ArticleNature2015
GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport.
Article in Nature, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 547 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
547 citing papers in PubMed, 1 synthesis or guideline pooled it, 860 citations in OpenAlex.
- Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD - a Systematic Review and Meta-Analysis.Cerebellum (London, England) · 2022Pooled it
- Two dipeptide repeat proteins are produced from mammalian telomeric RNA previously thought to be a long non-coding RNA.RNA biology · 2026Review
- Importin-8 silencing reduces Ataxin-3 aggregation and alleviates Machado-Joseph disease/spinocerebellar ataxia type 3.iScience · 2026Article
- Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation.Nucleic acids research · 2026Article
- Revealing the Mechanisms of Alzheimer's, Parkinson's and Huntington's Diseases Through Invertebrate Models.Biology · 2026Review
- Glial cell toxicity in a Drosophila C9orf72 neurodegeneration model.PLoS genetics · 2026Article
- Innate immune crosstalk in ALS/FTD pathogenesis.Cell insight · 2026Review
- Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation.bioRxiv : the preprint server for biology · 2026Article
- Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress.Nature communications · 2026Article
- Article
- The contribution of short tandem repeats to splicing variation in the human cortex.bioRxiv : the preprint server for biology · 2026Article
- Pathologies at the gateway: exploring the link between nucleoporins and inherited diseases.Cellular and molecular life sciences : CMLS · 2026Review
- TMEM106B C-terminal fragments drive nucleocytoplasmic transport failure and TDP-43 mislocalization in the aging human brain.bioRxiv : the preprint server for biology · 2026Article
- Phototriggered Morphological and Compositional Change of UGGAA Repeat RNA Foci by Photoswitchable RNA-Binding Ligand.Angewandte Chemie (International ed. in English) · 2026Article
- Predictive Cellular Signatures from Live Human Motor Neurons Distinguish TDP-43 ALS and Enable ALS Subtype Stratification.bioRxiv : the preprint server for biology · 2026Article
- Direct targeting of C9ORF72 repeat RNA with fluorinated antisense oligonucleotides.Nucleic acids research · 2026Article
- Experimental Models to Study Polyglutamine Spinocerebellar Ataxias: From Mechanisms to Therapeutic Developments.Cerebellum (London, England) · 2026Review
- Splicing the narrative: alternative TARDBP splicing and its relation to neurodegeneration in ALS and FTD.The Journal of clinical investigation · 2026Review
- Increased neuronal activity restores circadian function in Drosophila models of C9orf72-ALS/FTD.iScience · 2026Article
- Aberrant CDK4/6-driven cell-cycle reentry drives neuronal loss and defines a therapeutic target in C9orf72 ALS/FTD.iScience · 2026Article
487 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 5 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.