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The C9orf72 repeat expansion disrupts nucleocytoplasmic transport
Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ et al.. Nature, 2015-08-26
Topic: Brain proteins, microglia and lab models
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.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Zhang, K., Donnelly, C. J., Haeusler, A. R., Grima, J. C., Machamer, J. B., Steinwald, P., et al. (2015). The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. https://doi.org/10.1038/nature14973
Vancouver
Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015. doi:10.1038/nature14973. PMID: 26308891.
BibTeX
@article{zhang2015-26308891,
author = {Zhang, K. and Donnelly, C. J. and Haeusler, A. R. and Grima, J. C. and Machamer, J. B. and Steinwald, P. and Daley, E. L. and Miller, S. J. and others},
title = {{The C9orf72 repeat expansion disrupts nucleocytoplasmic transport}},
journal = {Nature},
year = {2015},
doi = {10.1038/nature14973},
pmid = {26308891},
url = {https://doi.org/10.1038/nature14973}
}
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Key findings
- 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.
Why it matters
In a fly model and C9orf72 patient-derived neurons, the repeat expansion impaired nuclear import, and these deficits were rescued by small molecules and antisense oligonucleotides targeting the repeat RNA structures. This identifies nucleocytoplasmic transport defects as a possible pathway amenable to pharmacotherapeutic intervention, but it is early model-based work, not a treatment tested in patients.
Study details
- Evidence strengthLow
How this study scored 57/100
Published in a top-tier journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature) |
| Journal's citation record | 4 / 4 | Nature: journal h-index 1,841 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2015 — within 20 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 983 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 75.6 citations a year over 13 year(s) since 2015 |
| Impact for its field and year | 6 / 6 | Cited 67.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 24 other studies in this library |
| Still being cited | 3 / 4 | Cited 169 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Jeffrey D. Rothstein: h-index 118 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Johns Hopkins University: institution h-index 2,306 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 26308891) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 57 / 100 | — |
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