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Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism

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. Green open access

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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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