title: Modeling Huntington disease in Drosophila: Insights into axonal transport defects and modifiers of toxicity.
abstract: Huntington disease (HD) is an inherited neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in the huntingtin (Htt) gene. Despite years of research, there is no treatment that extends life for patients with the disorder. Similarly, little is known about which cellular pathways that are altered by pathogenic Huntingtin (Htt) protein expression are correlated with neuronal loss. As part of a longstanding effort to gain insights into HD pathology, we have been studying the protein in the context of the fruitfly Drosophila melanogaster. We generated transgenic HD models in Drosophila by engineering flies that carry a 12-exon fragment of the human Htt gene with or without the toxic trinucleotide repeat expansion. We also created variants with a monomeric red fluorescent protein (mRFP) tag fused to Htt that allows in vivo imaging of Htt protein localization and aggregation. While wild-type Htt remains diffuse throughout the cytoplasm of cells, pathogenic Htt forms insoluble aggregates that accumulate in neuronal soma and axons. Aggregates can physically block transport of numerous organelles along the axon. We have also observed that aggregates are formed quickly, within just a few hours of mutant Htt expression. To explore mechanisms of neurodegeneration in our HD model, we performed in vivo and in vitro screens to search for modifiers of viability and pathogenic Htt aggregation. Our results identified several novel candidates for HD therapeutics that can now be tested in mammalian models of HD. Furthermore, these experiments have highlighted the complex relationship between aggregates and toxicity that exists in HD.
authors.affiliation: The Picower Institute for Learning and Memory; Department of Brain and Cognitive Sciences; Department of Biology; Massachusetts Institute of Technology; Cambridge, MA USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Krench
authors.affiliation: The Picower Institute for Learning and Memory; Department of Brain and Cognitive Sciences; Department of Biology; Massachusetts Institute of Technology; Cambridge, MA USA.
authors.forename: J Troy
authors.initials: JT
authors.lastname: Littleton
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000378:metabolism; D001692:Biological Transport; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000235:genetics*; D066329:Protein Aggregates
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D066329:Protein Aggregates
keywords: Drosophila; Huntington disease; aggregates; axonal transport; polyglutamine
references.citation: J Biol Chem. 2006 Jun 9;281(23):15916-22
references.pmid: 16595690
references.citation: Annu Rev Neurosci. 2007;30:575-621
references.pmid: 17417937
references.citation: Hum Mol Genet. 2005 Nov 15;14(22):3425-33
references.pmid: 16204350
references.citation: Brain Res. 2008 Jan 10;1188:61-8
references.pmid: 18062944
references.citation: Nature. 2004 Oct 14;431(7010):805-10
references.pmid: 15483602
references.citation: PLoS One. 2011;6(8):e23841
references.pmid: 21909362
references.citation: Mol Cell Neurosci. 2009 Feb;40(2):121-7
references.pmid: 18992820
references.citation: Trends Biochem Sci. 2003 Aug;28(8):425-33
references.pmid: 12932731
references.citation: N Engl J Med. 1986 Nov 13;315(20):1267-76
references.pmid: 2877396
references.citation: Neuron. 2005 May 5;46(3):433-44
references.pmid: 15882643
references.citation: Cell. 1993 Mar 26;72(6):971-83
references.pmid: 8458085
references.citation: Cell. 2009 Apr 3;137(1):60-72
references.pmid: 19345187
references.citation: Genetics. 2012 Feb;190(2):581-600
references.pmid: 22095086
references.citation: Neurobiol Dis. 2009 May;34(2):389-95
references.pmid: 19268537
references.citation: Hum Mol Genet. 1999 Sep;8(9):1807-15
references.pmid: 10441347
references.citation: PLoS One. 2010 Dec 28;5(12):e15245
references.pmid: 21209946
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9701-5
references.pmid: 10920207
references.citation: Hum Mol Genet. 2011 Apr 1;20(7):1424-37
references.pmid: 21245084
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16685-9
references.pmid: 17925440
references.citation: Nat Genet. 1999 Dec;23(4):425-8
references.pmid: 10581028
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):892-7
references.pmid: 15642944
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3224-9
references.pmid: 14978262
references.citation: Hum Mol Genet. 2000 Jan 1;9(1):13-25
references.pmid: 10587574
references.citation: Nat Chem Biol. 2011 May 29;7(7):453-60
references.pmid: 21623356
references.citation: Neuron. 2003 Sep 25;40(1):25-40
references.pmid: 14527431
references.citation: Curr Med Chem. 2010;17(27):3058-68
references.pmid: 20629626
references.citation: Neuron. 2010 Sep 23;67(6):897-9
references.pmid: 20869586
references.citation: Mol Cell Biol. 2004 Sep;24(18):8195-209
references.pmid: 15340079
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2898-903
references.pmid: 10717003
references.citation: Curr Opin Neurobiol. 2007 Feb;17(1):35-42
references.pmid: 17229568
references.citation: J Neurocytol. 2000 Sep;29(9):679-702
references.pmid: 11353291
references.citation: J Neurosci. 2001 Nov 1;21(21):8473-81
references.pmid: 11606636
references.citation: Cell. 2000 Mar 31;101(1):57-66
references.pmid: 10778856
references.citation: Neuron. 2008 Jan 10;57(1):27-40
references.pmid: 18184562
references.citation: Cell. 2006 Jun 16;125(6):1179-91
references.pmid: 16777606
references.citation: Lancet. 2007 Jan 20;369(9557):218-28
references.pmid: 17240289
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11402-7
references.pmid: 16076956