| Title |
Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons
|
|---|---|
| Published in |
Acta Neuropathologica, July 2013
|
| DOI | 10.1007/s00401-013-1149-y |
| Pubmed ID | |
| Authors |
Sandra Almeida, Eduardo Gascon, Hélène Tran, Hsin Jung Chou, Tania F. Gendron, Steven DeGroot, Andrew R. Tapper, Chantal Sellier, Nicolas Charlet-Berguerand, Anna Karydas, William W. Seeley, Adam L. Boxer, Leonard Petrucelli, Bruce L. Miller, Fen-Biao Gao |
| Abstract |
The recently identified GGGGCC repeat expansion in the noncoding region of C9ORF72 is the most common pathogenic mutation in patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). We generated a human neuronal model and investigated the pathological phenotypes of human neurons containing GGGGCC repeat expansions. Skin biopsies were obtained from two subjects who had >1,000 GGGGCC repeats in C9ORF72 and their respective fibroblasts were used to generate multiple induced pluripotent stem cell (iPSC) lines. After extensive characterization, two iPSC lines from each subject were selected, differentiated into postmitotic neurons, and compared with control neurons to identify disease-relevant phenotypes. Expanded GGGGCC repeats exhibit instability during reprogramming and neuronal differentiation of iPSCs. RNA foci containing GGGGCC repeats were present in some iPSCs, iPSC-derived human neurons and primary fibroblasts. The percentage of cells with foci and the number of foci per cell appeared to be determined not simply by repeat length but also by other factors. These RNA foci do not seem to sequester several major RNA-binding proteins. Moreover, repeat-associated non-ATG (RAN) translation products were detected in human neurons with GGGGCC repeat expansions and these neurons showed significantly elevated p62 levels and increased sensitivity to cellular stress induced by autophagy inhibitors. Our findings demonstrate that key neuropathological features of FTD/ALS with GGGGCC repeat expansions can be recapitulated in iPSC-derived human neurons and also suggest that compromised autophagy function may represent a novel underlying pathogenic mechanism. |
X Demographics
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Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Japan | 1 | 50% |
| United States | 1 | 50% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 2 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 397 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 3 | <1% |
| Netherlands | 1 | <1% |
| Colombia | 1 | <1% |
| United Kingdom | 1 | <1% |
| Poland | 1 | <1% |
| Unknown | 390 | 98% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 108 | 27% |
| Student > Bachelor | 56 | 14% |
| Researcher | 50 | 13% |
| Student > Master | 35 | 9% |
| Student > Doctoral Student | 27 | 7% |
| Other | 59 | 15% |
| Unknown | 62 | 16% |
| Readers by discipline | Count | As % |
|---|---|---|
| Agricultural and Biological Sciences | 108 | 27% |
| Neuroscience | 77 | 19% |
| Biochemistry, Genetics and Molecular Biology | 69 | 17% |
| Medicine and Dentistry | 39 | 10% |
| Chemistry | 5 | 1% |
| Other | 24 | 6% |
| Unknown | 75 | 19% |
Attention Score in Context
This research output has an Altmetric Attention Score of 341. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 04 March 2024.
All research outputs
#96,100
of 25,373,627 outputs
Outputs from Acta Neuropathologica
#15
of 2,527 outputs
Outputs of similar age
#554
of 206,467 outputs
Outputs of similar age from Acta Neuropathologica
#1
of 22 outputs
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