ArticleActa neuropathologica2022
HNRNPK alleviates RNA toxicity by counteracting DNA damage in C9orf72 ALS.
Article in Acta neuropathologica, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 21 citations in OpenAlex.
- Global transcriptional changes across multiple isogeniciScience · 2026Article
- RNA-binding protein hnRNPK: a multifunctional regulator of skeletal muscle biology and disease.Biochemical Society transactions · 2026Review
- Heterogeneous nuclear ribonucleoprotein K in cancer biology and its therapeutic applications (Review).Molecular medicine reports · 2026Review
- The Heterogeneous Nuclear Ribonucleoprotein K (Animals : an open access journal from MDPI · 2026Article
- Gut microbiota-derived xanthohumol protects against heatstroke by inhibiting macrophage pyroptosis in mice.Journal of advanced research · 2026Article
- Prion propagation is controlled by a hierarchical network involving the nuclear Tfap2c and hnRNP K factors and the cytosolic mTORC1 complex.PLoS pathogens · 2026Article
- A novel KRT17-hnRNP K-CXCR3 axis promotes esophageal squamous cell carcinoma metastasis via nuclear-cytoplasmic redistribution.Scientific reports · 2026Article
- Dominant-negative isoform of TDP-43 is regulated by ALS-linked RNA-binding proteins.The Journal of cell biology · 2025Article
- Small Extracellular Vesicles Orchestrate Cisplatin-Induced Ototoxicity: Potential Biomarker and Targets Discovery.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Targeting GeneInternational journal of molecular sciences · 2025Review
- Gene therapy breakthroughs in ALS: a beacon of hope for 20% of ALS patients.Translational neurodegeneration · 2025Review
- Article
- The Roles of hnRNP Family in the Brain and Brain-Related Disorders.Molecular neurobiology · 2024Review
- Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit.Neurology and therapy · 2023Article
- Review
- Article
- Editorial: The role of gene mutations in the neuropathology of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD)- Progress and challenges.Frontiers in neurology · 2023Article
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Authors and funding
18 authors at 5 institutions in 3 countries.
Funding
Abstract
A 'GGGGCC' repeat expansion in the first intron of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The exact mechanism resulting in these neurodegenerative diseases remains elusive, but C9 repeat RNA toxicity has been implicated as a gain-of-function mechanism. Our aim was to use a zebrafish model for C9orf72 RNA toxicity to identify modifiers of the ALS-linked phenotype. We discovered that the RNA-binding protein heterogeneous nuclear ribonucleoprotein K (HNRNPK) reverses the toxicity of both sense and antisense repeat RNA, which is dependent on its subcellular localization and RNA recognition, and not on C9orf72 repeat RNA binding. We observed HNRNPK cytoplasmic mislocalization in C9orf72 ALS patient fibroblasts, induced pluripotent stem cell (iPSC)-derived motor neurons and post-mortem motor cortex and spinal cord, in line with a disrupted HNRNPK function in C9orf72 ALS. In C9orf72 ALS/FTD patient tissue, we discovered an increased nuclear translocation, but reduced expression of ribonucleotide reductase regulatory subunit M2 (RRM2), a downstream target of HNRNPK involved in the DNA damage response. Last but not least, we showed that increasing the expression of HNRNPK or RRM2 was sufficient to mitigate DNA damage in our C9orf72 RNA toxicity zebrafish model. Overall, our study strengthens the relevance of RNA toxicity as a pathogenic mechanism in C9orf72 ALS and demonstrates its link with an aberrant DNA damage response, opening novel therapeutic avenues for C9orf72 ALS/FTD.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.