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

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    Author
    Conlon, E.G.
    Fagegaltier, D.
    Agius, P.
    Date
    2018
    Journal
    eLife
    Publisher
    eLife Sciences Publications Ltd
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://dx.doi.org/10.7554/eLife.37754
    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. Copyright 2018, eLife Sciences Publications Ltd. All rights reserved.
    Sponsors
    This work was supported by NIH grant R35 GM 118136 to JLM. EGC was supported in part by NIH training grant 5T32GM008798. RNA sequencing and related analyses at the NYGC were supported by the ALS Association (grant 15-LGCA-234) and the Tow Foundation.
    Keyword
    Amyotrophic Lateral Sclerosis
    Brain
    C9orf72 Protein
    DNA-Binding Proteins
    Frontotemporal Dementia
    Heterogeneous-Nuclear Ribonucleoproteins
    Humans
    Mutagenesis, Insertional
    Polypyrimidine Tract-Binding Protein
    RNA Splicing
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85052201257&doi=10.7554%2feLife.37754&partnerID=40&md5=b833487b0744b52d7c2b8be4aebfcb6a; http://hdl.handle.net/10713/9781
    ae974a485f413a2113503eed53cd6c53
    10.7554/eLife.37754
    Scopus Count
    Collections
    UMB Open Access Articles 2018

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