The C9orf72 repeat expansion disrupts nucleocytoplasmic transport.
Open accessAbstract
The hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G4C2 RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.
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Disruption of NCC is a well-established effect of aging across species and is directly associated with ALS and FTD.
“Disruption of NCC is a well-established effect of aging across species and is directly associated with other diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).”
From Chemically induced reprogramming to reverse cellular aging (2023) · cites this paper as [62]
The Discussion (page unavailable) links nucleocytoplasmic transport defects to C9ORF72-associated ALS and FTD. It also says nuclear pore integrity is lost during normal aging, but describes a role for pore dysfunction in age-related neurodegeneration as speculative; it does not establish transport disruption as an effect of aging across species. (LLM, conf=0.87)
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 [10]
The Results section on the Ran gradient reports a reduced nuclear-to-cytoplasmic Ran ratio in C9-ALS iPS neurons, while the nuclear-pore-pathology Results and Extended Data describe abnormal RanGAP1, Nup205, and Nup107 localization in C9-ALS patient tissue and models. The paper does not establish a disturbance of nuclear pore architecture as distinct from component pathology, or document all three findings across ALS/FTLD-TDP samples and models generally. (LLM, conf=0.86)
Experimental — accuracy not yet measuredGenetic 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 [10]
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Hawrot, J., Imhof, S., & Wainger, B. J. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104680 · Cited by 74 · see citing works
Todd, T. W., & Petrucelli, L. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13623 · Cited by 73 · see citing works
Dysregulation of chromatin remodelling complexes in amyotrophic lateral sclerosis
Tibshirani, M., Zhao, B., Gentil, B. J., Minotti, S., Marques, C., Keith, J., Rogaeva, E., Zinman, L., Rouaux, C., Robertson, J., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx301 · Cited by 42 · see citing works
Axon Biology in ALS: Mechanisms of Axon Degeneration and Prospects for Therapy
Coleman, M. P. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01297-6 · Cited by 33 · see citing works
“For example, the neurotoxicity of C9orf72 hexanucleotide repeat expansions, the most common known cause of familial ALS and a common risk factor for sporadic ALS, can be potently suppressed in Drosophila by RanGAP, a regulator of nuclear-cytoplasmic transport [42], and there is additional support for such a mechanism…”
BackgroundStatus of ALS treatment, insights into therapeutic challenges and dilemmas
Khamaysa, M., & Pradat, P.-F. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12101601 · Cited by 28 · see citing works
Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS
Bekier, M. E., Pinarbasi, E., Krishnan, G., Mesojedec, J. J., Hurley, M., Harikumar Sheela, H., Collins, C. A., Ghaffari, L., de Majo, M., Ullian, E. M., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci188138 · Cited by 2 · see citing works
“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 (10–12).”
- Authors
- Zhang, K., Donnelly, C. J., Haeusler, A. R., Grima, J. C., Machamer, J. B., Steinwald, P., Daley, E. L., Miller, S. J., Cunningham, K. M., Vidensky, S., Gupta, S., Thomas, M. A., Hong, I., Chiu, S.-L., Huganir, R. L., Ostrow, L. W., Matunis, M. J., Wang, J., Sattler, R., Lloyd, T. E., & Rothstein, J. D.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Lloyd, Thomas E.
- Rothstein, Jeffrey D.
- ORCID
- Venue
- Nature
- Published
- 2015-08-26
- Volume
- 525
- Issue
- 7567
- Pages
- 56-61
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4800742
- OpenAlex
- W1797572428
- Cited by
- 982
- References
- 50
- Citations by year
- 2026: 40 · 2025: 56 · 2024: 74 · 2023: 74 · 2022: 71 · 2021: 130 · 2020: 113 · 2019: 92 · 2018: 110 · 2017: 98 · 2016: 102 · 2015: 22
- FWCI
- 77.72
- 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)
- Funders
- National Institutes of Health (P40OD018537)
- National Institute on Aging (P01AG012992)
- National Cancer Institute (CA009110, T32CA009110)
- National Institute of General Medical Sciences (R01GM084947, R01GM060980)
- National Institute of Neurological Disorders and Stroke (R00NS091486, R01NS085207, NS089616, U54NS091046, K99NS091486, NS091046, RC2NS069395, U24NS078736, R01NS082563, R01NS094239, R01NS074324, R01NS089616)
- 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, hexanucleotide repeat expansion, amyotrophic lateral sclerosis, frontotemporal dementia, RanGAP1, RanGAP, nuclear transport, nuclear import, nuclear export, G-quadruplex, antisense oligonucleotides, small molecules, neurodegeneration
- MeSH terms
- C9orf72 Protein, Amyotrophic Lateral Sclerosis, Animals, Brain, Cell Nucleus, Drosophila melanogaster, Female, Humans, Neurons, Nuclear Proteins, Proteins, RNA, Open Reading Frames, Oligonucleotides, Antisense, GTPase-Activating Proteins, Active Transport, Cell Nucleus, Nuclear Pore, Drosophila Proteins, DNA Repeat Expansion, G-Quadruplexes, Induced Pluripotent Stem Cells, Frontotemporal Dementia
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