ArticleNucleic acids research2021
ZNF598 co-translationally titrates poly(GR) protein implicated in the pathogenesis of C9ORF72-associated ALS/FTD.
Article in Nucleic acids research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Two dipeptide repeat proteins are produced from mammalian telomeric RNA previously thought to be a long non-coding RNA.RNA biology · 2026Review
- The Role of ZNF598 in Translational Quality Control: Mechanisms and Emerging Biological Functions.Biology · 2026Review
- RAN Translation-Coupled Decay of theInternational journal of molecular sciences · 2026Article
- Quality control and signaling pathways at stalled ribosomes.Experimental & molecular medicine · 2026Review
- CRISPR activation of the ribosome-associated quality control factor ASCC3 ameliorates fragile X syndrome phenotypes in mice.Science translational medicine · 2025Article
- Ribosome-Associated Quality Control Mediated by Rqc2 Contributes to the Lytic Cycle and Stage Conversion ofMicroorganisms · 2025Article
- Pelota-mediated ribosome-associated quality control counteracts aging and age-associated pathologies across species.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Dysregulated ribosome quality control in human diseases.The FEBS journal · 2025Review
- RNA dysregulation in neurodegenerative diseases.The EMBO journal · 2025Review
- Trends and Implications of Ribosome-associated Protein Quality Control in Diseases: A Bibliographic Analysis.Current medicinal chemistry · 2025Review
- Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.Autophagy · 2024Article
- Ribosomal quality control factors inhibit repeat-associated non-AUG translation from GC-rich repeats.Nucleic acids research · 2024Article
- Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis.Nature communications · 2024Article
- Reconstitution of C9orf72 GGGGCC repeat-associated non-AUG translation with purified human translation factors.Scientific reports · 2023Article
- Cdk5 phosphorylation-dependent C9orf72 degradation promotes neuronal death in Parkinson's disease models.CNS neuroscience & therapeutics · 2023Article
- Single-molecule imaging reveals distinct elongation and frameshifting dynamics between frames of expanded RNA repeats in C9ORF72-ALS/FTD.Nature communications · 2023Article
- Single-molecule imaging reveals distinct elongation and frameshifting dynamics between frames of expanded RNA repeats in C9ORF72-ALS/FTD.Nature communications · 2023Article
- Translation of dipeptide repeat proteins ineLife · 2023Article
- Translation dysregulation in neurodegenerative diseases: a focus on ALS.Molecular neurodegeneration · 2023Review
- Impaired ribosome-associated quality control of C9orf72 arginine-rich dipeptide-repeat proteins.Brain : a journal of neurology · 2023Article
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6 authors.
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Abstract
C9ORF72-derived dipeptide repeat proteins have emerged as the pathogenic cause of neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms underlying their expression are not fully understood. Here, we demonstrate that ZNF598, the rate-limiting factor for ribosome-associated quality control (RQC), co-translationally titrates the expression of C9ORF72-derived poly(GR) protein. A Drosophila genetic screen identified key RQC factors as potent modifiers of poly(GR)-induced neurodegeneration. ZNF598 overexpression in human neuroblastoma cells inhibited the nuclear accumulation of poly(GR) protein and decreased its cytotoxicity, whereas ZNF598 deletion had opposing effects. Poly(GR)-encoding sequences in the reporter RNAs caused translational stalling and generated ribosome-associated translation products, sharing molecular signatures with canonical RQC substrates. Furthermore, ZNF598 and listerin 1, the RQC E3 ubiquitin-protein ligase, promoted poly(GR) degradation via the ubiquitin-proteasome pathway. An ALS-relevant ZNF598R69C mutant displayed loss-of-function effects on poly(GR) expression, as well as on general RQC. Moreover, RQC function was impaired in C9-ALS patient-derived neurons, whereas lentiviral overexpression of ZNF598 lowered their poly(GR) expression and suppressed proapoptotic caspase-3 activation. Taken together, we propose that an adaptive nature of the RQC-relevant ZNF598 activity allows the co-translational surveillance to cope with the atypical expression of pathogenic poly(GR) protein, thereby acquiring a neuroprotective function in C9-ALS/FTD.
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