Yamamoto S, Jaiswal M, Charng WL, Gambin T, Karaca E, Mirzaa G, Wiszniewski W, Sandoval H, Haelterman NA, Xiong B, Zhang K, Bayat V, David G, Li T, Chen K, Gala U, Harel T, Pehlivan D, Penney S, Vissers LE, de Ligt J, Jhangiani SN, Xie Y, Tsang SH, Parman Y, Sivaci M, Battaloglu E, Muzny D, Wan YW, Liu Z, Lin-Moore AT, Clark RD, Curry CJ, Link N, Schulze KL, Boerwinkle E, Dobyns WB, Allikmets R, Gibbs RA, Chen R, Lupski JR, Wangler MF, Bellen HJ. A Drosophila Genetic Resource of Mutants to Study Mechanisms Underlying Human Genetic Diseases. Cell. 2014 Sep 25;159(1):200-214. PMID: 25259927.
From the abstract: "... We conducted a mosaic genetic screen of lethal mutations on the Drosophila X chromosome to identify genes required for the development, function, and maintenance of the nervous system. We identified 165 genes, most of whose function has not been studied in vivo. In parallel, we investigated rare variant alleles in 1,929 human exomes from families with unsolved Mendelian disease. Genes that are essential in flies and have multiple human homologs were found to be likely to be associated with human diseases. Merging the human data sets with the fly genes allowed us to identify disease-associated mutations in six families and to provide insights into microcephaly associated with brain dysgenesis. This bidirectional synergism between fly genetics and human genomics facilitates the functional annotation of evolutionarily conserved genes involved in human health."
Saturday, September 27, 2014
Anlaysis of a fly Alzheimer's disease model suggests it's not what it might seem
Allan K, Perez KA, Barnham KJ, Camakaris J, Burke R. A commonly used Drosophila model of Alzheimer's disease generates an aberrant species of amyloid-β with an additional N-terminal glutamine residue. FEBS Lett. 2014 Oct 16;588(20):3739-43. PMID: 25171862.
Abstract: "Expression of human amyloid-β (Aβ) in Drosophila is frequently used to investigate its toxicity in vivo. We expressed Aβ1-42 in the fly using a secretion signal derived from the Drosophila necrotic gene, as described in several previous publications. Surface-enhanced laser desorption/ionization TOF MS analysis revealed that the Aβ produced contained an additional glutamine residue at the N-terminus. AβQ+1-42 was found to have increased protein abundance and to cause more severe neurodegenerative effects than wild type Aβ1-42 as assessed by locomotor activity and lifespan assays. These data reveal that a commonly used model of Alzheimer's disease generates incorrect Aβ peptide."
Abstract: "Expression of human amyloid-β (Aβ) in Drosophila is frequently used to investigate its toxicity in vivo. We expressed Aβ1-42 in the fly using a secretion signal derived from the Drosophila necrotic gene, as described in several previous publications. Surface-enhanced laser desorption/ionization TOF MS analysis revealed that the Aβ produced contained an additional glutamine residue at the N-terminus. AβQ+1-42 was found to have increased protein abundance and to cause more severe neurodegenerative effects than wild type Aβ1-42 as assessed by locomotor activity and lifespan assays. These data reveal that a commonly used model of Alzheimer's disease generates incorrect Aβ peptide."
Bromine: You've got to have it
McCall AS, Cummings CF, Bhave G, Vanacore R, Page-McCaw A, Hudson BG. Bromine is an essential trace element for assembly of collagen IV scaffolds in tissue development and architecture. Cell. 2014 Jun 5;157(6):1380-92. PMID: 24906154; PMCID: PMC4144415.
From the abstract: "... Dietary Br deficiency is lethal in Drosophila, whereas Br replenishment restores viability ... Importantly, Br-deficient flies phenocopy the developmental and BM [basement membrane] defects observed in peroxidasin mutants and indicate a functional connection between Br(-), collagen IV, and peroxidasin. We establish that Br(-) is required for sulfilimine formation within collagen IV, an event critical for BM assembly and tissue development. Thus, bromine is an essential trace element for all animals, and its deficiency may be relevant to BM alterations observed in nutritional and smoking-related disease."
From the abstract: "... Dietary Br deficiency is lethal in Drosophila, whereas Br replenishment restores viability ... Importantly, Br-deficient flies phenocopy the developmental and BM [basement membrane] defects observed in peroxidasin mutants and indicate a functional connection between Br(-), collagen IV, and peroxidasin. We establish that Br(-) is required for sulfilimine formation within collagen IV, an event critical for BM assembly and tissue development. Thus, bromine is an essential trace element for all animals, and its deficiency may be relevant to BM alterations observed in nutritional and smoking-related disease."
Fly study related to pesticide-induced neurotoxicity--links to Parkinson's disease
Cassar M, Issa AR, Riemensperger T, Petitgas C, Rival T, Coulom H, Iché-Torres M, Han KA, Birman S. A dopamine receptor contributes to paraquat-induced neurotoxicity in Drosophila. Hum Mol Genet. 2014 Aug 25. pii: ddu430. PMID: 25158689.
From the abstract: "Long-term exposure to environmental oxidative stressors, like the herbicide paraquat (PQ), has been linked to the development of Parkinson's disease (PD), the most frequent neurodegenerative movement disorder. Paraquat is thus frequently used in the fruit fly Drosophila melanogaster and other animal models to study PD and the degeneration of dopaminergic neurons (DNs) that characterizes this disease. Here, we show that a D1-like dopamine (DA) receptor, DAMB, actively contributes to the fast central nervous system (CNS) failure induced by PQ in the fly. ... Further studies of DAMB signaling in Drosophila could have implications for better understanding DA-related neurodegenerative disorders in humans."
From the abstract: "Long-term exposure to environmental oxidative stressors, like the herbicide paraquat (PQ), has been linked to the development of Parkinson's disease (PD), the most frequent neurodegenerative movement disorder. Paraquat is thus frequently used in the fruit fly Drosophila melanogaster and other animal models to study PD and the degeneration of dopaminergic neurons (DNs) that characterizes this disease. Here, we show that a D1-like dopamine (DA) receptor, DAMB, actively contributes to the fast central nervous system (CNS) failure induced by PQ in the fly. ... Further studies of DAMB signaling in Drosophila could have implications for better understanding DA-related neurodegenerative disorders in humans."
Catching up--papers related to flies and neurodegnerative diseases
Wu K, Liu J, Zhuang N, Wang T. UCP4A protects against mitochondrial dysfunction and degeneration in pink1/parkin models of Parkinson's disease. FASEB J. 2014 Aug 21. pii: fj.14-255802. PMID: 25145627.
Long DM, Blake MR, Dutta S, Holbrook SD, Kotwica-Rolinska J, Kretzschmar D, Giebultowicz JM. Relationships between the Circadian System and Alzheimer's Disease-Like Symptoms in Drosophila. PLoS One. 2014 Aug 29;9(8):e106068. PMID: 25171136; PMCID: PMC4149435.
Dietz KN, Di Stefano L, Maher RC, Zhu H, Macdonald ME, Gusella JF, Walker JA. The Drosophila Huntington's disease gene ortholog dhtt influences chromatin regulation during development. Hum Mol Genet. 2014 Aug 28. pii: ddu446. PMID: 25168387.
Long DM, Blake MR, Dutta S, Holbrook SD, Kotwica-Rolinska J, Kretzschmar D, Giebultowicz JM. Relationships between the Circadian System and Alzheimer's Disease-Like Symptoms in Drosophila. PLoS One. 2014 Aug 29;9(8):e106068. PMID: 25171136; PMCID: PMC4149435.
Dietz KN, Di Stefano L, Maher RC, Zhu H, Macdonald ME, Gusella JF, Walker JA. The Drosophila Huntington's disease gene ortholog dhtt influences chromatin regulation during development. Hum Mol Genet. 2014 Aug 28. pii: ddu446. PMID: 25168387.
New fly Alzheimer's disease model
Mhatre SD, Michelson SJ, Gomes J, Tabb LP, Saunders AJ, Marenda DR. Development and characterization of an aged onset model of Alzheimer's disease in Drosophila melanogaster. Exp Neurol. 2014 Aug 27;261C:772-781. PMID: 25173219.
Review--models of Fragile X-associated primary ovarian insufficiency
Sherman SL, Curnow EC, Easley CA, Jin P, Hukema RK, Tejada MI, Willemsen R, Usdin K. Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI). J Neurodev Disord. 2014;6(1):26. PMID: 25147583; PMCID: PMC4139715.
From the abstract: "... Vertebrate (mouse and rat) and invertebrate (Drosophila melanogaster) animal studies for the FMR1 premutation and ovarian function exist and have been instrumental in advancing our understanding of the disease phenotype. ... Here, we review the characterization of the current models and describe the development and potential of the new models. Finally, we will discuss some of the molecular mechanisms that might be responsible for FXPOI."
From the abstract: "... Vertebrate (mouse and rat) and invertebrate (Drosophila melanogaster) animal studies for the FMR1 premutation and ovarian function exist and have been instrumental in advancing our understanding of the disease phenotype. ... Here, we review the characterization of the current models and describe the development and potential of the new models. Finally, we will discuss some of the molecular mechanisms that might be responsible for FXPOI."
Flies & SMA
Praveen K, Wen Y, Gray KM, Noto JJ, Patlolla AR, Van Duyne GD, Matera AG. SMA-causing missense mutations in survival motor neuron (Smn) display a wide range of phenotypes when modeled in Drosophila. PLoS Genet. 2014 Aug 21;10(8):e1004489. PMID: 25144193; PMCID: PMC4140637.
Huntington's and the heart
Melkani GC, Trujillo AS, Ramos R, Bodmer R, Bernstein SI, Ocorr K. Huntington's disease induced cardiac amyloidosis is reversed by modulating protein folding and oxidative stress pathways in the Drosophila heart. PLoS Genet. 2013;9(12):e1004024. PMID: 24367279; PMCID: PMC3868535.
From the abstract: "... We conclude that modulation of both protein unfolding and oxidative stress pathways in the Drosophila heart model can ameliorate the detrimental PolyQ effects, thus providing unique insights into the genetic mechanisms underlying amyloid-induced cardiac failure in HD patients."
From the abstract: "... We conclude that modulation of both protein unfolding and oxidative stress pathways in the Drosophila heart model can ameliorate the detrimental PolyQ effects, thus providing unique insights into the genetic mechanisms underlying amyloid-induced cardiac failure in HD patients."
Review--Drosophila as a model for inflammation, innate immunity and cancer
Wang L, Kounatidis I, Ligoxygakis P. Drosophila as a model to study the role of blood cells in inflammation, innate immunity and cancer. Front Cell Infect Microbiol. 2014 Jan 9;3:113. PMID: 24409421; PMCID: PMC3885817.
Fly study related to spincerebellar ataxia
Liman J, Deeg S, Voigt A, Voßfeldt H, Dohm CP, Karch A, Weishaupt J, Schulz JB, Bähr M, Kermer P. CDK5 protects from caspase-induced Ataxin-3 cleavage and neurodegeneration. J Neurochem. 2014 Jun;129(6):1013-23. PMID: 24548080.
Sunday, September 7, 2014
Peripheral motor neuron syndrome study--patient mutations explored using Drosophila
Herrmann DN, Horvath R, Sowden JE, Gonzales M, Sanchez-Mejias A, Guan Z, Whittaker RG, Almodovar JL, Lane M, Bansagi B, Pyle A, Boczonadi V, Lochmüller H, Griffin H, Chinnery PF, Lloyd TE, Littleton JT, Zuchner S. Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy. Am J Hum Genet. 2014 Sep 4;95(3):332-9. PMID: 25192047.
From the abstract: "Synaptotagmin 2 is a synaptic vesicle protein that functions as a calcium sensor for neurotransmission ... Via whole-exome sequencing, we identified heterozygous missense mutations in the C2B calcium-binding domain of the gene encoding Synaptotagmin 2 in two multigenerational families presenting with peripheral motor neuron syndromes. ... Characterization of the mutation homologous to the human c.920A>C variant in Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle exocytosis ..."
From the abstract: "Synaptotagmin 2 is a synaptic vesicle protein that functions as a calcium sensor for neurotransmission ... Via whole-exome sequencing, we identified heterozygous missense mutations in the C2B calcium-binding domain of the gene encoding Synaptotagmin 2 in two multigenerational families presenting with peripheral motor neuron syndromes. ... Characterization of the mutation homologous to the human c.920A>C variant in Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle exocytosis ..."
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