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

Abstract
Data availability
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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

The following previously published data sets were used

1. The UniProt Consortium
(2015) UniProt: a hub for protein information
Publicly available at UniProt (Registry identifier MIR:00000005).

http://www.uniprot.org
1. The Gene Ontology Consortium
(2015) Gene Ontology Consortium: going forward
Publicly available at the Gene Ontology Consortium (Registry identifier MIR:00000022).

http://www.geneontology.org
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6. Stransky M
7. Waegele B
8. Schmidt T
9. Doudieu ON
10. Stumpflen V
11. Mewes HW
(2008) CORUM: the comprehensive resource of mammalian protein complexes
Publicly available at CORUM (Registry identifier MIR:00100571).

http://mips.helmholtz-muenchen.de/corum/#

Article and author information

Author details

Barbara Celona

Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
John von Dollen

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Sarat C Vatsavayai

Department of Neurology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Risa Kashima

Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Jeffrey R Johnson

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Amy A Tang

Department of Pathology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Akiko Hata

Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Bruce L Miller

Department of Neurology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Eric J Huang

Department of Pathology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Nevan J Krogan

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
William W Seeley

Department of Neurology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Brian L Black

Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States

For correspondence
brian.black@ucsf.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6664-8913

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

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.