1. Biochemistry and Chemical Biology
  2. Medicine

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

  1. Erin G Conlon
  2. Delphine Fagegaltier
  3. Phaedra Agius
  4. Julia Davis-Porada
  5. James Gregory
  6. Isabel Hubbard
  7. Kristy Kang
  8. Duyang Kim
  9. The New York Genome Center ALS Consortium
  10. Hemali Phatnani
  11. Neil A Shneider
  12. James L Manley  Is a corresponding author
  1. Columbia University, United States
  2. New York Genome Center, United States
https://doi.org/10.7554/eLife.37754
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  1. Erin G Conlon
  2. Delphine Fagegaltier
  3. Phaedra Agius
  4. Julia Davis-Porada
  5. James Gregory
  6. Isabel Hubbard
  7. Kristy Kang
  8. Duyang Kim
  9. The New York Genome Center ALS Consortium
  10. Hemali Phatnani
  11. Neil A Shneider
  12. James L Manley
(2018)
Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism
eLife 7:e37754.
https://doi.org/10.7554/eLife.37754
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  3. Download .RIS

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 post-mortem 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.

Data availability

All raw RNASeq data from Target ALS samples is immediately made publicly available. Access to the data can be requested by emailing ALSData@nygenome.org.All RNASeq data from the ALS Consortium is made immediately available to all members of the Consortium and with other Consortia with whom we have a reciprocal sharing arrangement. Data have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) (accession no. GSE116622). Data will be released upon acceptance.

The following data sets were generated

Article and author information

Author details

  1. Erin G Conlon

    Department of Biological Sciences, Columbia University, New York, United States
    Competing interests
    No competing interests declared.

  2. Delphine Fagegaltier

    Center for Genomics of Neurodegenerative disease, New York Genome Center, New York, United States
    Competing interests
    No competing interests declared.

  3. Phaedra Agius

    Center for Genomics of Neurodegenerative disease, New York Genome Center, New York, United States
    Competing interests
    No competing interests declared.

  4. Julia Davis-Porada

    Department of Biological Sciences, Columbia University, New York, United States
    Competing interests
    No competing interests declared.

  5. James Gregory

    Center for Genomics of Neurodegenerative disease, New York Genome Center, New York, United States
    Competing interests
    No competing interests declared.

  6. Isabel Hubbard

    Center for Genomics of Neurodegenerative disease, New York Genome Center, New York, United States
    Competing interests
    No competing interests declared.

  7. Kristy Kang

    Center for Genomics of Neurodegenerative disease, New York Genome Center, New York, United States
    Competing interests
    No competing interests declared.

  8. Duyang Kim

    Center for Genomics of Neurodegenerative disease, New York Genome Center, New York, United States
    Competing interests
    No competing interests declared.

  9. The New York Genome Center ALS Consortium

  10. Hemali Phatnani

    Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, United States
    Competing interests
    No competing interests declared.

  11. Neil A Shneider

    Department of Neurology, Columbia University, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3223-7366

  12. James L Manley

    Department of Biological Sciences, Columbia University, New York, United States
    For correspondence
    jlm2@columbia.edu
    Competing interests
    James L Manley, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8341-1459

Funding

NIH Office of the Director (R35 GM 118136)

  • James L Manley

NIH Office of the Director (5T32GM008798)

  • Erin G Conlon

ALS Association (15-LGCA-234)

  • Hemali Phatnani

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Human post-mortem brain samples were donated for research purposes by next of kin.

Copyright

© 2018, Conlon et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Erin G Conlon
  2. Delphine Fagegaltier
  3. Phaedra Agius
  4. Julia Davis-Porada
  5. James Gregory
  6. Isabel Hubbard
  7. Kristy Kang
  8. Duyang Kim
  9. The New York Genome Center ALS Consortium
  10. Hemali Phatnani
  11. Neil A Shneider
  12. James L Manley
(2018)
Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism
eLife 7:e37754.
https://doi.org/10.7554/eLife.37754

Share this article

https://doi.org/10.7554/eLife.37754

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Further reading

    1. Biochemistry and Chemical Biology

    The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS brains

    Erin G Conlon, Lei Lu ... James L Manley
    Research Article Updated

    An expanded GGGGCC hexanucleotide in C9ORF72 (C9) is the most frequent known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It has been proposed that expanded transcripts adopt G-quadruplex (G-Q) structures and associate with proteins, but whether this occurs and contributes to disease is unknown. Here we show first that the protein that predominantly associates with GGGGCC repeat RNA in vitro is the splicing factor hnRNP H, and that this interaction is linked to G-Q formation. We then show that G-Q RNA foci are more abundant in C9 ALS patient fibroblasts and astrocytes compared to those without the expansion, and more frequently colocalize with hnRNP H. Importantly, we demonstrate dysregulated splicing of multiple known hnRNP H-target transcripts in C9 patient brains, which correlates with elevated insoluble hnRNP H/G-Q aggregates. Together, our data implicate C9 expansion-mediated sequestration of hnRNP H as a significant contributor to neurodegeneration in C9 ALS/FTD.

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    RNA-Binding Proteins: A matter of balance

    Aaron D Gitler, John D Fryer
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    New analyses shift the view that some forms of amyotrophic lateral sclerosis and frontotemporal dementia are due to defects in a single RNA-binding protein.

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