title: GGGGCC microsatellite RNA is neuritically localized, induces branching defects, and perturbs transport granule function.
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 amyotrophic lateral sclerosis/frontotemporal dementia 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 fragile X mental retardation protein (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 orthologs of these modifiers are misregulated in induced pluripotent stem cell-differentiated neurons (iPSNs) from GGGGCC expansion carriers. These data suggest that expanded repeat RNAs interact with the messenger RNA 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.
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, United States.
authors.forename: Alondra Schweizer
authors.initials: AS
authors.lastname: Burguete
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Sandra
authors.initials: S
authors.lastname: Almeida
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Fen-Biao
authors.initials: FB
authors.lastname: Gao
authors.affiliation: Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Kalb
authors.affiliation: Department of Biology, Drexel University, Philadelphia, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Akins
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, United States.
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Bonini
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D000073885:C9orf72 Protein; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000378:metabolism*; D004195:Disease Models, Animal; D004330:Drosophila; D006801:Humans; D018895:Microsatellite Repeats; D016501:Neurites / Q000378:metabolism*; D011506:Proteins / Q000235:genetics*; D012313:RNA / Q000235:genetics / Q000378:metabolism*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins; D012313:RNA
keywords: ALS; D. melanogaster; FMRP; FTD; GGGGCC; c9orf72; cell biology; spinal cord neurons