Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106
Barbara Celona,
John von Dollen,
Sarat C Vatsavayai,
Risa Kashima,
Jeffrey R Johnson,
Amy A Tang,
Akiko Hata,
Bruce L Miller,
Eric J Huang,
Nevan J Krogan,
William W Seeley,
Brian L Black
Affiliations
Barbara Celona
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
John von Dollen
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Sarat C Vatsavayai
Department of Neurology, University of California, San Francisco, San Francisco, United States
Risa Kashima
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Jeffrey R Johnson
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Amy A Tang
Department of Pathology, University of California, San Francisco, San Francisco, United States
Akiko Hata
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Bruce L Miller
Department of Neurology, University of California, San Francisco, San Francisco, United States
Eric J Huang
Department of Pathology, University of California, San Francisco, San Francisco, United States
Nevan J Krogan
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
William W Seeley
Department of Neurology, University of California, San Francisco, San Francisco, United States; Department of Pathology, University of California, San Francisco, San Francisco, United States
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
Expanded GGGGCC repeats in the first intron of the C9orf72 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 Zfp106 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 Drosophila model of C9orf72 ALS. Thus, these studies identify Zfp106 as an RNA binding protein with important implications for ALS.