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GGGGCC microsatellite RNA is neuritically localized, induces branching defects, and perturbs transport granule function

  1. Alondra Schweizer Burguete
  2. Sandra Almeida
  3. Fen-Biao Gao
  4. Robert Kalb
  5. Michael R Akins
  6. Nancy M Bonini  Is a corresponding author
  1. University of Pennsylvania, United States
  2. University of Massachusetts Medical School, United States
  3. University of Pennsylvania School of Medicine, United States
  4. Drexel University, United States
Research Article
  • Cited 46
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Cite this article as: eLife 2015;4:e08881 doi: 10.7554/eLife.08881

Abstract

Microsatellite expansions are the leading cause of numerous neurodegenerative disorders. Here we demonstrate that GGGGCC and CAG microsatellite repeat RNAs associated with C9orf72 in ALS/FTD and with polyglutamine diseases, respectively, localize to neuritic granules that undergo active transport into distal neuritic segments. In cultured mammalian spinal cord neurons, the presence of neuritic GGGGCC repeat RNA correlates with neuronal branching defects and the repeat RNA localizes to granules that label with FMRP, a transport granule component. Using a Drosophila GGGGCC expansion disease model, we characterize dendritic branching defects that are modulated by FMRP and Orb2. The human orthologues of these modifiers are misregulated in induced pluripotent stem cell-differentiated neurons from GGGGCC expansion carriers. These data suggest that expanded repeat RNAs interact with the mRNA transport and translation machinery, causing transport granule dysfunction. This could be a novel mechanism contributing to the neuronal defects associated with C9orf72 and other microsatellite expansion diseases.

Article and author information

Author details

  1. Alondra Schweizer Burguete

    Department of Biology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Sandra Almeida

    Department of Neurology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Fen-Biao Gao

    Department of Neurology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Robert Kalb

    Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Michael R Akins

    Department of Biology, Drexel University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Nancy M Bonini

    Department of Biology, University of Pennsylvania, Philadelphia, United States
    For correspondence
    nbonini@sas.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: The studies with animal tissue were performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#597) of Children's Hospital of Philadelphia. The human stem cell studies were performed with approval by the Institutional Biosafety Committee, protocol number I-435-10, of the University of Massachusetts Medical School, Worcester, MA.

Reviewing Editor

  1. Robert H Singer, Albert Einstein College of Medicine, United States

Publication history

  1. Received: May 21, 2015
  2. Accepted: November 30, 2015
  3. Accepted Manuscript published: December 9, 2015 (version 1)
  4. Accepted Manuscript updated: December 15, 2015 (version 2)
  5. Version of Record published: February 4, 2016 (version 3)

Copyright

© 2015, Schweizer Burguete 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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