Monday, April 20, 2015

Researcher describes sickening smell from fungi post-Hurricane Katrina and how her lab now uses various approaches including Drosophila studies to help identify and study volatile fungal toxins

Bennett JW. Silver linings: a personal memoir about Hurricane Katrina and fungal volatiles. Front Microbiol. 2015 Mar 18;6:206. PMID: 25852666; PMCID: PMC4364291.

From the abstract: "In the aftermath of Hurricane Katrina ... I traveled home with a suitcase full of Petri dishes and sampling equipment so as to study the fungi ... the air itself was full of concentrated mold odor ... The smell made me feel bad and I had to take regular breaks as I sampled. ... So why was I feeling sick? ..."

Study in humans with follow-up in mice and flies points to role for coronin 7 (fly pod1) in obesity

Eriksson A, Williams MJ, Voisin S, Hansson I, Krishnan A, Philippot G, Yamskova O, Herisson FM, Dnyansagar R, Moschonis G, Manios Y, Chrousos GP, Olszewski PK, Frediksson R, Schiöth HB. Implication of coronin 7 in body weight regulation in humans, mice and flies. BMC Neurosci. 2015 Mar 14;16(1):13. PMID: 25887538.

From the abstract: "... Although various genome-wide association studies have identified more than 40 genes associated with obesity, these genes cannot fully explain the heritability of obesity, suggesting there may be other contributing factors, including epigenetic effects. We performed genome wide DNA methylation profiling ... Of note, obese children had significantly lower methylation levels at a CpG site located near coronin 7 (CORO7), which encodes a tryptophan-aspartic acid dipeptide (WD)-repeat containing protein ... profiling of coronin 7 (Coro7) mRNA expression in mice revealed that it is highly expressed in appetite and energy balance regulating regions ... food deprivation in mice downregulates hypothalamic Coro7 mRNA levels ... Knocking down the pod1 in the Drosophila adult nervous system increased their resistance to starvation. Furthermore, feeding flies a high-calorie diet significantly increased pod1 expression. We conclude that coronin 7 is involved in the regulation of energy homeostasis and this role stems, to some degree, from the effect on feeding for calories and reward."

Friday, April 17, 2015

Review highlights fly research contributions to understanding muscular dystrophies

Plantié E, Migocka-Patrzałek M, Daczewska M, Jagla K. Model Organisms in the Fight against Muscular Dystrophy: Lessons from Drosophila and Zebrafish. Molecules. 2015 Apr 9;20(4):6237-6253. PMID: 25859781.

Table 1 from Plantie et al. Click to view the Open Access review.
From the abstract: "Muscular dystrophies (MD) are a heterogeneous group of genetic disorders that cause muscle weakness, abnormal contractions and muscle wasting, often leading to premature death. ... Structurally, physiologically and biochemically, MDs affect different types of muscles and cause individual symptoms such that genetic and molecular pathways underlying their pathogenesis thus remain poorly understood. To improve our knowledge of how MD-caused muscle defects arise and to find efficacious therapeutic treatments, different animal models have been generated and applied. Among these, simple non-mammalian Drosophila and zebrafish models have proved most useful. This review discusses how zebrafish and Drosophila MD have helped to identify genetic determinants of MDs and design innovative therapeutic strategies with a special focus on DMD, DM1 and congenital MDs."

Monday, April 13, 2015

Flies and neurodegeneration--research report on A beta 43 toxicity in flies and review of findings from fly models of tauopathies

Burnouf S, Gorsky MK, Dols J, Grönke S, Partridge L. Aβ(43) is neurotoxic and primes aggregation of Aβ(40) in vivo. Acta Neuropathol. 2015 Apr 11. PMID: 25862636.

From the abstract: "... Besides the well-studied Aβ40 and Aβ42 species, recent data have raised the possibility that Aβ43 peptides might be instrumental in AD pathogenesis, because they are frequently observed in both dense and diffuse amyloid plaques from human AD brains and are highly amyloidogenic in vitro. However, whether Aβ43 is toxic in vivo is currently unclear. Using Drosophila transgenic models of amyloid pathology, we show that Aβ43 peptides are mainly insoluble and highly toxic in vivo ... Altogether, our study demonstrates high pathogenicity of Aβ43 species in vivo and supports the idea that Aβ43 contributes to the pathological events leading to neurodegeneration in AD."

Sun M, Chen L. Studying Tauopathies in Drosophila: A Fruitful Model. Exp Neurol. 2015 Apr 7. pii: S0014-4886(15)00105-3. PMID: 25862286.

From the abstract:
"... summarize key features of transgenic Drosophila models of tauopathies and ... insights into disease mechanisms as well as therapeutic implications gained from the fruit fly models."

Friday, April 10, 2015

Two reports implicate Drosophila ImpL2 in wasting phenotype with similarities to cancer cachexia

Kwon Y, Song W, Droujinine IA, Hu Y, Asara JM, Perrimon N. Systemic Organ Wasting Induced by Localized Expression of the Secreted Insulin/IGF Antagonist ImpL2. Dev Cell. 2015 Apr 6;33(1):36-46. PMID: 25850671.

From the abstract: "Organ wasting, related to changes in nutrition and metabolic activity of cells and tissues, is observed under conditions of starvation and in the context of diseases, including cancers. We have developed a model for organ wasting in adult Drosophila .... These organ-wasting phenotypes are associated with a reduction in systemic insulin/IGF signaling due to increased expression of the secreted insulin/IGF antagonist ImpL2 from the overproliferating gut. ..."

Figueroa-Clarevega A, Bilder D. Malignant Drosophila Tumors Interrupt Insulin Signaling to Induce Cachexia-like Wasting. Dev Cell. 2015 Apr 6;33(1):47-55. PMID: 25850672.

From the abstract: "Tumors kill patients not only through well-characterized perturbations to their local environment but also through poorly understood pathophysiological interactions with distant tissues. ... We identify the insulin growth factor binding protein (IGFBP) homolog ImpL2, an antagonist of insulin signaling, as a secreted factor mediating wasting. ImpL2 is sufficient to drive tissue loss, and insulin activity is reduced in peripheral tissues of tumor-bearing hosts. ..."

Wednesday, April 8, 2015

Results of cross-species study suggest Pseudomonas aeruginosa virulence factors are largely host-specific

Dubern JF, Cigana C, De Simone M, Lazenby J, Juhas M, Schwager S, Bianconi I, Döring G, Eberl L, Williams P, Bragonzi A, Cámara M. Integrated whole genome screening for Pseudomonas aeruginosa virulence genes using multiple disease models reveals that pathogenicity is host specific. Environ Microbiol. 2015 Apr 3. doi: 10.1111/1462-2920.12863. PMID: 25845292.

From the abstract: "Pseudomonas aeruginosa is a multi-host opportunistic pathogen causing a wide range of diseases ... Using an integrated whole-genome approach we searched for P. aeruginosa virulence genes with multi-host relevance. ... pleotropic mutants were assayed for reduced toxicity in Drosophila melanogaster, Caenorhabditis elegans, human cell lines, and mice. Surprisingly, the screening revealed that the virulence of the majority of P. aeruginosa mutants varied between disease models ... These findings have important implication when searching for novel anti-virulence targets to develop new treatments against P. aeruginosa."

Review highlights contribution of Drosophila research to understanding Parkinson's disease

Vanhauwaert R, Verstreken P. Flies with Parkinson's disease. Exp Neurol. 2015 Feb 20. pii: S0014-4886(15)00043-6. doi: 10.1016/j.expneurol.2015.02.020. PMID: 25708988.

From the abstract: "Parkinson's disease is an incurable neurodegenerative disease. Most cases of the disease are of sporadic origin, but about 10% of the cases are familial. The genes thus far identified in Parkinson's disease are well conserved. Drosophila is ideally suited to study the molecular neuronal cell biology of these genes and the pathogenic mutations in Parkinson's disease. ... fruit flies recapitulate many of the cellular and molecular defects also seen in patients ... Drosophila has played a prominent role in Parkinson's disease research and has provided invaluable insight into the molecular mechanisms of this disease."
Sanhueza M, Chai A, Smith C, McCray BA, Simpson TI, Taylor JP, Pennetta G. Network Analyses Reveal Novel Aspects of ALS Pathogenesis. PLoS Genet. 2015 Mar 31;11(3):e1005107. PMID: 25826266.
Sanhueza et al. Fig. 2

From the abstract: "Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease ... Mutations in the human VAMP-associated protein B (hVAPB) cause a heterogeneous group of motor neuron diseases including ALS8. Despite extensive research, the molecular mechanisms underlying ALS pathogenesis remain largely unknown. Genetic screens for key interactors of hVAPB activity in the intact nervous system, however, represent a fundamental approach towards understanding the in vivo function of hVAPB and its role in ALS pathogenesis. Targeted expression of the disease-causing allele leads to neurodegeneration and progressive decline in motor performance when expressed in the adult Drosophila, eye or in its entire nervous system, respectively. By using these two phenotypic readouts, we carried out a systematic survey of the Drosophila genome to identify modifiers of hVAPB-induced neurotoxicity. ... Collectively, these results not only lead to a better understanding of hVAPB function but also point to potentially relevant targets for therapeutic intervention."

Mammalian screen with fly follow-up identifies potential drug target for treatment of Huntington's Disease

Jimenez-Sanchez M, Lam W, Hannus M, Sönnichsen B, Imarisio S, Fleming A, Tarditi A, Menzies F, Ed Dami T, Xu C, Gonzalez-Couto E, Lazzeroni G, Heitz F, Diamanti D, Massai L, Satagopam VP, Marconi G, Caramelli C, Nencini A, Andreini M, Sardone GL, Caradonna NP, Porcari V, Scali C, Schneider R, Pollio G, O'Kane CJ, Caricasole A, Rubinsztein DC. siRNA screen identifies QPCT as a druggable target for Huntington's disease. Nat Chem Biol. 2015 Apr 6. doi: 10.1038/nchembio.1790. PMID: 25848931.

From the abstract: "Huntington's disease (HD) is a currently incurable neurodegenerative condition caused by an abnormally expanded polyglutamine tract in huntingtin (HTT). We identified new modifiers of mutant HTT toxicity by performing a large-scale 'druggable genome' siRNA screen in human cultured cells, followed by hit validation in Drosophila. ... Our data reveal a new HD druggable target affecting mutant HTT aggregation and provide proof of principle for a discovery pipeline from druggable genome screen to drug development."

Wednesday, April 1, 2015

Varmus tells NYTimes "if we become slackers on funding the absolutely most fundamental things, we will not hit upon the real answers"

Research in Drosophila has contributed many pioneering discoveries relevant to cancer and other diseases. Readers of this blog might be interested to read a NYTimes interview with Harold Varmus titled "The Condition Cancer Research Is In."

From the article:  "People feel their likelihood of getting funded is greater if they work on things that may have a clinical application. I’m worried about that, because I look at the big things that have changed the face of health care, and it’s usually the result of some pioneering discovery not made in conjunction with the notion of how to treat somebody. ... if we become slackers on funding the absolutely most fundamental things, we will not hit upon the real answers."

Review suggests "collaboration between neurologists, human geneticists, and the Drosophila research community holds great promise to accelerate progress in the post-genomic era"

Shulman JM. Drosophila and experimental neurology in the post-genomic era. Exp Neurol. 2015 Mar 24. pii: S0014-4886(15)00084-9. PMID: 25814441.

From the abstract: "... I focus here on four critical challenges emerging from recent advances in our understanding of the genomic basis of human neurologic disorders where innovative experimental strategies are urgently needed: (1) pinpointing causal genes from associated genomic loci; (2) confirming the functional impact of allelic variants; (3) elucidating nervous system roles for novel or poorly studied genes; and (4) probing network interactions within implicated regulatory pathways. Drosophila genetic approaches are ideally suited to address each of these potential translational roadblocks, and will therefore contribute to mechanistic insights and potential breakthrough therapies for complex genetic disorders in the coming years. Strategic collaboration between neurologists, human geneticists, and the Drosophila research community holds great promise to accelerate progress in the post-genomic era."

Drosophila study contributes to understanding of autism spectrum disorders-associated gene variants

Grice SJ, Liu JL, Webber C. Synergistic Interactions between Drosophila Orthologues of Genes Spanned by De Novo Human CNVs Support Multiple-Hit Models of Autism. PLoS Genet. 2015 Mar 27;11(3):e1004998. PMID: 25816101.

Fig. 1 from Grice et al. 2015 PLoS Genet.
From the abstract: "Autism spectrum disorders (ASDs) are highly heritable ... Although a number of highly penetrant ASD gene variants have been identified, there is growing evidence to support a causal role for combinatorial effects arising from the contributions of multiple loci. By examining synaptic and circadian neurological phenotypes resulting from the dosage variants of unique human:fly orthologues in Drosophila, we observe numerous synergistic interactions between pairs of informatically-identified candidate genes whose orthologues are jointly affected by large de novo copy number variants (CNVs). ... We first demonstrate that dosage alterations of the unique Drosophila orthologues of candidate genes from de novo CNVs that harbour only a single candidate gene display neurological defects similar to those previously reported in Drosophila models of ASD-associated variants. We then considered pairwise dosage changes within the set of orthologues of candidate genes that were affected by the same single human de novo CNV. ... Our study illustrates mechanisms through which synergistic effects resulting from large structural variation can contribute to human disease."