title: Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation.
abstract: The expansion of the GGGGCC hexanucleotide repeat in the non-coding region of the Chromosome 9 open-reading frame 72 (C9orf72) gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This genetic alteration leads to the accumulation of five types of poly-dipeptides translated from the GGGGCC hexanucleotide repeat. Among these, poly-proline-arginine (poly-PR) and poly-glycine-arginine (poly-GR) peptides are known to be neurotoxic. However, the mechanisms of neurotoxicity associated with these poly-dipeptides are not clear. A proteomics approach identified a number of interacting proteins with poly-PR peptide, including mRNA-binding proteins, ribosomal proteins, translation initiation factors and translation elongation factors. Immunostaining of brain sections from patients with C9orf72 ALS showed that poly-GR was colocalized with a mRNA-binding protein, hnRNPA1. In vitro translation assays showed that poly-PR and poly-GR peptides made insoluble complexes with mRNA, restrained the access of translation factors to mRNA, and blocked protein translation. Our results demonstrate that impaired protein translation mediated by poly-PR and poly-GR peptides plays a role in neurotoxicity and reveal that the pathways altered by the poly-dipeptides-mRNA complexes are potential therapeutic targets for treatment of C9orf72 FTD/ALS.
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Department of Molecular Pathology, Tokyo Medical University, Tokyo 160-8402, Japan and.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Kanekura
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yagi
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Cammack
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research.
authors.forename: Jana
authors.initials: J
authors.lastname: Mahadevan
authors.affiliation: Department of Molecular Pathology, Tokyo Medical University, Tokyo 160-8402, Japan and.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kuroda
authors.affiliation: Department of Neurology, Columbia University College of Physicians and Surgeon, New York, NY 10032, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Harms
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Miller
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Department of Pathology and Immunology and urano@dom.wustl.edu.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Urano
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000073885:C9orf72 Protein; D016022:Case-Control Studies; D002478:Cells, Cultured; D042622:DNA Repeat Expansion / Q000187:drug effects / Q000235:genetics; D004151:Dipeptides / Q000494:pharmacology*; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism; D006801:Humans; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D014176:Protein Biosynthesis / Q000187:drug effects*; D011506:Proteins / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004151:Dipeptides; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C000619657:Hnrnpa1 protein, mouse; D011506:Proteins; C000619656:hnRNPA1 protein, human