CRISPR–Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity
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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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Cancer cell line screens have limitations for neurological disease research, including that most neurological diseases involve specific cell types, that disease-relevant genes may not be expressed in the line, and that survival control differs between cancer and untransformed cells.
“Even though such screens have been able to uncover genes that were then validated in relevant cell types such as neurons63,65,68, they have obvious limitations for the study of neurological disease.”
From CRISPR-based functional genomics for neurological disease (2020) · cites this paper as [68]
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Self-citation
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- Authors
- Kramer, N. J., Haney, M. S., Morgens, D. W., Jovičić, A., Couthouis, J., Li, A., Ousey, J., Ma, R., Bieri, G., Tsui, C. K., Shi, Y., Hertz, N. T., Tessier-Lavigne, M., Ichida, J. K., Bassik, M. C., & Gitler, A. D.
- Affiliations
- Stanford Medicine (US)
- Genentech (US)
- University of Southern California (US)
- Stanford University (US)
- Corresponding author
- Bassik, Michael C.
- Gitler, Aaron D.
- ORCID
- Venue
- Nature Genetics
- Published
- 2018-03-05
- Volume
- 50
- Issue
- 4
- Pages
- 603-612
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5893388
- OpenAlex
- W2949846456
- Cited by
- 226
- References
- 81
- Citations by year
- 2026: 12 · 2025: 18 · 2024: 20 · 2023: 38 · 2022: 19 · 2021: 36 · 2020: 29 · 2019: 35 · 2018: 17 · 2017: 1
- FWCI
- 20.04
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Science Foundation
- Johns Hopkins University
- Target ALS
- National Institutes of Health (1dp2hd084069-01)
- National Human Genome Research Institute (T32HG000044)
- National Institute of General Medical Sciences (T32GM007790)
- National Institute of Neurological Disorders and Stroke (R01NS097850, P30NS069375, R35NS097263)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (DP2 HD084069)
- Robert Packard Center for ALS Research, Johns Hopkins University
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- C9orf72, dipeptide repeat proteins, hexanucleotide repeat expansion, amyotrophic lateral sclerosis, frontotemporal dementia, CRISPR/Cas9 genome-wide screen, endoplasmic reticulum stress, nuclear transport, proteasome, RNA processing, chromatin modification, neurodegeneration
- MeSH terms
- C9orf72 Protein, rab7 GTP-Binding Proteins, Amyotrophic Lateral Sclerosis, Animals, HeLa Cells, Humans, Membrane Proteins, Motor Neurons, Thioredoxins, Microsatellite Repeats, K562 Cells, rab GTP-Binding Proteins, Active Transport, Cell Nucleus, DNA Repeat Expansion, Mice, Gene Knockout Techniques, Frontotemporal Dementia, Endoplasmic Reticulum Stress, CRISPR-Cas Systems
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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