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      The Tiny Drosophila Melanogaster for the Biggest Answers in Huntington’s Disease

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          Abstract

          The average life expectancy for humans has increased over the last years. However, the quality of the later stages of life is low and is considered a public health issue of global importance. Late adulthood and the transition into the later stage of life occasionally leads to neurodegenerative diseases that selectively affect different types of neurons and brain regions, producing motor dysfunctions, cognitive impairment, and psychiatric disorders that are progressive, irreversible, without remission periods, and incurable. Huntington’s disease (HD) is a common neurodegenerative disorder. In the 25 years since the mutation of the huntingtin ( HTT) gene was identified as the molecule responsible for this neural disorder, a variety of animal models, including the fruit fly, have been used to study the disease. Here, we review recent research that used Drosophila as an experimental tool for improving knowledge about the molecular and cellular mechanisms underpinning HD.

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          Most cited references111

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          Evolution of genes and genomes on the Drosophila phylogeny.

          Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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            TOR, a Central Controller of Cell Growth

            Cell, 103(2), 253-262
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              Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila.

              Proteins with expanded polyglutamine repeats cause Huntington's disease and other neurodegenerative diseases. Transcriptional dysregulation and loss of function of transcriptional co-activator proteins have been implicated in the pathogenesis of these diseases. Huntington's disease is caused by expansion of a repeated sequence of the amino acid glutamine in the abnormal protein huntingtin (Htt). Here we show that the polyglutamine-containing domain of Htt, Htt exon 1 protein (Httex1p), directly binds the acetyltransferase domains of two distinct proteins: CREB-binding protein (CBP) and p300/CBP-associated factor (P/CAF). In cell-free assays, Httex1p also inhibits the acetyltransferase activity of at least three enzymes: p300, P/CAF and CBP. Expression of Httex1p in cultured cells reduces the level of the acetylated histones H3 and H4, and this reduction can be reversed by administering inhibitors of histone deacetylase (HDAC). In vivo, HDAC inhibitors arrest ongoing progressive neuronal degeneration induced by polyglutamine repeat expansion, and they reduce lethality in two Drosophila models of polyglutamine disease. These findings raise the possibility that therapy with HDAC inhibitors may slow or prevent the progressive neurodegeneration seen in Huntington's disease and other polyglutamine-repeat diseases, even after the onset of symptoms.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                14 August 2018
                August 2018
                : 19
                : 8
                : 2398
                Affiliations
                [1 ]Unidad de Imagenología, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
                [2 ]Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden; argel.estrada@ 123456comunidad.unam.mx
                [3 ]Laboratorio de Neurociencias, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago 9160000, Chile; ricardop@ 123456ug.uchile.cl
                [4 ]Departamento de Ciencias Químicas y Biológicas, Universidad Bernardo O’Higgins, Santiago 8370993, Chile
                [5 ]Facultad de Ciencias de la Salud, Universidad de Las Américas, Santiago 7500972, Chile; carola.mantellero@ 123456usach.cl
                [6 ]Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia 5090000, Chile
                [7 ]Center for Interdisciplinary Studies on the Nervous System (CISNe), Universidad Austral de Chile, Valdivia 5090000, Chile
                Author notes
                [* ]Correspondence: arosasar@ 123456email.ifc.unam.mx or a_rosasar@ 123456fisio.cinvestav.mx (A.R.-A.); macastro@ 123456uach.cl (M.A.C.); Tel.: +52-555-622-5610 (A.R.-A.); +56-632-221-474 (M.A.C.); Fax: +56-632-221-332 (M.A.C.)
                Author information
                https://orcid.org/0000-0003-1422-9538
                https://orcid.org/0000-0002-1359-4659
                https://orcid.org/0000-0003-1422-9538
                Article
                ijms-19-02398
                10.3390/ijms19082398
                6121572
                30110961
                d018b527-1ed4-457c-be45-3f2b44c6cda5
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 02 July 2018
                : 09 August 2018
                Categories
                Review

                Molecular biology
                neurodegenerative diseases,it15,lomars,htt,hd,huntingtin,mhtt,polyq,polyglutamine disorders,chorea,neostriatum,fruit fly

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