Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106
- University of California, San Francisco, United States
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.
Data availability
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UniProt: a hub for protein informationPublicly available at UniProt (Registry identifier MIR:00000005).
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Gene Ontology Consortium: going forwardPublicly available at the Gene Ontology Consortium (Registry identifier MIR:00000022).
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CORUM: the comprehensive resource of mammalian protein complexesPublicly available at CORUM (Registry identifier MIR:00100571).
Article and author information
Author details
Funding
American Heart Association (14POST1862005)
- Barbara Celona
Sandler Foundation
- Barbara Celona
National Institutes of Health (HL064658)
- Brian L Black
National Institutes of Health (HL089707)
- Brian L Black
Amyotrophic Lateral Sclerosis Association (17-IIP-358)
- Brian L Black
National Institutes of Health (P01AG019724)
- Bruce L Miller
- William W Seeley
National Institutes of Health (P50AG023501)
- Bruce L Miller
- William W Seeley
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments using vertebrate animals were reviewed and approved by the University of California, San Francisco Institutional Animal Care and Use Committee (IACUC) under protocols AN108111 and AN087046, and all animal research complied with all institutional and federal guidelines.
Copyright
© 2017, Celona et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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