Friday, November 20, 2015

Now free in PMC--Drosophila model included in study relating microtubule acetylation to reduction of deficits caused by mutations in LRRK2

Godena VK, Brookes-Hocking N, Moller A, Shaw G, Oswald M, Sancho RM, Miller CC, Whitworth AJ, De Vos KJ. Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations. Nat Commun. 2014 Oct 15;5:5245. PMID: 25316291; PMCID: PMC4208097.

From the abstract: "Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease. LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson's disease, but whether LRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila ... In vivo knockdown of the deacetylases HDAC6 and Sirt2, or administration of TSA rescues both axonal transport and locomotor behavior. ..."

Thursday, November 19, 2015

Drosophila models of Parkinsons Disease included in study the traditional chinese medicine Tianma Gouteng Yin

Liu LF, Song JX, Lu JH, Huang YY, Zeng Y, Chen LL, Durairajan SS, Han QB, Li M. Tianma Gouteng Yin, a Traditional Chinese Medicine decoction, exerts neuroprotective effects in animal and cellular models of Parkinson's disease. Sci Rep. 2015 Nov 18;5:16862. PMID: 26578166.

From the abstract: "Tianma Gouteng Yin (TGY) is a traditional Chinese medicine (TCM) decoction widely used to treat symptoms associated with typical Parkinson's disease (PD). In this study, the neuroprotective effects of water extract of TGY were tested on rotenone-intoxicated and human α-synuclein transgenic Drosophila PD models. ... In rotenone-induced PD models, TGY improved survival rate, alleviated impaired locomotor function of Drosophila, mitigated the loss of dopaminergic neurons in hemi-parkinsonian rats and alleviated apoptotic cell death in SH-SY5Y cells; in α-synuclein transgenic Drosophila, TGY reduced the level of α-synuclein and prevented degeneration of dopaminergic neurons. ..."

Review of Drosophila a model for neuropsychopharmacology-related research

Narayanan AS, Rothenfluh A. I Believe I Can Fly!: Use of Drosophila as a Model Organism in Neuropsychopharmacology Research. Neuropsychopharmacology. 2015 Oct 30. PMID: 26576740.

From the abstract:  "... Here, we outline why we study an invertebrate organism in the context of neuropsychiatric disorders, and we discuss how we can gain insight from studies in Drosophila. ... Highlighting some translational examples, we underline the fact that their brains works more like ours than one would have anticipated."

Their Fig. 1 provides a nice graphical summary of translational approaches.

Tuesday, November 17, 2015

FlyRNAi: in vivo RNAi used to validate at gene level hits i...

FlyRNAi: in vivo RNAi used to validate at gene level hits i...: Talsma AD, Chaves JF, LaMonaca A, Wieczorek ED, Palladino MJ. Genome-wide screen for modifiers of Na (+) /K (+) ATPase alleles identifies cr...

Using the fly to identify new human genes associated with disorders, even when the GWAS stats are shaky

Yu J, Wu H, Wen Y, Liu Y, Zhou T, Ni B, Lin Y, Dong J, Zhou Z, Hu Z, Guo X, Sha J, Tong C. Identification of seven genes essential for male fertility through a genome-wide association study of non-obstructive azoospermia and RNA interference-mediated large-scale functional screening in Drosophila. Hum Mol Genet. 2015 Mar 1;24(5):1493-503. PMID: 25361961.

From the abstract: "Non-obstructive azoospermia (NOA) is a complex and severe condition ... In a genome-wide association study (GWAS) of NOA in Chinese men, few loci reached genome-wide significance ... Single nucleotide polymorphisms (SNPs) without genome-wide significance may also indicate genes that are essential for fertility, and multiple stage validation can lead to false-negative results. To perform large-scale functional screening of the genes surrounding these SNPs, we used in vivo RNA interference (RNAi) in Drosophila ... 7 (31.8%) of the 22 analyzed orthologous Drosophila genes were essential for male fertility. ... Our study thus demonstrates that SNPs without genome-wide significance in GWAS may also provide clues to disease-related genes and therefore warrant functional analysis."

When a lack of gene conservation becomes a plus--fly as a model of Epidermolysis Bullosa Simplex

Bohnekamp J, Cryderman DE, Paululat A, Baccam GC, Wallrath LL, Magin TM. A Drosophila Model of Epidermolysis Bullosa Simplex. J Invest Dermatol. 2015 Aug;135(8):2031-9. PMID: 25830653; PMCID: PMC4519992.

From the abstract: "The blistering skin disorder epidermolysis bullosa simplex (EBS) results from dominant mutations in keratin 5 (K5) or keratin 14 (K14) genes, encoding the intermediate filament (IF) network of basal epidermal keratinocytes. ... Drosophila lacks cytoplasmic IFs, providing a 'null' environment to examine the formation of keratin networks and determine mechanisms by which mutant keratins cause pathology. Here, we report that ubiquitous co-expression of transgenes encoding wild-type human K14 and K5 resulted in the formation of extensive keratin networks in Drosophila epithelial and non-epithelial tissues, causing no overt phenotype. Similar to mammalian cells, treatment of transgenic fly tissues with phosphatase inhibitors caused keratin network collapse, validating Drosophila as a genetic model system to investigate keratin dynamics. Co-expression of K5 and a K14(R125C) mutant that causes the most severe form of EBS resulted in widespread formation of EBS-like cytoplasmic keratin aggregates ... This Drosophila model of EBS is valuable for the identification of pathways altered by mutant keratins and for the development of EBS therapies."

Tuesday, November 3, 2015

Drosophila myotonic dystrophy model responds to drug used to treat human patients with the condition

Chakraborty M, Selma-Soriano E, Magny E, Couso JP, Pérez-Alonso M, Charlet-Berguerand N, Artero R, Llamusi B. Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction. Dis Model Mech. 2015 Oct 29. PMID: 26515653.

From the abstract: "Up to 80% of myotonic dystrophy type 1 (DM1) patients will develop cardiac abnormalities ... very few animal model studies have focused on the heart dysfunction in DM1. Here, we describe the characterization of the heart phenotype in a Drosophila model expressing pure expanded CUG repeats under the control of the cardiomyocyte-specific driver GMH5-Gal4. ... Similarly to what has been reported in human DM1 patients, heart-specific expression of toxic RNA resulted in reduced survival, increased arrhythmia, altered diastolic and systolic function ... As a proof of concept that the fly heart model can be used for in vivo testing of promising therapeutic compounds, we fed flies with pentamidine, a compound previously described to improve DM1 phenotypes. Pentamidine not only released Muscleblind and reduced ribonuclear formation in the Drosophila heart but rescued heart arrhythmicity and contractility, and improved fly survival in animals expressing 250 CUG repeats."