Wednesday, July 29, 2015

New fly model of Meier-Gorlin syndrome

Maxim Balasov, Katarina Akhmetova andIgor Chesnokov. Drosophila model of Meier-Gorlin syndrome based on the mutation in a conserved C-Terminal domain of Orc6. Article first published online: 2 JUL 2015. DOI: 10.1002/ajmg.a.37214

From the abstract: "Meier-Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, primordial dwarfism, small ears, and skeletal abnormalities. Patients with MGS often carry mutations in the genes encoding the components of the pre-replicative complex such as Origin Recognition Complex (ORC) subunits Orc1, Orc4, Orc6, and helicase loaders Cdt1 and Cdc6. ... we introduced MGS mutation in Orc6 and established Drosophila model of MGS ..."

Tuesday, July 28, 2015

Study including fly models of Parkinson's points to possible dietary mitochondrial signal

Senyilmaz D, Virtue S, Xu X, Tan CY, Griffin JL, Miller AK, Vidal-Puig A, Teleman AA. Regulation of mitochondrial morphology and function by stearoylation of TFR1. Nature. 2015 Jul 27. PMID: 26214738.

From the abstract:  "Mitochondria are involved in a variety of cellular functions, including ATP production, amino acid and lipid biogenesis and breakdown, signalling and apoptosis. Mitochondrial dysfunction has been linked to neurodegenerative diseases, cancer and ageing. ... Here we identify the metabolite stearic acid (C18:0) and human transferrin receptor 1 (TFR1; also known as TFRC) as mitochondrial regulators. We elucidate a signalling pathway whereby C18:0 stearoylates TFR1, thereby inhibiting its activation of JNK signalling. ... We find that animal cells are poised to respond to both increases and decreases in C18:0 levels... Intriguingly, dietary C18:0 supplementation can counteract the mitochondrial dysfunction caused by genetic defects such as loss of the Parkinson's disease genes Pink or Parkin in Drosophila. This work identifies the metabolite C18:0 as a signalling molecule regulating mitochondrial function in response to diet."

Drosophila study suggests TNF receptor links cell polarity and neoplastic growth

Andersen DS, Colombani J, Palmerini V, Chakrabandhu K, Boone E, Röthlisberger M, Toggweiler J, Basler K, Mapelli M, Hueber AO, Léopold P. The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth. Nature. 2015 Jun 25;522(7557):482-6. PMID: 25874673.

From the abstract: "Disruption of epithelial polarity is a key event in the acquisition of neoplastic growth. JNK signalling is known to play an important part in driving the malignant progression of many epithelial tumours, although the link between loss of polarity and JNK signalling remains elusive. In a Drosophila genome-wide genetic screen designed to identify molecules implicated in neoplastic growth, we identified grindelwald (grnd), a gene encoding a transmembrane protein with homology to members of the tumour necrosis factor receptor (TNFR) superfamily. Here we show that Grnd mediates the pro-apoptotic functions of Eiger (Egr), the unique Drosophila TNF, and that overexpression of an active form of Grnd lacking the extracellular domain is sufficient to activate JNK signalling in vivo. ... Grnd represents the first example of a TNFR that integrates signals from both Egr and apical polarity determinants to induce JNK-dependent cell death or tumour growth. "

Monday, July 27, 2015

"At a glance" review and poster summarize results from fly and other models regarding retromer complex

Wang S, Bellen HJ. The retromer complex in development and disease. Development. 2015 Jul 15;142(14):2392-6. PMID: 26199408.

From the abstract: "The retromer complex is a multimeric protein complex involved in recycling proteins from endosomes to the trans-Golgi network or plasma membrane. ... a number of recent studies implicate aberrant retromer function in photoreceptor degeneration, Alzheimer's disease and Parkinson's disease. Here, and in the accompanying poster, we provide an overview of the molecular and cellular mechanisms of retromer-mediated protein trafficking, highlighting key examples of retromer function in vivo. "

Review of fly tools and models for the study of neurodegeneratiave diseases

Lepesant JA. The promises of neurodegenerative disease modeling. C R Biol. 2015 Jul 22. pii: S1631-0691(15)00179-1. PMID: 26210484.

From the abstract: "... This review will focus on the advantages offered by the genetic tools available in Drosophila for combining powerful strategies in order to tackle the causative factors of these complex pathologies and help to elaborate efficient drugs to treat them."

Wednesday, July 22, 2015

Methods chapter reviews fly as model for spetraplakin-related diseases

Hahn I, Ronshaugen M, Sánchez-Soriano N, Prokop A. Functional and genetic analysis of spectraplakins in Drosophila. In: Intermediate filament associated proteins. Methods in enzymology: Elsevier; 2015. p. in press. Corrected proof is available through the authors' institutional site.

From the abstract: "The cytoskeleton is a dynamic network of filamentous protein polymers required for virtually all cellular processes. ... One unique class of proteins, the spectraplakins, bind, regulate, and integrate the functions of ... three classes of cytoskeleton proteins. ... They have OMIM-listed disease links to epidermolysis bullosa and hereditary sensory and autonomic neuropathy (HSAN). ... To study the broad range of functions and complexity of these proteins, Drosophila is a powerful model. ... Here we use the example of Shot to illustrate how the various tools and strategies available for Drosophila can be employed to decipher and dissect cellular roles and molecular mechanisms of spectraplakins."

Friday, July 17, 2015

Cheaper treatment for some cancers? Results of Drosophila study and follow-up suggests it might be possible

FlyRNAi: Fly cell screen leads to findings relevant to canc...: Thomas S, Fisher KH, Snowden JA, Danson SJ, Brown S, Zeidler MP. Methotrexate Is a JAK/STAT Pathway Inhibitor. PLoS One. 2015 Jul 1;10(7):e...

New fly models of Spinocerebellar ataxia type 17

Hsu TC, Wang CK, Yang CY, Lee LC, Hsieh-Li HM, Ro LS, Chen CM, Lee-Chen GJ, Su MT. Deactivation of TBP contributes to SCA17 pathogenesis. Hum Mol Genet. 2014 Dec 20;23(25):6878-93. PMID: 25104854.

From the abstract: "Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant cerebellar ataxia caused by the expansion of polyglutamine (polyQ) within the TATA box-binding protein (TBP). ... In this study, we generated novel Drosophila models for SCA17 that recapitulate pathological features such as aggregate formation, mobility defects and premature death. ... downregulation of TBP activity enhances retinal degeneration in SCA3 and Huntington's disease fly models, indicating that the deactivation of TBP is likely to play a common role in polyQ-induced neurodegeneration. "

Huntington's disease-related study includes work in flies--specific HTT cleavages related to toxicity

El-Daher MT, Hangen E, Bruyère J, Poizat G, Al-Ramahi I, Pardo R, Bourg N, Souquere S, Mayet C, Pierron G, Lévêque-Fort S, Botas J, Humbert S, Saudou F. Huntingtin proteolysis releases non-polyQ fragments that cause toxicity through dynamin 1 dysregulation. EMBO J. 2015 Jul 12. pii: e201490808. PMID: 26165689.

From the abstract: "... we show that specific cleavages are required to disrupt intramolecular interactions within HTT and to cause toxicity in cells and flies ..."

Link between Hh and zinc revealed in flies could have relevance to several human diseases

Xie J, Owen T, Xia K, Singh AV, Tou E, Li L, Arduini B, Li H, Wan LQ, Callahan B, Wang C. Zinc inhibits Hedgehog autoprocessing: linking zinc deficiency with Hedgehog activation. J Biol Chem. 2015 May 1;290(18):11591-600. PMID: 25787080; PMCID: PMC4416862.

From the abstract:  "Zinc is an essential trace element with wide-ranging biological functions, whereas the Hedgehog (Hh) signaling pathway plays crucial roles in both development and disease. Here we show that there is a mechanistic link between zinc and Hh signaling. ... In normal physiology, zinc likely acts as a negative regulator of Hh autoprocessing and inhibits the generation of Hh ligand and Hh signaling. In many diseases, zinc deficiency and elevated level of Hh ligand co-exist, including prostate cancer, lung cancer, ovarian cancer, and autism. Our data suggest a causal relationship between zinc deficiency and the overproduction of Hh ligand."

Saturday, July 11, 2015

Review--lipid physiology in worms and flies

Zhu H, Han M. Exploring developmental and physiological functions of fatty acid and lipid variants through worm and fly genetics. Annu Rev Genet. 2014;48:119-48. PMID: 25195508.

From the abstract: "Lipids are more than biomolecules for energy storage and membrane structure. With ample structural variation, lipids critically participate in nearly all aspects of cellular function. Lipid homeostasis and metabolism are closely related to major human diseases and health problems. However, lipid functional studies have been significantly underdeveloped ... Here, we review a subset of these studies using Caenorhabditis elegans and Drosophila melanogaster."

Review--Drosophila as a model for study of sleep disorders

Donelson NC, Sanyal S. Use of Drosophila in the investigation of Sleep Disorders. Exp Neurol. 2015 Jul 6. pii: S0014-4886(15)30034-0. PMID: 26160555.

From the abstract:
"Genetic underpinnings for sleep disorders in humans remain poorly identified, investigated and understood. ... On the other hand, there have been steady and remarkable developments in the investigation of sleep using model organisms such as Drosophila. ... Here, we discuss the opportunities and limitations of studying sleep disorders in Drosophila and propose that a greater convergence of basic sleep research in model organisms and human genetics should catalyze better understanding of sleep disorders and generate viable therapeutic options."

Friday, July 10, 2015

Fly model points to possible new target pathway for treatment of Friedreich’s ataxia

Pablo Calap-Quintana, Sirena Soriano, José Vicente Llorens, Ismael Al-Ramahi, Juan Botas, María Dolores Moltó, María José Martínez-Sebastián. TORC1 Inhibition by Rapamycin Promotes Antioxidant Defences in a Drosophila Model of Friedreich’s Ataxia. PLOS Published: July 9, 2015 DOI: 10.1371/journal.pone.0132376

From the abstract: "Friedreich’s ataxia (FRDA) ... is a multisystemic disease caused by a significant decrease in the frataxin level. ... we performed a candidate genetic screen in a Drosophila RNAi-based model of FRDA. We found that genetic reduction in TOR Complex 1 (TORC1) signalling improves the impaired motor performance phenotype of FRDA model flies. ... These results point to the TORC1 pathway as a new potential therapeutic target for FRDA and as a guide to finding new promising molecules for disease treatment."

Suppression of TDP-43 toxicity by newly identified factor in fly models of ALS

Chou CC, Alexeeva OM, Yamada S, Pribadi A, Zhang Y, Mo B, Williams KR, Zarnescu DC, Rossoll W. PABPN1 suppresses TDP-43 toxicity in ALS disease models. Hum Mol Genet. 2015 Jun 30. pii: ddv238. PMID: 26130692.

From the abstract: "TAR DNA-binding protein 43 (TDP-43) is a major disease protein in amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases. Both the cytoplasmic accumulation of toxic ubiquitinated and hyperphosphorylated TDP-43 fragments and the loss of normal TDP-43 from the nucleus may contribute to the disease progression by impairing normal RNA and protein homeostasis. Therefore, both the removal of pathological protein and the rescue of TDP-43 mislocalization may be critical for halting or reversing TDP-43 proteinopathies. Here, we report poly(A)-binding protein nuclear 1 (PABPN1) as a novel TDP-43 interaction partner that acts as a potent suppressor of TDP-43 toxicity. ... These findings demonstrate a role for PABPN1 in rescuing several cytopathological features of TDP-43 proteinopathy by increasing the turnover of pathologic proteins."

Quantifying climbing defects in fly models of neurodegeneration--protocol video

Madabattula ST, Strautman JC, Bysice AM, O'Sullivan JA, Androschuk A, Rosenfelt C, Doucet K, Rouleau G, Bolduc F. Quantitative Analysis of Climbing Defects in a Drosophila Model of Neurodegenerative Disorders. J Vis Exp. 2015 Jun 13;(100). PMID: 26132637.

From the abstract: "... The assay is performed in a glass graduated cylinder, which is sealed with a wax barrier film. By increasing the threshold distance to be climbed to 17.5 cm and increasing the experiment duration to 2 min we have observed a greater sensitivity in detecting mild mobility dysfunctions. ..."

New fly model of obesity-related heart disease

Hardy CM, Birse RT, Wolf MJ, Yu L, Bodmer R, Gibbs AG. Obesity-associated Cardiac Dysfunction in Starvation-Selected Drosophila melanogaster. Am J Physiol Regul Integr Comp Physiol. 2015 Jul 1:ajpregu.00160.2015. PMID: 26136533.

Translation in fly models of CMT neuropathy

Niehues S, Bussmann J, Steffes G, Erdmann I, Köhrer C, Sun L, Wagner M, Schäfer K, Wang G, Koerdt SN, Stum M, RajBhandary UL, Thomas U, Aberle H, Burgess RW, Yang XL, Dieterich D, Storkebaum E. Impaired protein translation in Drosophila models for Charcot-Marie-Tooth neuropathy caused by mutant tRNA synthetases. Nat Commun. 2015 Jul 3;6:7520. PMID: 26138142.