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Nat Genet. 2018 Apr;50(4):603-612. doi: 10.1038/s41588-018-0070-7. Epub 2018 Mar 5.

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Author information

1
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
2
Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
3
Department of Molecular Biology, Genentech, South San Francisco, CA, USA.
4
Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA, USA.
5
Department of Biology, Stanford University, Stanford, CA, USA.
6
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. bassik@stanford.edu.
7
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. agitler@stanford.edu.

Abstract

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases.

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