Conlon, EG;
Fagegaltier, D;
Agius, P;
Davis-Porada, J;
Gregory, J;
Hubbard, I;
Kang, K;
... Manley, JL; + view all
(2018)
Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism.
eLife
, 7
, Article e37754. 10.7554/eLife.37754.
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Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism.pdf - Published Version Download (6MB) | Preview |
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of a disease spectrum with shared clinical, genetic and pathological features. These include near ubiquitous pathological inclusions of the RNA-binding protein (RBP) TDP-43, and often the presence of a GGGGCC expansion in the C9ORF72 (C9) gene. Previously, we reported that the sequestration of hnRNP H altered the splicing of target transcripts in C9ALS patients (Conlon et al., 2016). Here, we show that this signature also occurs in half of 50 postmortem sporadic, non-C9 ALS/FTD brains. Furthermore, and equally surprisingly, these ‘like-C9’ brains also contained correspondingly high amounts of insoluble TDP-43, as well as several other disease-related RBPs, and this correlates with widespread global splicing defects. Finally, we show that the like-C9 sporadic patients, like actual C9ALS patients, were much more likely to have developed FTD. We propose that these unexpected links between C9 and sporadic ALS/FTD define a common mechanism in this disease spectrum.
| Type: | Article |
|---|---|
| Title: | Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.7554/eLife.37754 |
| Publisher version: | https://doi.org/10.7554/eLife.37754 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biology, Life Sciences & Biomedicine - Other Topics, AMYOTROPHIC-LATERAL-SCLEROSIS, RNA-BINDING PROTEINS, PRION-LIKE DOMAINS, FRONTOTEMPORAL DEMENTIA, REPEAT EXPANSION, PHASE-TRANSITIONS, NEURODEGENERATIVE DISEASE, HEXANUCLEOTIDE REPEAT, SPLICING REGULATION, STRESS GRANULES |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10057184 |
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