Suppression of <i>C9orf72</i> RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106.

Abstract

Expanded GGGGCC repeats in the first intron of the <i>C9orf72</i> 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 <i>Zfp106</i> 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 <i>Drosophila</i> model of <i>C9orf72</i> ALS. Thus, these studies identify Zfp106 as an RNA binding protein with important implications for ALS.