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

Elife. 2017 Jan 10;6:e19032. doi: 10.7554/eLife.19032.

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.

Keywords: D. melanogaster; RNA binding protein; knockout animals; mouse; neurodegeneration; neuroscience; transgenic animals; zinc finger protein.

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Animals
  • C9orf72 Protein / genetics*
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Drosophila
  • Genetic Complementation Test
  • Mice, Knockout
  • Mice, Transgenic
  • Protein Binding
  • Protein Interaction Mapping
  • RNA-Binding Protein FUS / metabolism
  • RNA-Binding Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • C9orf72 Protein
  • C9orf72 protein, mouse
  • DNA-Binding Proteins
  • FUS protein, mouse
  • RNA-Binding Protein FUS
  • RNA-Binding Proteins
  • TDP-43 protein, mouse
  • Zfp106 protein, mouse