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C9orf72 nucleotide repeat structures initiate molecular cascades of disease
Haeusler AR, Donnelly CJ, Periz G, Simko EA, Shaw PG, Kim MS, Maragakis NJ, Troncoso JC et al.. Nature, 2014-03-05
Topic: Brain proteins, microglia and lab models
A hexanucleotide repeat expansion (HRE), (GGGGCC)n, in C9orf72 is the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we identify a molecular mechanism by which structural polymorphism of the HRE leads to ALS/FTD pathology and defects. The HRE forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA•DNA hybrids (R-loops). The structural polymorphism causes a repeat-length-dependent accumulation of transcripts aborted in the HRE region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin, an essential nucleolar protein, preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. Our results demonstrate that distinct C9orf72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Haeusler, A. R., Donnelly, C. J., Periz, G., Simko, E. A., Shaw, P. G., Kim, M. S., et al. (2014). C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature. https://doi.org/10.1038/nature13124
Vancouver
Haeusler AR, Donnelly CJ, Periz G, Simko EA, Shaw PG, Kim MS, et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature. 2014. doi:10.1038/nature13124. PMID: 24598541.
BibTeX
@article{haeusler2014-24598541,
author = {Haeusler, A. R. and Donnelly, C. J. and Periz, G. and Simko, E. A. and Shaw, P. G. and Kim, M. S. and Maragakis, N. J. and Troncoso, J. C. and others},
title = {{C9orf72 nucleotide repeat structures initiate molecular cascades of disease}},
journal = {Nature},
year = {2014},
doi = {10.1038/nature13124},
pmid = {24598541},
url = {https://doi.org/10.1038/nature13124}
}
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Key findings
- Our results demonstrate that distinct C9orf72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases.
Why it matters
This laboratory study describes how a repeated stretch of DNA in the C9orf72 gene folds into unusual shapes and triggers molecular events that may lead to ALS and frontotemporal dementia. It provides a model for how these repeats cause disease but does not test any treatment 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 | 2014 — 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 985 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 70.4 citations a year over 14 year(s) since 2014 |
| Impact for its field and year | 6 / 6 | Cited 66.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 16 other studies in this library |
| Still being cited | 3 / 4 | Cited 143 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Jiou Wang: h-index 36 (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 24598541) |
| Free to read | 2 / 2 | Free to read |
| Total | 57 / 100 | — |
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