Thursday, December 10, 2015

Drosophila model used to explore mechanisms underlying microsatellite expansion-induced neurodegeneration

Schweizer Burguete A, Almeida S, Gao FB, Kalb R, Akins MR, Bonini NM. GGGGCC microsatellite RNA is neuritically localized, induces branching defects, and perturbs transport granule function. Elife. 2015 Dec 9;4. PMID: 26650351.

From the abstract: "Microsatellite expansions are the leading cause of numerous neurodegenerative disorders. Here we demonstrate that GGGGCC and CAG microsatellite repeat RNAs associated with C9orf72 in ALS/FTD and with polyglutamine diseases, respectively, localize to neuritic granules that undergo active transport into distal neuritic segments. ... Using a Drosophila GGGGCC expansion disease model, we characterize dendritic branching defects that are modulated by FMRP and Orb2. ... These data suggest that expanded repeat RNAs interact with the mRNA transport and translation machinery, causing transport granule dysfunction. This could be a novel mechanism contributing to the neuronal defects associated with C9orf72 and other microsatellite expansion diseases."

Wednesday, December 9, 2015

The holo'ome. Fly and mouse model of colon-microbial interplay in the context of colon cancer

Panagi M, Georgila K, Eliopoulos AG, Apidianakis Y. Constructing personalized longitudinal holo'omes of colon cancer-prone humans and their modeling in flies and mice. Oncotarget. 2015 Dec 4. PMID: 26643871.

From the abstract: "Specific host genes and intestinal microbes, dysbiosis, aberrant immune responses and lifestyle may contribute to intestinal inflammation and cancer, but each of these parameters does not suffice to explain why sporadic colon cancer develops at an old age and only in some of the people with the same profile. ... longitudinal multi-omic and personalized studies will help to pinpoint combinations of ... factors ... The intestinal holo'ome - defined as the combination of host and microbiota genomes, transcriptomes, proteomes, and metabolomes - may be imbalanced and shift to disease when the wrong host gene expression profile meets the wrong microbiota composition. ... Detrimental combinations of factors could therefore be pinpointed computationally and validated using animal models, such as mice and flies. ... treatment strategies that break these harmful combinations could be tested in clinical trials. ... we provide an overview of the literature and a roadmap to this end."

Saturday, December 5, 2015

Drosophila study relevant to NTE-related motor neuron disorder reveals possible contribution of glia to pathology of the disease

Dutta S, Rieche F, Eckl N, Duch C, Kretzschmar D. Glial expression of Swiss-cheese (SWS), the Drosophila orthologue of Neuropathy Target Esterase, is required for neuronal ensheathment and function. Dis Model Mech. 2015 Dec 3. PMID: 26634819.

From the abstract: "Swiss-cheese (SWS) and its vertebrate ortholog Neuropathy Target Esterase (NTE) cause progressive neuronal degeneration in Drosophila and mice and a complex syndrome in humans that includes mental retardation, spastic paraplegia, and blindness. SWS and NTE are widely expressed in neurons but can also be found in glia ... We have used a knockdown approach to specifically address SWS function in glia ... loss of SWS in pseudocartridge glia causes the formation of multi-layered glial whorls in the lamina cortex, the first optic neuropil. This phenotype can be rescued by the expression of SWS and NTE suggesting that the glial function is conserved in the vertebrate protein. ... the loss of SWS in glia impairs neuronal function, thereby playing an important role in the phenotypes described in the sws mutant. It is therefore likely that changes in glia also contribute to the pathology observed in patients that carry mutations in NTE."

Wednesday, December 2, 2015

New fly model of Pitt-Hopkins syndrome (PTHS)--human TCF4 can rescue mutations in Drosophila ortholog daugherless

Tamberg L, Sepp M, Timmusk T, Palgi M. Introducing Pitt-Hopkins syndrome-associated mutations of TCF4 to Drosophila daughterless. Biol Open. 2015 Nov 30. PMID: 26621827.

From the abstract: "Pitt-Hopkins syndrome (PTHS) is caused by haploinsufficiency of Transcription factor 4 (TCF4), one of the three human class I basic helix-loop-helix transcription factors called E-proteins. Drosophila has a single E-protein, Daughterless (Da), homologous to all three mammalian counterparts. ... human TCF4 can rescue Da deficiency during fruit fly nervous system development. ... We generated da transgenic fruit fly strains with corresponding missense mutations R578H, R580W, R582P and A614V found in TCF4 of PTHS patients and studied the impact of these mutations in vivo. ... All studied PTHS-associated mutations that we introduced into Da led to similar effects in vivo as the same mutations in TCF4 in vitro. ... our Drosophila models of PTHS are applicable for further studies aiming to unravel the molecular mechanisms of this disorder."