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C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles
Lee KH, Zhang P, Kim HJ, Mitrea DM, Sarkar M, Freibaum BD, Cika J, Coughlin M et al.. Cell, 2016-10-01
Topic: Brain proteins, microglia and lab models
Expansion of a hexanucleotide repeat GGGGCC (G 4 C 2 ) in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Transcripts carrying (G 4 C 2 ) expansions undergo unconventional, non-ATG-dependent translation, generating toxic dipeptide repeat (DPR) proteins thought to contribute to disease. Here, we identify the interactome of all DPRs and find that arginine-containing DPRs, polyGly-Arg (GR) and polyPro-Arg (PR), interact with RNA-binding proteins and proteins with low complexity sequence domains (LCDs) that often mediate the assembly of membrane-less organelles. Indeed, most GR/PR interactors are components of membrane-less organelles such as nucleoli, the nuclear pore complex and stress granules. Genetic analysis in Drosophila demonstrated the functional relevance of these interactions to DPR toxicity. Furthermore, we show that GR and PR altered phase separation of LCD-containing proteins, insinuating into their liquid assemblies and changing their material properties, resulting in perturbed dynamics and/or functions of multiple membrane-less organelles.
Key findings
- Genetic analysis in Drosophila demonstrated the functional relevance of these interactions to DPR toxicity.
Why it matters
Arginine-containing dipeptide repeat proteins polyGly-Arg and polyPro-Arg interacted with RNA-binding proteins and proteins with low complexity sequence domains that often mediate assembly of membrane-less organelles, and genetic analysis in Drosophila demonstrated the functional relevance of these interactions to dipeptide repeat toxicity. The proteins altered phase separation of low-complexity-domain-containing proteins, changing the material properties of these assemblies and perturbing the dynamics and/or functions of multiple membrane-less organelles.
Study details
- Evidence strengthLow
How this study scored 54/100
Published in a peer-reviewed 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 | 7 / 10 | Tier 3 — peer-reviewed journal (Cell) |
| Journal's citation record | 4 / 4 | Cell: journal h-index 1,220 (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 | 2016 — 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 690 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 57.5 citations a year over 12 year(s) since 2016 |
| Impact for its field and year | 6 / 6 | Cited 49.9× 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 139 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author J. Paul Taylor: h-index 89 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Howard Hughes Medical Institute: institution h-index 2,008 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 27768896) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 54 / 100 | — |
What each of these 20 components measures, and what this score is not →
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APA 7th
Lee, K. H., Zhang, P., Kim, H. J., Mitrea, D. M., Sarkar, M., Freibaum, B. D., et al. (2016). C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles. Cell. https://doi.org/10.1016/j.cell.2016.10.002
Vancouver
Lee KH, Zhang P, Kim HJ, Mitrea DM, Sarkar M, Freibaum BD, et al. C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles. Cell. 2016. doi:10.1016/j.cell.2016.10.002. PMID: 27768896.
BibTeX
@article{lee2016-27768896,
author = {Lee, K. H. and Zhang, P. and Kim, H. J. and Mitrea, D. M. and Sarkar, M. and Freibaum, B. D. and Cika, J. and Coughlin, M. and others},
title = {{C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles}},
journal = {Cell},
year = {2016},
doi = {10.1016/j.cell.2016.10.002},
pmid = {27768896},
url = {https://doi.org/10.1016/j.cell.2016.10.002}
}
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