title: Suppression ofC9orf72RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106.
abstract: Expanded GGGGCC repeats in the first intron of theC9orf72gene represent the most common cause of familial amyotrophic lateral sclerosis (ALS), but the mechanisms underlying repeat-induced disease remain incompletely resolved. One proposed gain-of-function mechanism is that repeat-containing RNA forms aggregates that sequester RNA binding proteins, leading to altered RNA metabolism in motor neurons. Here, we identify the zinc finger protein Zfp106 as a specific GGGGCC RNA repeat-binding protein, and using affinity purification-mass spectrometry, we show that Zfp106 interacts with multiple other RNA binding proteins, including the ALS-associated factors TDP-43 and FUS. We also show thatZfp106knockout mice develop severe motor neuron degeneration, which can be suppressed by transgenic restoration of Zfp106 specifically in motor neurons. Finally, we show that Zfp106 potently suppresses neurotoxicity in aDrosophilamodel ofC9orf72ALS. Thus, these studies identify Zfp106 as an RNA binding protein with important implications for ALS.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States.
authors.forename: Barbara
authors.initials: B
authors.lastname: Celona
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
authors.forename: John von
authors.initials: JV
authors.lastname: Dollen
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, United States.
authors.forename: Sarat C
authors.initials: SC
authors.lastname: Vatsavayai
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States.
authors.forename: Risa
authors.initials: R
authors.lastname: Kashima
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Johnson
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, United States.
authors.forename: Amy A
authors.initials: AA
authors.lastname: Tang
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hata
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, United States.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, United States.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
authors.forename: Nevan J
authors.initials: NJ
authors.lastname: Krogan
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, United States.|Department of Pathology, University of California, San Francisco, San Francisco, United States.
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States.|Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.
authors.forename: Brian L
authors.identifier: 0000-0002-6664-8913
authors.initials: BL
authors.lastname: Black
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology*; D000818:Animals; D000073885:C9orf72 Protein / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila; D005816:Genetic Complementation Test; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011485:Protein Binding; D025941:Protein Interaction Mapping; D034702:RNA-Binding Protein FUS / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000073885:C9orf72 Protein; D004268:DNA-Binding Proteins; D034702:RNA-Binding Protein FUS; D016601:RNA-Binding Proteins; C000606498:C9orf72 protein, mouse; C000599551:FUS protein, mouse; C578077:Tardbp protein, mouse; C116200:Zfp106 protein, mouse
keywords: D. melanogaster; RNA binding protein; knockout animals; mouse; neurodegeneration; neuroscience; transgenic animals; zinc finger protein