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

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

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.

Original languageEnglish
Article numbere19032
JournaleLife
Volume6
DOIs
StatePublished - 10 Jan 2017
Externally publishedYes

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