title: Reduced hnRNPA3 increases C9orf72 repeat RNA levels and dipeptide-repeat protein deposition.
abstract: Intronic hexanucleotide (G4C2) repeat expansions in C9orf72 are genetically associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The repeat RNA accumulates within RNA foci but is also translated into disease characterizing dipeptide repeat proteins (DPR). Repeat-dependent toxicity may affect nuclear import. hnRNPA3 is a heterogeneous nuclear ribonucleoprotein, which specifically binds to the G4C2 repeat RNA We now report that a reduction of nuclear hnRNPA3 leads to an increase of the repeat RNA as well as DPR production and deposition in primary neurons and a novel tissue culture model that reproduces features of the C9orf72 pathology. In fibroblasts derived from patients carrying extended C9orf72 repeats, nuclear RNA foci accumulated upon reduction of hnRNPA3. Neurons in the hippocampus of C9orf72 patients are frequently devoid of hnRNPA3. Reduced nuclear hnRNPA3 in the hippocampus of patients with extended C9orf72 repeats correlates with increased DPR deposition. Thus, reduced hnRNPA3 expression in C9orf72 cases leads to increased levels of the repeat RNA as well as enhanced production and deposition of DPR proteins and RNA foci.
authors.affiliation: Biomedical Center (BMC), Ludwig-Maximilians-University Munich, Munich, Germany christian.haass@mail03.med.uni-muenchen.de kmori@psy.med.osaka-u.ac.jp.
authors.forename: Kohji
authors.initials: K
authors.lastname: Mori
authors.affiliation: Biomedical Center (BMC), Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nihei
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany Center for Neuopathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Arzberger
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Qihui
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Pathology, University of British Columbia and Vancouver General Hospital, Vancouver, Canada.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackenzie
authors.affiliation: Deptartment of Neurology and Center for Regenerative Therapies Dresden (CRTD), Technical University Dresden, Dresden, Germany German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hermann
authors.affiliation: Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany Department of Neurology, Vivantes Humboldt-Klinikum, Berlin, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Hanisch
authors.affiliation: Biomedical Center (BMC), Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Frits
authors.initials: F
authors.lastname: Kamp
authors.affiliation: Biomedical Center (BMC), Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Nuscher
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Orozco
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany Munich Cluster for System Neurology (SyNergy), Munich, Germany.
authors.forename: Dieter
authors.identifier: 0000-0002-7186-4653
authors.initials: D
authors.lastname: Edbauer
authors.affiliation: Biomedical Center (BMC), Ludwig-Maximilians-University Munich, Munich, Germany German Center for Neurodegenerative Diseases (DZNE), Munich, Germany Munich Cluster for System Neurology (SyNergy), Munich, Germany christian.haass@mail03.med.uni-muenchen.de kmori@psy.med.osaka-u.ac.jp.
authors.forename: Christian
authors.identifier: 0000-0003-2629-0723
authors.initials: C
authors.lastname: Haass
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D000073885:C9orf72 Protein; D004151:Dipeptides / Q000378:metabolism*; D005347:Fibroblasts; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D011506:Proteins / Q000235:genetics*; D017966:Pyramidal Cells / Q000378:metabolism; D034443:RNA Transport; D012333:RNA, Messenger / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004151:Dipeptides; C502034:HNRNPA3 protein, human; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering
keywords: C9orf72; dipeptide repeat proteins; frontotemporal lobar degeneration; hnRNPA3; neurodegeneration