From the abstract: "Nonmammalian model organisms ... provide numerous experimental advantages for drug discovery including genetic and molecular tractability, amenability to high-throughput screening methods and reduced experimental costs and increased experimental throughput compared to traditional mammalian models. ... This review will provide an overview of C. elegans, Drosophila, and zebrafish biology and husbandry and will discuss how these models are being used for phenotype-based drug screening and for identification of drug targets and mechanisms of action. ..."

Wednesday, January 11, 2017

Modified fly cultured cells as a biotherapeutic? Study suggests this could one day be an effective approach

Roy DG, Power AT, Bourgeois-Daigneault MC, Falls T, Ferreira L, Stern A, Tanese de Souza C, McCart JA, Stojdl DF, Lichty BD, Atkins H, Auer RC, Bell JC, Le Boeuf F. Programmable insect cell carriers for systemic delivery of integrated cancer biotherapy. J Control Release. 2015 Dec 28;220(Pt A):210-21. PMID: 26482080.

From the abstract: "Due to cancer's genetic complexity, significant advances in the treatment of metastatic disease will require sophisticated, multi-pronged therapeutic approaches. Here we demonstrate the utility of a Drosophila melanogaster cell platform for the production and in vivo delivery of multi-gene biotherapeutic systems. We show that cultured Drosophila S2 cell carriers can stably propagate oncolytic viral therapeutics that are highly cytotoxic for mammalian cancer cells without adverse effects on insect cell viability or gene expression. Drosophila cell carriers administered systemically to immunocompetent animals trafficked to tumors to deliver multiple biotherapeutics with little apparent off-target tissue homing or toxicity, resulting in a therapeutic effect. ..."

Monday, January 9, 2017

Journal issue focuses on fly models of disease

A special issue of Current Topics in Developmental Biology (vol. 121, January 2017) focuses on fly models of human diseases. Check out the journal issue titles to see what specific diseases and disorders are discussed in these expert-level review articles.

Wednesday, December 28, 2016

Results from Drosophila contribute to study of the neurodevelopmental disorder Vici syndrome

Byrne S, Jansen L, U-King-Im JM, Siddiqui A, Lidov HG, Bodi I, Smith L, Mein R, Cullup T, Dionisi-Vici C, Al-Gazali L, Al-Owain M, Bruwer Z, Al Thihli K, El-Garhy R, Flanigan KM, Manickam K, Zmuda E, Banks W, Gershoni-Baruch R, Mandel H, Dagan E, Raas-Rothschild A, Barash H, Filloux F, Creel D, Harris M, Hamosh A, Kölker S, Ebrahimi-Fakhari D, Hoffmann GF, Manchester D, Boyer PJ, Manzur AY, Lourenco CM, Pilz DT, Kamath A, Prabhakar P, Rao VK, Rogers RC, Ryan MM, Brown NJ, McLean CA, Said E, Schara U, Stein A, Sewry C, Travan L, Wijburg FA, Zenker M, Mohammed S, Fanto M, Gautel M, Jungbluth H. EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy. Brain. 2016 Mar;139(Pt 3):765-81. doi: 10.1093/brain/awv393. PubMed PMID: 26917586; PubMed Central PMCID: PMC4766378.

From the abstract: "Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. ... Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease."

Results of genetic and human transgene analyses in Drosophila contributes to study of XX gonadal dysgenesis

Weinberg-Shukron A, Renbaum P, Kalifa R, Zeligson S, Ben-Neriah Z, Dreifuss A, Abu-Rayyan A, Maatuk N, Fardian N, Rekler D, Kanaan M, Samson AO, Levy-Lahad E, Gerlitz O, Zangen D. A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis. J Clin Invest. 2015 Nov 2;125(11):4295-304. doi: 10.1172/JCI83553. PubMed PMID: 26485283; PubMed Central PMCID: PMC4639971.

From the abstract: "... XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder that is characterized by underdeveloped, dysfunctional ovaries ... Here, we report an extended consanguineous family .. in which 4 females exhibited XX-GD. ... we identified a recessive missense mutation in nucleoporin-107 (NUP107, c.1339G>A, p.D447N). ... NUP107 is a component of the nuclear pore complex ... In Drosophila, Nup107 knockdown in somatic gonadal cells resulted in female sterility, whereas males were fully fertile. Transgenic rescue of Drosophila females bearing the Nup107D364N mutation, which corresponds to the human NUP107 (p.D447N), resulted in almost complete sterility ..."