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

Abstract
Article and author information
Metrics

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

Alondra Schweizer Burguete

Department of Biology, University of Pennsylvania, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Sandra Almeida

Department of Neurology, University of Massachusetts Medical School, Worcester, United States

Competing interests
The authors declare that no competing interests exist.
Fen-Biao Gao

Department of Neurology, University of Massachusetts Medical School, Worcester, United States

Competing interests
The authors declare that no competing interests exist.
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.
Michael R Akins

Department of Biology, Drexel University, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
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.

Copyright

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.