ArticleNeuron2019
CRISPR-Cas9 Screens Identify the RNA Helicase DDX3X as a Repressor of C9ORF72 (GGGGCC)n Repeat-Associated Non-AUG Translation.
Article in Neuron, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 94 papers.
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Who cites it
94 citing papers in PubMed, 141 citations in OpenAlex.
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- RAN Translation-Coupled Decay of theInternational journal of molecular sciences · 2026Article
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- The Tale of the Guanosine Tract in Repeat Expansion Disorders.Molecular neurobiology · 2026Review
- Learning genetic perturbation effects with variational causal inference.PLoS computational biology · 2026Article
- CRISPR-based functional genomic screening in neurodegeneration: mechanistic insights into AD, PD, and ALS.Frontiers in aging neuroscience · 2026Review
- Article
- IGF2BPs directly regulate the noncanonical translation of toxic proteins from mutant FMR1 mRNA containing expanded CGG repeats.Nature communications · 2025Article
- Canonical translation factors eIF1A and eIF5B modulate the initiation step of repeat-associated non-AUG translation.Nucleic acids research · 2025Article
- Translational Control in Cardiac Pathophysiology and Therapeutic Development: When mRNA Meets the Heart.International journal of molecular sciences · 2025Review
- Learning Genetic Perturbation Effects with Variational Causal Inference.bioRxiv : the preprint server for biology · 2025Article
- Targeting GeneInternational journal of molecular sciences · 2025Review
- Article
- CRISPR-based genetic screens in human pluripotent stem cells derived neurons and brain organoids.Cell and tissue research · 2025Review
- A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in an AAV-C9ORF72 (GActa neuropathologica communications · 2024Article
- A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in a AAV- C9ORF72 (G 4 C 2) 66 mouse model.Research square · 2024Article
- Decoding Nucleotide Repeat Expansion Diseases: Novel Insights fromInternational journal of molecular sciences · 2024Review
- CRISPR/Cas13d targeting suppresses repeat-associated non-AUG translation of C9orf72 hexanucleotide repeat RNA.The Journal of clinical investigation · 2024Article
- A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in a AAV-C9ORF72 (GbioRxiv : the preprint server for biology · 2024Article
- Identifying dysregulated regions in amyotrophic lateral sclerosis through chromatin accessibility outliers.HGG advances · 2024Article
34 more citing papers are in PubMed but not listed here.
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Authors and funding
22 authors at 5 institutions in 1 country.
Funding
Abstract
Hexanucleotide GGGGCC repeat expansion in C9ORF72 is the most prevalent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One pathogenic mechanism is the aberrant accumulation of dipeptide repeat (DPR) proteins produced by the unconventional translation of expanded RNA repeats. Here, we performed genome-wide CRISPR-Cas9 screens for modifiers of DPR protein production in human cells. We found that DDX3X, an RNA helicase, suppresses the repeat-associated non-AUG translation of GGGGCC repeats. DDX3X directly binds to (GGGGCC)n RNAs but not antisense (CCCCGG)n RNAs. Its helicase activity is essential for the translation repression. Reduction of DDX3X increases DPR levels in C9ORF72-ALS/FTD patient cells and enhances (GGGGCC)n-mediated toxicity in Drosophila. Elevating DDX3X expression is sufficient to decrease DPR levels, rescue nucleocytoplasmic transport abnormalities, and improve survival of patient iPSC-differentiated neurons. This work identifies genetic modifiers of DPR protein production and provides potential therapeutic targets for C9ORF72-ALS/FTD.
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