title: Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration.
abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share phenotypic and pathologic overlap. Recently, an expansion of GGGGCC repeats in the first intron of C9orf72 was found to be a common cause of both illnesses; however, the molecular pathogenesis of this expanded repeat is unknown. Here we developed both Drosophila and mammalian models of this expanded hexanucleotide repeat and showed that expression of the expanded GGGGCC repeat RNA (rGGGGCC) is sufficient to cause neurodegeneration. We further identified Pur α as the RNA-binding protein of rGGGGCC repeats and discovered that Pur α and rGGGGCC repeats interact in vitro and in vivo in a sequence-specific fashion that is conserved between mammals and Drosophila. Furthermore, overexpression of Pur α in mouse neuronal cells and Drosophila mitigates rGGGGCC repeat-mediated neurodegeneration, and Pur α forms inclusions in the fly eye expressing expanded rGGGGCC repeats, as well as in cerebellum of human carriers of expanded GGGGCC repeats. These data suggest that expanded rGGGGCC repeats could sequester specific RNA-binding protein from their normal functions, ultimately leading to cell death. Taken together, these findings suggest that the expanded rGGGGCC repeats could cause neurodegeneration, and that Pur α may play a role in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia.
authors.affiliation: Department of Human Genetics, Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Zihui
authors.initials: Z
authors.lastname: Xu
authors.forename: Mickael
authors.initials: M
authors.lastname: Poidevin
authors.forename: Xuekun
authors.initials: X
authors.lastname: Li
authors.forename: Yujing
authors.initials: Y
authors.lastname: Li
authors.forename: Liqi
authors.initials: L
authors.lastname: Shu
authors.forename: David L
authors.initials: DL
authors.lastname: Nelson
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.forename: Chadwick M
authors.initials: CM
authors.lastname: Hales
authors.forename: Marla
authors.initials: M
authors.lastname: Gearing
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Wingo
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000473:pathology; D042622:DNA Repeat Expansion; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D005091:Exons; D057180:Frontotemporal Dementia / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007438:Introns; D051379:Mice; D009046:Motor Neurons / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics; D016366:Open Reading Frames; D010957:Plasmids / Q000378:metabolism; D012313:RNA / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D009841:Oligonucleotides; C501130:PURA protein, human; C545199:Pur-alpha protein, Drosophila; C121485:Pura protein, mouse; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D012313:RNA
keywords: RNA-mediated neurodegeneration; fly model
references.citation: Neurology. 2005 Aug 23;65(4):586-90
references.pmid: 16116120
references.citation: Science. 2009 Feb 27;323(5918):1208-1211
references.pmid: 19251628
references.citation: Lancet Neurol. 2012 Apr;11(4):323-30
references.pmid: 22406228
references.citation: Nat Genet. 2008 May;40(5):572-4
references.pmid: 18372902
references.citation: Annu Rev Neurosci. 2006;29:259-77
references.pmid: 16776586
references.citation: Acta Neuropathol. 2005 Jan;109(1):5-13
references.pmid: 15645263
references.citation: Development. 1993 Jun;118(2):401-15
references.pmid: 8223268
references.citation: Neuron. 2003 Aug 28;39(5):739-47
references.pmid: 12948442
references.citation: Science. 2013 Mar 15;339(6125):1335-8
references.pmid: 23393093
references.citation: Ann Neurol. 2007 May;61(5):427-34
references.pmid: 17469116
references.citation: J Mol Neurosci. 2011 Nov;45(3):663-75
references.pmid: 21901496
references.citation: J Med Genet. 2009 Feb;46(2):112-4
references.pmid: 18931000
references.citation: Neuron. 2011 Oct 20;72(2):257-68
references.pmid: 21944779
references.citation: Neuron. 2007 Aug 16;55(4):565-71
references.pmid: 17698010
references.citation: Lancet Neurol. 2012 Jan;11(1):54-65
references.pmid: 22154785
references.citation: Neuron. 2007 Aug 16;55(4):556-64
references.pmid: 17698009
references.citation: Acta Neuropathol. 2011 Dec;122(6):691-702
references.pmid: 22101323
references.citation: J Proteome Res. 2012 May 4;11(5):2721-38
references.pmid: 22416763
references.citation: Acta Neuropathol. 2013 Mar;125(3):413-23
references.pmid: 23381195
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):260-5
references.pmid: 21173221
references.citation: Neuron. 2011 Oct 20;72(2):245-56
references.pmid: 21944778
references.citation: Science. 2009 Feb 27;323(5918):1205-8
references.pmid: 19251627
references.citation: Brain. 2012 Mar;135(Pt 3):693-708
references.pmid: 22300873
references.citation: Neurology. 2002 Oct 8;59(7):1077-9
references.pmid: 12370467
references.citation: Nat Rev Neurol. 2012 Aug;8(8):423-34
references.pmid: 22732773
references.citation: Neuron. 2013 Feb 20;77(4):639-46
references.pmid: 23415312
references.citation: Cell Cycle. 2009 Feb 1;8(3):1-7
references.pmid: 19182532
references.citation: Neuron. 2004 Aug 19;43(4):513-25
references.pmid: 15312650
references.citation: Neurobiol Aging. 2012 Dec;33(12):2950.e5-7
references.pmid: 22840558
references.citation: Brain. 2012 Mar;135(Pt 3):723-35
references.pmid: 22300876
references.citation: Science. 2006 Oct 6;314(5796):130-3
references.pmid: 17023659