ArticleActa neuropathologica2020
Poly-glycine-alanine exacerbates C9orf72 repeat expansion-mediated DNA damage via sequestration of phosphorylated ATM and loss of nuclear hnRNPA3.
Article in Acta neuropathologica, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers, 2 of them syntheses that pooled it.
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Who cites it
44 citing papers in PubMed, 2 syntheses or guidelines pooled it, 65 citations in OpenAlex.
- Exploring dysregulated miRNAs in ALS: implications for disease pathogenesis and early diagnosis.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Pooled it
- C9orf72-related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review.Frontiers in molecular neuroscience · 2025Pooled it
- CD33 Isoform Splicing Dysregulation: A Molecular Determinant of Microglial Dysfunction in Alzheimer's Disease Pathology.Molecular neurobiology · 2026Review
- ASO therapy rescues NOTCH2NLC GGC repeat expansion-induced genomic damage, 3D chromatin structural abnormalities, and senescence.Nature communications · 2026Article
- hnRNPA3 promotes the proliferation of hepatocellular carcinoma cells by stabilizing GLI2 proteins and activating Hedgehog pathway.Hepatology international · 2026Article
- Targeting STAU1 prevents p53 apoptotic signaling in neurodegeneration.Cell death & disease · 2025Article
- Small molecule inhibitors of hnRNPA2B1-RNA interactions reveal a predictable sorting of RNA subsets into extracellular vesicles.Nucleic acids research · 2025Article
- Modeling ALS with Patient-Derived iPSCs: Recent Advances and Future Potentials.Brain sciences · 2025Review
- Article
- SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia.Nature communications · 2024Article
- PABPC1 mediates degradation ofiScience · 2024Article
- Neuronal STING activation in amyotrophic lateral sclerosis and frontotemporal dementia.Acta neuropathologica · 2024Article
- Molecular hallmarks of ageing in amyotrophic lateral sclerosis.Cellular and molecular life sciences : CMLS · 2024Review
- Pathomechanistic Networks of Motor System Injury in Amyotrophic Lateral Sclerosis.Current neuropharmacology · 2024Review
- Mechanisms and pathology of protein misfolding and aggregation.Nature reviews. Molecular cell biology · 2023Review
- Toxicity ofLife science alliance · 2023Article
- Repeat length of C9orf72-associated glycine-alanine polypeptides affects their toxicity.Acta neuropathologica communications · 2023Article
- Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology.Nature communications · 2023Article
- C9orf72 functions in the nucleus to regulate DNA damage repair.Cell death and differentiation · 2023Article
- RNA Dysmetabolism and Repeat-Associated Non-AUG Translation in Frontotemporal Lobar Degeneration/Amyotrophic Lateral Sclerosis due toJMA journal · 2023Review
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Authors and funding
16 authors at 6 institutions in 3 countries.
Funding
Abstract
Repeat expansion in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Expanded sense and antisense repeat RNA transcripts in C9orf72 are translated into five dipeptide-repeat proteins (DPRs) in an AUG-independent manner. We previously identified the heterogeneous ribonucleoprotein (hnRNP) A3 as an interactor of the sense repeat RNA that reduces its translation into DPRs. Furthermore, we found that hnRNPA3 is depleted from the nucleus and partially mislocalized to cytoplasmic poly-GA inclusions in C9orf72 patients, suggesting that poly-GA sequesters hnRNPA3 within the cytoplasm. We now demonstrate that hnRNPA3 also binds to the antisense repeat RNA. Both DPR production and deposition from sense and antisense RNA repeats are increased upon hnRNPA3 reduction. All DPRs induced DNA double strand breaks (DSB), which was further enhanced upon reduction of hnRNPA3. Poly-glycine-arginine and poly-proline-arginine increased foci formed by phosphorylated Ataxia Telangiectasia Mutated (pATM), a major sensor of DSBs, whereas poly-glycine-alanine (poly-GA) evoked a reduction of pATM foci. In dentate gyri of C9orf72 patients, lower nuclear hnRNPA3 levels were associated with increased DNA damage. Moreover, enhanced poly-GA deposition correlated with reduced pATM foci. Since cytoplasmic pATM deposits partially colocalized with poly-GA deposits, these results suggest that poly-GA, the most frequent DPR observed in C9orf72 patients, differentially causes DNA damage and that poly-GA selectively sequesters pATM in the cytoplasm inhibiting its recruitment to sites of DNA damage. Thus, mislocalization of nuclear hnRNPA3 caused by poly-GA leads to increased poly-GA production, which partially depletes pATM, and consequently enhances DSB.
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