Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106

• Published in: eLife Vol. 6
• Main Authors: Celona, Barbara, Dollen, John von, Vatsavayai, Sarat C, Kashima, Risa, Johnson, Jeffrey R, Tang, Amy A, Hata, Akiko, Miller, Bruce L, Huang, Eric J, Krogan, Nevan J, Seeley, William W, Black, Brian L
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 10-01-2017; eLife Sciences Publications, Ltd
• Subjects: Adaptor Proteins, Signal Transducing - deficiency; Adaptor Proteins, Signal Transducing - metabolism; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - physiopathology; Animals; C9orf72 Protein - genetics; Competition; Consortia; Degeneration; Disease Models, Animal; DNA-Binding Proteins - metabolism; Drosophila; FUS protein; Genetic Complementation Test; Genomes; Genotype & phenotype; Insects; knockout animals; Mass spectroscopy; Mice, Knockout; Mice, Transgenic; Motor neurons; neurodegeneration; Neuroscience; Neurotoxicity; Ontology; Pathology; Protein Binding; Protein Interaction Mapping; Protein purification; Proteins; Ribonucleic acid; RNA; RNA binding protein; RNA-Binding Protein FUS - metabolism; RNA-Binding Proteins - metabolism; Short Report; transgenic animals; zinc finger protein; Zinc finger proteins; California; mouse; transgenic animals; knockout animals; neuroscience; zinc finger protein; RNA binding protein; neurodegeneration; D. melanogaster
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.19032

Expanded GGGGCC repeats in the first intron of the
gene 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 that
knockout 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 a
model of
ALS. Thus, these studies identify Zfp106 as an RNA binding protein with important implications for ALS.