1. Neuroscience

Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106

  1. Barbara Celona
  2. John von Dollen
  3. Sarat C Vatsavayai
  4. Risa Kashima
  5. Jeffrey R Johnson
  6. Amy A Tang
  7. Akiko Hata
  8. Bruce L Miller
  9. Eric J Huang
  10. Nevan J Krogan
  11. William W Seeley
  12. Brian L Black  Is a corresponding author
  1. University of California, San Francisco, United States
https://doi.org/10.7554/eLife.19032
Share this article
Cite this article
  1. Barbara Celona
  2. John von Dollen
  3. Sarat C Vatsavayai
  4. Risa Kashima
  5. Jeffrey R Johnson
  6. Amy A Tang
  7. Akiko Hata
  8. Bruce L Miller
  9. Eric J Huang
  10. Nevan J Krogan
  11. William W Seeley
  12. Brian L Black
(2017)
Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106
eLife 6:e19032.
https://doi.org/10.7554/eLife.19032
  2. Download BibTeX
  3. Download .RIS

Abstract

Expanded GGGGCC repeats in the first intron of the C9orf72 gene represent the most common cause of familial amyotrophic lateral sclerosis (ALS), but the mechanisms underlying repeat-induced disease remain incompletely resolved. One proposed gain-of-function mechanism is that repeat-containing RNA forms aggregates that sequester RNA binding proteins, leading to altered RNA metabolism in motor neurons. Here, we identify the zinc finger protein Zfp106 as a specific GGGGCC RNA repeat-binding protein, and using affinity purification-mass spectrometry, we show that Zfp106 interacts with multiple other RNA binding proteins, including the ALS-associated factors TDP-43 and FUS. We also show that Zfp106 knockout mice develop severe motor neuron degeneration, which can be suppressed by transgenic restoration of Zfp106 specifically in motor neurons. Finally, we show that Zfp106 potently suppresses neurotoxicity in a Drosophila model of C9orf72 ALS. Thus, these studies identify Zfp106 as an RNA binding protein with important implications for ALS.

Data availability

The following previously published data sets were used
    1. The UniProt Consortium
    (2015) UniProt: a hub for protein information
    Publicly available at UniProt (Registry identifier MIR:00000005).
    http://www.uniprot.org
    1. The Gene Ontology Consortium
    (2015) Gene Ontology Consortium: going forward
    Publicly available at the Gene Ontology Consortium (Registry identifier MIR:00000022).
    http://www.geneontology.org

Article and author information

Author details

  1. Barbara Celona

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. John von Dollen

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Sarat C Vatsavayai

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Risa Kashima

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Jeffrey R Johnson

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Amy A Tang

    Department of Pathology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Akiko Hata

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Bruce L Miller

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Eric J Huang

    Department of Pathology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Nevan J Krogan

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. William W Seeley

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. Brian L Black

    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
    For correspondence
    brian.black@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6664-8913

Funding

American Heart Association (14POST1862005)

  • Barbara Celona

Sandler Foundation

  • Barbara Celona

National Institutes of Health (HL064658)

  • Brian L Black

National Institutes of Health (HL089707)

  • Brian L Black

Amyotrophic Lateral Sclerosis Association (17-IIP-358)

  • Brian L Black

National Institutes of Health (P01AG019724)

  • Bruce L Miller
  • William W Seeley

National Institutes of Health (P50AG023501)

  • Bruce L Miller
  • William W Seeley

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

Ethics

Animal experimentation: All experiments using vertebrate animals were reviewed and approved by the University of California, San Francisco Institutional Animal Care and Use Committee (IACUC) under protocols AN108111 and AN087046, and all animal research complied with all institutional and federal guidelines.

Copyright

© 2017, Celona 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.

Metrics

  • 3,974
    views
  • 1,068
    downloads
  • 46
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Barbara Celona
  2. John von Dollen
  3. Sarat C Vatsavayai
  4. Risa Kashima
  5. Jeffrey R Johnson
  6. Amy A Tang
  7. Akiko Hata
  8. Bruce L Miller
  9. Eric J Huang
  10. Nevan J Krogan
  11. William W Seeley
  12. Brian L Black
(2017)
Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106
eLife 6:e19032.
https://doi.org/10.7554/eLife.19032

Share this article

https://doi.org/10.7554/eLife.19032

Categories and tags

Research organisms

Further reading

    1. Neuroscience

    Prolactin-mediates a lactation-induced suppression of arcuate kisspeptin neuronal activity necessary for lactational infertility in mice

    Eleni Hackwell, Sharon R Ladyman ... David R Grattan
    Research Article

    The specific role that prolactin plays in lactational infertility, as distinct from other suckling or metabolic cues, remains unresolved. Here, deletion of the prolactin receptor (Prlr) from forebrain neurons or arcuate kisspeptin neurons resulted in failure to maintain normal lactation-induced suppression of estrous cycles. Kisspeptin immunoreactivity and pulsatile LH secretion were increased in these mice, even in the presence of ongoing suckling stimulation and lactation. GCaMP fibre photometry of arcuate kisspeptin neurons revealed that the normal episodic activity of these neurons is rapidly suppressed in pregnancy and this was maintained throughout early lactation. Deletion of Prlr from arcuate kisspeptin neurons resulted in early reactivation of episodic activity of kisspeptin neurons prior to a premature return of reproductive cycles in early lactation. These observations show dynamic variation in arcuate kisspeptin neuronal activity associated with the hormonal changes of pregnancy and lactation, and provide direct evidence that prolactin action on arcuate kisspeptin neurons is necessary for suppressing fertility during lactation in mice.

    1. Neuroscience

    Realistic mossy fiber input patterns to unipolar brush cells evoke a continuum of temporal responses comprised of components mediated by different glutamate receptors

    Vincent Huson, Wade G Regehr
    Research Article

    Unipolar brush cells (UBCs) are excitatory interneurons in the cerebellar cortex that receive mossy fiber (MF) inputs and excite granule cells. The UBC population responds to brief burst activation of MFs with a continuum of temporal transformations, but it is not known how UBCs transform the diverse range of MF input patterns that occur in vivo. Here, we use cell-attached recordings from UBCs in acute cerebellar slices to examine responses to MF firing patterns that are based on in vivo recordings. We find that MFs evoke a continuum of responses in the UBC population, mediated by three different types of glutamate receptors that each convey a specialized component. AMPARs transmit timing information for single stimuli at up to 5 spikes/s, and for very brief bursts. A combination of mGluR2/3s (inhibitory) and mGluR1s (excitatory) mediates a continuum of delayed, and broadened responses to longer bursts, and to sustained high frequency activation. Variability in the mGluR2/3 component controls the time course of the onset of firing, and variability in the mGluR1 component controls the duration of prolonged firing. We conclude that the combination of glutamate receptor types allows each UBC to simultaneously convey different aspects of MF firing. These findings establish that UBCs are highly flexible circuit elements that provide diverse temporal transformations that are well suited to contribute to specialized processing in different regions of the cerebellar cortex.

    1. Neuroscience

    Outer hair cells stir cochlear fluids

    Choongheon Lee, Mohammad Shokrian ... Jong-Hoon Nam
    Research Article

    We hypothesized that active outer hair cells drive cochlear fluid circulation. The hypothesis was tested by delivering the neurotoxin, kainic acid, to the intact round window of young gerbil cochleae while monitoring auditory responses in the cochlear nucleus. Sounds presented at a modest level significantly expedited kainic acid delivery. When outer-hair-cell motility was suppressed by salicylate, the facilitation effect was compromised. A low-frequency tone was more effective than broadband noise, especially for drug delivery to apical locations. Computational model simulations provided the physical basis for our observation, which incorporated solute diffusion, fluid advection, fluid–structure interaction, and outer-hair-cell motility. Active outer hair cells deformed the organ of Corti like a peristaltic tube to generate apically streaming flows along the tunnel of Corti and basally streaming flows along the scala tympani. Our measurements and simulations coherently suggest that active outer hair cells in the tail region of cochlear traveling waves drive cochlear fluid circulation.