title: Antibodies inhibit transmission and aggregation ofC9orf72poly-GA dipeptide repeat proteins.
abstract: Cell-to-cell transmission of protein aggregates is an emerging theme in neurodegenerative disease. Here, we analyze the dipeptide repeat (DPR) proteins that form neuronal inclusions in patients with hexanucleotide repeat expansionC9orf72, the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Sense and antisense transcripts of the (G4C2)nrepeat are translated by repeat-associated non-ATG (RAN) translation in all reading frames into five aggregating DPR proteins. We show that the hydrophobic DPR proteins poly-GA, poly-GP, and poly-PA are transmitted between cells using co-culture assays and cell extracts. Moreover, uptake or expression of poly-GA induces nuclear RNA foci in (G4C2)80-expressing cells and patient fibroblasts, suggesting an unexpected positive feedback loop. Exposure to recombinant poly-GA and cerebellar extracts ofC9orf72patients increases repeat RNA levels and seeds aggregation of all DPR proteins in receiver cells expressing (G4C2)80Treatment with anti-GA antibodies inhibits intracellular poly-GA aggregation and blocks the seeding activity ofC9orf72brain extracts. Poly-GA-directed immunotherapy may thus reduce DPR aggregation and disease progression inC9orf72ALS/FTD.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Qihui
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Lehmer
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Michaelsen
authors.affiliation: Biomedical Center, Biochemistry, Ludwig Maximilians-Universität München, Planegg-Martinsried, Germany.|Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kohji
authors.identifier: 0000-0003-2629-0723
authors.initials: K
authors.lastname: Mori
authors.affiliation: Institute for Immunology, Biomedical Center Munich, Ludwig Maximilians-Universität München, Planegg-Martinsried, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Alterauge
authors.affiliation: Institute for Immunology, Biomedical Center Munich, Ludwig Maximilians-Universität München, Planegg-Martinsried, Germany.
authors.forename: Dirk
authors.identifier: 0000-0001-8385-8288
authors.initials: D
authors.lastname: Baumjohann
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Schludi
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Greiling
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Farny
authors.affiliation: Monoclonal Antibody Core Facility and Research Group, Institute for Diabetes and Obesity, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), Munich, Germany.
authors.forename: Andrew
authors.initials: A
authors.lastname: Flatley
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.|Monoclonal Antibody Core Facility and Research Group, Institute for Diabetes and Obesity, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), Munich, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Feederle
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: May
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Schreiber
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Center for Neuropathology and Prion Research, Ludwig Maximilians-Universität München, Planegg-Martinsried, Germany.|Department of Psychiatry and Psychotherapy, Ludwig Maximilians-Universität München, Planegg-Martinsried, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Arzberger
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.|Department of Neurology, Friedrich-Baur-Institute, Ludwig Maximilians-Universität München, Planegg-Martinsried, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kuhm
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.|Department of Neurology, Friedrich-Baur-Institute, Ludwig Maximilians-Universität München, Planegg-Martinsried, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.affiliation: Department of Neurology and Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden and German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hermann
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.|Biomedical Center, Biochemistry, Ludwig Maximilians-Universität München, Planegg-Martinsried, Germany.
authors.forename: Christian
authors.identifier: 0000-0002-4869-1627
authors.initials: C
authors.lastname: Haass
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany dieter.edbauer@dzne.de.|Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.|Biomedical Center, Biochemistry, Ludwig Maximilians-Universität München, Planegg-Martinsried, Germany.
authors.forename: Dieter
authors.identifier: 0000-0002-7186-4653
authors.initials: D
authors.lastname: Edbauer
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D000073885:C9orf72 Protein / Q000235:genetics*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051381:Rats
chemical_list: D000906:Antibodies; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human
keywords: C9orf72; RAN translation; amyotrophic lateral sclerosis; immunotherapy; seeding