GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport
Open accessAbstract
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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Genetic screens in ALS model systems have repeatedly uncovered nuclear pore and nucleocytoplasmic transport factors as potent disease modifiers.
“Genetic screens in ALS model systems have repeatedly uncovered nuclear pore and nucleocytoplasmic transport factors as potent disease modifiers, confirming the significance of these pathways in disease pathogenesis (9–11).”
From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [11]
The paper’s study description reports one genetic screen in a C9ORF72 ALS/FTD fly model that identified nuclear pore and nucleocytoplasmic transport genes as modifiers. It also identifies strong suppressors and links transport defects to degeneration. This source supports an instance of the finding, but does not itself establish that genetic screens have repeatedly found it. (LLM, conf=0.85)
Experimental — accuracy not yet measuredDisruption of the Ran gradient, mislocalization of nuclear pore components, and disturbance of nuclear pore architecture have likewise been described in ALS/FTLD-TDP samples and disease models.
“Disruption of the Ran gradient, mislocalization of nuclear pore components, and disturbance of nuclear pore architecture — all of which we observed upon NLK overexpression — have likewise been described in ALS/FTLD-TDP samples and disease models (9–11, 50).”
From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [11]
The paper’s results (Fig. 3a–c; page unavailable in our copy) describe mislocalized Nup107 and abnormal nuclear-envelope architecture in a C9ORF72 repeat-expansion fly model. Its patient-derived neurons show altered RNA distribution, but the copy does not describe a disrupted Ran gradient or establish these structural findings across ALS/FTLD-TDP samples generally. (LLM, conf=0.86)
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- Authors
- Freibaum, B. D., Lu, Y., Lopez-Gonzalez, R., Kim, N. C., Almeida, S., Lee, K.-H., Badders, N., Valentine, M., Miller, B. L., Wong, P. C., Petrucelli, L., Kim, H. J., Gao, F.-B., & Taylor, J. P.
- Affiliations
- St. Jude Children's Research Hospital (US)
- University of Massachusetts Chan Medical School (US)
- University of California, San Francisco (US)
- Johns Hopkins University (US)
- Mayo Clinic in Florida (US)
- Corresponding author
- Gao, Fen-Biao
- Taylor, J. Paul
- ORCID
- Venue
- Nature
- Published
- 2015-08-26
- Volume
- 525
- Issue
- 7567
- Pages
- 129-133
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4631399
- OpenAlex
- W1796096082
- Cited by
- 841
- References
- 6
- Citations by year
- 2026: 35 · 2025: 48 · 2024: 61 · 2023: 57 · 2022: 62 · 2021: 102 · 2020: 96 · 2019: 83 · 2018: 95 · 2017: 91 · 2016: 90 · 2015: 21
- FWCI
- 69.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Public Health Service (N079725)
- National Institute on Aging (P50AG005146, AG019724, P01AG019724)
- National Cancer Institute (P30CA021765)
- National Institute of Neurological Disorders and Stroke (NS079725, R01NS057553, R01NS079725)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- C9orf72, G4C2 repeat expansion, nuclear transport, amyotrophic lateral sclerosis, frontotemporal dementia, RanGAP, nuclear pores, dipeptide repeat proteins, repeat-associated non-AUG translation, G-quadruplex, antisense oligonucleotides, small molecules, neurodegeneration
- MeSH terms
- C9orf72 Protein, Amyotrophic Lateral Sclerosis, Animals, Drosophila melanogaster, Eye, Female, HeLa Cells, Humans, Male, Muscles, Neurons, Phenotype, Proteins, RNA, Salivary Glands, Protein Biosynthesis, Open Reading Frames, Active Transport, Cell Nucleus, Nuclear Pore, Animals, Genetically Modified, RNA Transport, DNA Repeat Expansion, Induced Pluripotent Stem Cells, Frontotemporal Dementia
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