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https://www.readbyqxmd.com/read/28529046/targeted-downregulation-of-dmyc-restricts-neurofibrillary-tangles-mediated-pathogenesis-of-human-neuronal-tauopathies-in-drosophila
#1
Soram Idiyasan Chanu, Surajit Sarkar
Formation of Neurofibrillary Tangles (NFTs) in neuronal tissues has been implicated as the hallmark of disease pathogenesis and tau mediated toxicity in human and mammalian models. However, previous studies had failed to correlate NFT formation with pathogenesis of human neuronal tauopathies in Drosophila disease models. Though, a recent report suggests formation of tau mediated NFTs like structures confined to dopaminergic neurons in Drosophila adult brain, by utilizing various approaches, we demonstrate distinct and recurrent formation of NFTs in Drosophila neuronal tissues upon expression of wild type or mutant isoforms of human tau, and this appears as the key mediator of the pathogenesis of human neuronal tauopathy in Drosophila...
May 18, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28523286/synthetic-lethality-screens-using-rnai-in-combination-with-crispr-based-knockout-in-drosophila-cells
#2
Benjamin E Housden, Hilary E Nicholson, Norbert Perrimon
A synthetic lethal interaction is a type of genetic interaction where the disruption of either of two genes individually has little effect but their combined disruption is lethal. Knowledge of synthetic lethal interactions can allow for elucidation of network structure and identification of candidate drug targets for human diseases such as cancer. In Drosophila, combinatorial gene disruption has been achieved previously by combining multiple RNAi reagents. Here we describe a protocol for high-throughput combinatorial gene disruption by combining CRISPR and RNAi...
February 5, 2017: Bio-protocol
https://www.readbyqxmd.com/read/28515229/unique-cell-biological-profiles-of-retinal-disease-causing-missense-mutations-in-the-polarity-protein-crumbs
#3
Milena Pellikka, Ulrich Tepass
Mutations in human CRB1 are a major cause of retinal disease that lead to blindness. CRB1 is a transmembrane protein found in the inner segment of photoreceptor cells (PRCs) and the apical membrane of Müller glia. The function of the extracellular region of CRB1 is poorly understood although more than 80 disease-causing missense mutations have been mapped to it. We have recreated four mutations in Drosophila Crumbs (Crb) that affect different extracellular domains. Crb regulates epithelial polarity and growth, and contributes to PRC differentiation and survival...
May 17, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28512194/ancient-antagonism-between-celf-and-rbfox-families-tunes-mrna-splicing-outcomes
#4
Matthew R Gazzara, Michael J Mallory, Renat Roytenberg, John Lindberg, Anupama Jha, Kristen W Lynch, Yoseph Barash
Over 95% of human multi-exon genes undergo alternative splicing, a process important in normal development and often dysregulated in disease. We sought to analyze the global splicing regulatory network of CELF2 in human T cells, a well-studied splicing regulator critical to T cell development and function. By integrating high-throughput sequencing data for binding and splicing quantification with sequence features and probabilistic splicing code models, we find evidence of splicing antagonism between CELF2 and the RBFOX family of splicing factors...
May 16, 2017: Genome Research
https://www.readbyqxmd.com/read/28497117/rna-interference-restricts-rift-valley-fever-virus-in-multiple-insect-systems
#5
Isabelle Dietrich, Stephanie Jansen, Gamou Fall, Stephan Lorenzen, Martin Rudolf, Katrin Huber, Anna Heitmann, Sabine Schicht, El Hadji Ndiaye, Mick Watson, Ilaria Castelli, Benjamin Brennan, Richard M Elliott, Mawlouth Diallo, Amadou A Sall, Anna-Bella Failloux, Esther Schnettler, Alain Kohl, Stefanie C Becker
The emerging bunyavirus Rift Valley fever virus (RVFV) is transmitted to humans and livestock by a large number of mosquito species. RNA interference (RNAi) has been characterized as an important innate immune defense mechanism used by mosquitoes to limit replication of positive-sense RNA flaviviruses and togaviruses; however, little is known about its role against negative-strand RNA viruses such as RVFV. We show that virus-specific small RNAs are produced in infected mosquito cells, in Drosophila melanogaster cells, and, most importantly, also in RVFV vector mosquitoes...
May 2017: MSphere
https://www.readbyqxmd.com/read/28495673/parallel-imaging-of-drosophila-embryos-for-quantitative-analysis-of-genetic-perturbations-of-the-ras-pathway
#6
Yogesh Goyal, Thomas J Levario, Henry H Mattingly, Susan Holmes, Stanislav Y Shvartsman, Hang Lu
The Ras pathway patterns the poles of the Drosophila embryo by downregulating the levels and activity of a DNA-binding transcriptional repressor Capicua (Cic). We demonstrate that the spatiotemporal pattern of Cic during this signaling event can be harnessed for functional studies of the Ras-pathway mutations from human diseases. Our approach relies on a new microfluidic device that enables parallel imaging of Cic dynamics in dozens of live embryos. We found that although the pattern of Cic in early embryos is complex, it can be accurately approximated by a product of one spatial profile and one time-dependent amplitude...
May 11, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28488382/neuron-specific-knockdown-of-the-drosophila-fat-induces-reduction-of-life-span-deficient-locomotive-ability-shortening-of-motoneuron-terminal-branches-and-defects-in-axonal-targeting
#7
Aya Nakamura, Ryo Tanaka, Kazushige Morishita, Hideki Yoshida, Yujiro Higuchi, Hiroshi Takashima, Masamitsu Yamaguchi
Mutations in FAT4 gene, one of the human FAT family genes, have been identified in Van Maldergem syndrome (VMS) and Hennekam lymphangiectasia-lymphedema syndrome (HS). The FAT4 gene encodes a large protein with extracellular cadherin repeats, EGF-like domains and Laminin G-like domains. FAT4 plays a role in tumor suppression and planar cell polarity. Drosophila contains a human FAT4 homologue, fat. Drosophila fat has been mainly studied with Drosophila eye and wing systems. Here, we specially knocked down Drosophila fat in nerve system...
May 9, 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/28485711/mctp-is-an-er-resident-calcium-sensor-that-stabilizes-synaptic-transmission-and-homeostatic-plasticity
#8
Özgür Genç, Dion Kai Dickman, Wenpei Ma, Amy Tong, Richard D Fetter, Graeme W Davis
Presynaptic homeostatic plasticity (PHP) controls synaptic transmission in organisms from Drosophila to human and is hypothesized to be relevant to the cause of human disease. However, the underlying molecular mechanisms of PHP are just emerging and direct disease associations remain obscure. In a forward genetic screen for mutations that block PHP we identified mctp (Multiple C2 Domain Proteins with Two Transmembrane Regions). Here we show that MCTP localizes to the membranes of the endoplasmic reticulum (ER) that elaborate throughout the soma, dendrites, axon and presynaptic terminal...
May 9, 2017: ELife
https://www.readbyqxmd.com/read/28467418/a-kcnc3-mutation-causes-a-neurodevelopmental-non-progressive-sca13-subtype-associated-with-dominant-negative-effects-and-aberrant-egfr-trafficking
#9
Swati Khare, Jerelyn A Nick, Yalan Zhang, Kira Galeano, Brittany Butler, Habibeh Khoshbouei, Sruti Rayaprolu, Tyisha Hathorn, Laura P W Ranum, Lisa Smithson, Todd E Golde, Martin Paucar, Richard Morse, Michael Raff, Julie Simon, Magnus Nordenskjöld, Karin Wirdefeldt, Diego E Rincon-Limas, Jada Lewis, Leonard K Kaczmarek, Pedro Fernandez-Funez, Harry S Nick, Michael F Waters
The autosomal dominant spinocerebellar ataxias (SCAs) are a diverse group of neurological disorders anchored by the phenotypes of motor incoordination and cerebellar atrophy. Disease heterogeneity is appreciated through varying comorbidities: dysarthria, dysphagia, oculomotor and/or retinal abnormalities, motor neuron pathology, epilepsy, cognitive impairment, autonomic dysfunction, and psychiatric manifestations. Our study focuses on SCA13, which is caused by several allelic variants in the voltage-gated potassium channel KCNC3 (Kv3...
2017: PloS One
https://www.readbyqxmd.com/read/28455141/identification-of-potential-therapeutic-compounds-for-parkinson-s-disease-using-drosophila-and-human-cell-models
#10
Francisco José Sanz, Cristina Solana-Manrique, Verónica Muñoz-Soriano, Pablo Calap-Quintana, María Dolores Moltó, Nuria Paricio
Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. It is caused by a loss of dopaminergic neurons in the substantia nigra pars compacta, leading to a decrease in dopamine levels in the striatum and thus producing movement impairment. Major physiological causes of neurodegeneration in PD are oxidative stress (OS) and mitochondrial dysfunction; these pathophysiological changes can be caused by both genetic and environmental factors. Although most PD cases are sporadic, it has been shown that 5-10% of them are familial forms caused by mutations in certain genes...
April 25, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28438980/host-and-bacterial-factors-control-susceptibility-of-drosophila-melanogaster-to-coxiella-burnetii-infection
#11
Reginaldo G Bastos, Zachary P Howard, Aoi Hiroyasu, Alan G Goodman
Coxiella burnetii is the causative agent of Q fever, a zoonotic disease that threatens both human and animal health. Due to the paucity of experimental animal models, little is known about how host factors interface with bacterial components and affect pathogenesis. Here we used Drosophila melanogaster, in conjunction with the BSL2 Nine Mile phase II (NMII) clone 4 strain of C. burnetii, as a model to investigate host and bacterial components implicated in infection. We demonstrated that adult Drosophila are susceptible to C...
April 24, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28428331/a-personalized-model-of-coq2-nephropathy-rescued-by-the-wild-type-coq2-allele-or-dietary-coenzyme-q10-supplementation
#12
Jun-Yi Zhu, Yulong Fu, Adam Richman, Zhanzheng Zhao, Patricio E Ray, Zhe Han
Clinical studies have identified patients with nephrotic syndrome caused by mutations in genes involved in the biosynthesis of coenzyme Q10 (CoQ10), a lipid component of the mitochondrial electron transport chain and an important antioxidant. However, the cellular mechanisms through which these mutations induce podocyte injury remain obscure. Here, we exploited the striking similarities between Drosophila nephrocytes and human podocytes to develop a Drosophila model of these renal diseases, and performed a systematic in vivo analysis assessing the role of CoQ10 pathway genes in renal function...
April 20, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28420493/etiology-of-human-genetic-disease-on-the-fly
#13
REVIEW
Clement Y Chow, Lawrence T Reiter
The model organism Drosophila melanogaster has been at the forefront of genetic studies since before the discovery of DNA. Although human disease modeling in flies may still be rather novel, recent advances in genetic tool design and genome sequencing now confer huge advantages in the fly system when modeling human disease. In this review, we focus on new genomic tools for human gene variant analysis; new uses for the Drosophila Genetic Reference Panel (DGRP) in detection of background alleles that influence a phenotype; and several examples of how multigenic conditions, both complex disorders and duplication and/or deletion syndromes, can be effectively studied in the fly model system...
April 15, 2017: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/28418693/validating-the-predicted-effect-of-astemizole-and-ketoconazole-using-a-drosophila-model-of-parkinson-s-disease
#14
Katarzyna Styczyńska-Soczka, Luigi Zechini, Lysimachos Zografos
Parkinson's disease is a growing threat to an ever-ageing population. Despite progress in our understanding of the molecular and cellular mechanisms underlying the disease, all therapeutics currently available only act to improve symptoms and do not stop the disease process. It is therefore imperative that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson's. Drug repurposing has been recognized as being equally as promising as de novo drug discovery in the field of neurodegeneration and Parkinson's disease specifically...
April 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28415023/drosophila-models-of-prionopathies-insight-into-prion-protein-function-transmission-and-neurotoxicity
#15
REVIEW
Pedro Fernandez-Funez, Jonatan Sanchez-Garcia, Diego E Rincon-Limas
Prion diseases (PrD) are unique neurodegenerative conditions with sporadic, genetic, and infectious etiologies. The agent responsible for these pathologies is a misfolded conformation of the prion protein (PrP). Although a process of autocatalytic "conversion" is known to mediate disease transmission, important gaps still remain regarding the physiological function of PrP and its relevance to pathogenesis, the molecular and cellular mechanisms mediating neurotoxicity and transmission, and the PrP conformations responsible for neurotoxicity...
April 14, 2017: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/28409340/drosophila-malpighian-tubules-a-model-for-understanding-kidney-development-function-and-disease
#16
Naveen Kumar Gautam, Puja Verma, Madhu G Tapadia
The Malpighian tubules of insects are structurally simple but functionally important organs, and their integrity is important for the normal excretory process. They are functional analogs of human kidneys which are important physiological organs as they maintain water and electrolyte balance in the blood and simultaneously help the body to get rid of waste and toxic products after various metabolic activities. In addition, it receives early indications of insults to the body such as immune challenge and other toxic components and is essential for sustaining life...
2017: Results and Problems in Cell Differentiation
https://www.readbyqxmd.com/read/28406522/inhibition-of-polyglutamine-aggregation-by-similar-huntingtin-n-terminal-sequences-prospective-molecules-for-preclinical-evaluation-in-huntington-s-disease
#17
Gunasekhar Burra, Ashwani Kumar Thakur
The mutant huntingtin protein (mHtt) fragments with expanded polyglutamine sequence forms microscopically visible aggregates in neurons, a hallmark of Huntington's disease (HD). The aggregation process and aggregates are possible targets of therapeutic intervention in HD. Due to lack of treatment and cure, the patients die within 15-20 years after the disease onset. Therefore, discovering therapeutic molecules that may either inhibit the aggregation mechanism or downregulate the toxic effects of mhtt are highly needed...
April 12, 2017: Biopolymers
https://www.readbyqxmd.com/read/28405636/when-transporters-fail-to-be-transported-how-to-rescue-folding-deficient-slc6-transporters
#18
Sonja Sucic, Ameya Kasture, H M Mazhar Asjad, Carina Kern, Ali El-Kasaby, Michael Freissmuth
The human dopamine transporter (hDAT) belongs to the solute carrier 6 (SLC6) gene family. Point mutations in hDAT (SLC6A3) have been linked to a syndrome of dopamine transporter deficiency or infantile dystonia/parkinsonism. The mutations impair DAT folding, causing retention of variant DATs in the endoplasmic reticulum and subsequently impair transport activity. The folding trajectory of DAT itself is not understood, though many insights have been gained from studies of folding-deficient mutants of the closely related serotonin transporter (SERT); i...
December 30, 2016: Journal of Neurology & Neuromedicine
https://www.readbyqxmd.com/read/28404605/proteomics-analysis-identifies-orthologs-of-human-chitinase-like-proteins-as-inducers-of-tube-morphogenesis-defects-in-drosophila
#19
Sandra G Zimmerman, Gennifer E Merrihew, Michael J MacCoss, Celeste A Berg
Elevated levels of human chitinase-like proteins (CLPs) are associated with numerous chronic inflammatory diseases and several cancers, often correlating with poor prognosis. Nevertheless, there is scant knowledge of their function. The CLPs normally mediate immune responses and wound healing, and when upregulated, they can promote disease progression by remodeling tissue, activating signaling cascades, stimulating proliferation and migration, and by regulating adhesion. We identified Imaginal disc growth factors (Idgfs), orthologs of human CLPs CHI3L1, CHI3L2, and OVGP1, in a proteomics analysis designed to discover factors that regulate tube morphogenesis in a Drosophila melanogaster model of tube formation...
April 12, 2017: Genetics
https://www.readbyqxmd.com/read/28401457/comparative-studies-of-vertebrate-iduronate-2-sulfatase-ids-genes-and-proteins-evolution-of-a-mammalian-x-linked-gene
#20
REVIEW
Roger S Holmes
IDS is responsible for the lysosomal degradation of heparan sulfate and dermatan sulfate and linked to an X-linked lysosomal storage disease, mucopolysaccharidosis 2 (MPS2), resulting in neurological damage and early death. Comparative IDS amino acid sequences and structures and IDS gene locations were examined using data from several vertebrate genome projects. Vertebrate IDS sequences shared 60-99% identities with each other. Human IDS showed 47% sequence identity with fruit fly (Drosophila melanogaster) IDS...
May 2017: 3 Biotech
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