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Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity
Zhang YJ, Guo L, Gonzales PK, Gendron TF, Wu Y, Jansen-West K, O'Raw AD, Pickles SR et al.. Science (New York, N.Y.), 2019-02-01
Topic: Brain proteins, microglia and lab models
How hexanucleotide GGGGCC (G 4 C 2 ) repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded G 4 C 2 repeats. The expression of green fluorescent protein-conjugated (PR) 50 (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1α (HP1α) liquid-phase disruptions, decreases in HP1α expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1α, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Thus, we uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of C9orf72 -associated FTD and ALS.
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APA 7th
Zhang, Y. J., Guo, L., Gonzales, P. K., Gendron, T. F., Wu, Y., Jansen-West, K., et al. (2019). Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity. Science (New York, N.Y.). https://doi.org/10.1126/science.aav2606
Vancouver
Zhang YJ, Guo L, Gonzales PK, Gendron TF, Wu Y, Jansen-West K, et al. Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity. Science (New York, N.Y.). 2019. doi:10.1126/science.aav2606. PMID: 30765536.
BibTeX
@article{zhang2019-30765536,
author = {Zhang, Y. J. and Guo, L. and Gonzales, P. K. and Gendron, T. F. and Wu, Y. and Jansen-West, K. and O'Raw, A. D. and Pickles, SR. and others},
title = {{Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity}},
journal = {Science (New York, N.Y.)},
year = {2019},
doi = {10.1126/science.aav2606},
pmid = {30765536},
url = {https://doi.org/10.1126/science.aav2606}
}
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Key findings
- We found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1α (HP1α) liquid-phase disruptions, decreases in HP1α expression, abnormal histone methylation, and nuclear lamina invaginations.
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Study details
- Evidence strengthLow
How this study scored 43/100
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. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 25 of the 58 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Science (New York, N.Y.)) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 2 / 5 | 2019 — within 10 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 | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 30765536) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 25 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 25 of the 58 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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