title: C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins.
abstract: An expanded GGGGCC repeat in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. A fundamental question is whether toxicity is driven by the repeat RNA itself and/or by dipeptide repeat proteins generated by repeat-associated, non-ATG translation. To address this question, we developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats, but not stop codon-interrupted "RNA-only" repeats in Drosophila caused adult-onset neurodegeneration. Thus, expanded repeats promoted neurodegeneration through dipeptide repeat proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence revealed that both poly-(glycine-arginine) and poly-(proline-arginine) proteins caused neurodegeneration. These findings are consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9orf72-mediated neurodegeneration.
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mizielinska
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Grönke
authors.affiliation: Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, UCL, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Teresa
authors.initials: T
authors.lastname: Niccoli
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Ridler
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Clayton
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Anny
authors.initials: A
authors.lastname: Devoy
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.|Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, UCL, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Moens
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Norona
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Ione O C
authors.initials: IOC
authors.lastname: Woollacott
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Pietrzyk
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Cleverley
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.|MRC Prion Unit, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Nicoll
authors.affiliation: Institute of Brain, Behaviour and Mental Health, Faculty of Human and Medical Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Pickering-Brown
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Dols
authors.affiliation: Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, UCL, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Melissa
authors.initials: M
authors.lastname: Cabecinha
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hendrich
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.|MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Pietro
authors.initials: P
authors.lastname: Fratta
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.|MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Elizabeth M C
authors.initials: EMC
authors.lastname: Fisher
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany.|Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, UCL, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Partridge
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Isaacs
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000073885:C9orf72 Protein; D045744:Cell Line, Tumor; D042622:DNA Repeat Expansion / Q000235:genetics*; D004151:Dipeptides / Q000378:metabolism; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics*; D004926:Escherichia coli; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004151:Dipeptides; D011506:Proteins
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