GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport.

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  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE
    • Publication Information:
      Publication: Basingstoke : Nature Publishing Group
      Original Publication: London, Macmillan Journals ltd.
    • Subject Terms:
    • Abstract:
      The GGGGCC (G4C2) repeat expansion in a noncoding region of C9orf72 is the most common cause of sporadic and familial forms of amyotrophic lateral sclerosis and frontotemporal dementia. The basis for pathogenesis is unknown. To elucidate the consequences of G4C2 repeat expansion in a tractable genetic system, we generated transgenic fly lines expressing 8, 28 or 58 G4C2-repeat-containing transcripts that do not have a translation start site (AUG) but contain an open-reading frame for green fluorescent protein to detect repeat-associated non-AUG (RAN) translation. We show that these transgenic animals display dosage-dependent, repeat-length-dependent degeneration in neuronal tissues and RAN translation of dipeptide repeat (DPR) proteins, as observed in patients with C9orf72-related disease. This model was used in a large-scale, unbiased genetic screen, ultimately leading to the identification of 18 genetic modifiers that encode components of the nuclear pore complex (NPC), as well as the machinery that coordinates the export of nuclear RNA and the import of nuclear proteins. Consistent with these results, we found morphological abnormalities in the architecture of the nuclear envelope in cells expressing expanded G4C2 repeats in vitro and in vivo. Moreover, we identified a substantial defect in RNA export resulting in retention of RNA in the nuclei of Drosophila cells expressing expanded G4C2 repeats and also in mammalian cells, including aged induced pluripotent stem-cell-derived neurons from patients with C9orf72-related disease. These studies show that a primary consequence of G4C2 repeat expansion is the compromise of nucleocytoplasmic transport through the nuclear pore, revealing a novel mechanism of neurodegeneration.
    • Comments:
      Comment in: Nature. 2015 Sep 3;525(7567):36-7. (PMID: 26308896)
      Comment in: Nat Rev Neurol. 2015 Dec;11(12):670-2. (PMID: 26526532)
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    • Grant Information:
      NS079725 United States NS NINDS NIH HHS; P50 AG005146 United States AG NIA NIH HHS; P01 AG019724 United States AG NIA NIH HHS; P30 CA021765 United States CA NCI NIH HHS; AG019724 United States AG NIA NIH HHS; United States Howard Hughes Medical Institute; R01 NS057553 United States NS NINDS NIH HHS; N079725 United States PHS HHS; R01 NS079725 United States NS NINDS NIH HHS
    • Accession Number:
      0 (C9orf72 Protein)
      0 (C9orf72 protein, human)
      0 (Proteins)
      63231-63-0 (RNA)
    • Publication Date:
      Date Created: 20150827 Date Completed: 20151001 Latest Revision: 20181113
    • Publication Date:
      20240104
    • Accession Number:
      PMC4631399
    • Accession Number:
      10.1038/nature14974
    • Accession Number:
      26308899