ArticleScientific reports2022
C9orf72 dipeptides disrupt the nucleocytoplasmic transport machinery and cause TDP-43 mislocalisation to the cytoplasm.
Article in Scientific reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed.
- Integrative synaptosome multi-omics reveals disrupted synapse organization and localized cryptic transcripts in C9ORF72-frontotemporal dementia.Acta neuropathologica · 2026Article
- Adenosine Deaminase-Mediated Purine Dysfunction Leads to DNA Repair Inhibition and Senescence in Sporadic Amyotrophic Lateral Sclerosis.International journal of molecular sciences · 2026Article
- Cell Death in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets.MedComm · 2026Review
- Article
- RanGAP1 accumulates in stress-induced cytoplasmic compartments that are distinct from stress granules and P-bodies.microPublication biology · 2026Article
- Distinct brain extracellular vesicle microRNA profiles differ in frontotemporal dementia and Alzheimer's disease.Brain communications · 2026Article
- PolyGR-containing aggregates link with pathology and clinical features of Alzheimer's disease.Acta neuropathologica · 2025Article
- C9orf72 ALS-causing mutations lead to mislocalization and aggregation of nucleoporin Nup107 into stress granules.FEBS letters · 2025Article
- Article
- Tracing neuropathological signatures: TARDBP and C9orf72 double mutations in a Sicilian family.Human molecular genetics · 2025Article
- Blueprint of Collapse: Precision Biomarkers, Molecular Cascades, and the Engineered Decline of Fast-Progressing ALS.International journal of molecular sciences · 2025Review
- Divergent and convergent TMEM106B pathology in murine models of neurodegeneration and human disease.Acta neuropathologica communications · 2025Article
- Gene therapy breakthroughs in ALS: a beacon of hope for 20% of ALS patients.Translational neurodegeneration · 2025Review
- Review
- Using ALS to understand profilin 1's diverse roles in cellular physiology.Cytoskeleton (Hoboken, N.J.) · 2025Review
- Nuclear poly-glutamine aggregates rupture the nuclear envelope and hinder its repair.The Journal of cell biology · 2024Article
- NEMF mutations in mice illustrate how Importin-β specific nuclear transport defects recapitulate neurodegenerative disease hallmarks.PLoS genetics · 2024Article
- The prion-like effect and prion-like protein targeting strategy in amyotrophic lateral sclerosis.Heliyon · 2024Review
- Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB.Molecular neurobiology · 2024Article
- LINC complex alterations are a key feature of sporadic and familial ALS/FTD.Acta neuropathologica communications · 2024Article
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Abstract
A repeat expansion in C9orf72 is the major cause of both frontotemporal dementia and amyotrophic lateral sclerosis, accounting for approximately 1 in 12 cases of either disease. The expansion is translated to produce five dipeptide repeat proteins (DPRs) which aggregate in patient brain and are toxic in numerous models, though the mechanisms underlying this toxicity are poorly understood. Recent studies highlight nucleocytoplasmic transport impairments as a potential mechanism underlying neurodegeneration in C9orf72-linked disease, although the contribution of DPRs to this remains unclear. We expressed DPRs in HeLa cells, in the absence of repeat RNA. Crucially, we expressed DPRs at repeat-lengths found in patients (> 1000 units), ensuring our findings were relevant to disease. Immunofluorescence imaging was used to investigate the impact of each DPR on the nucleus, nucleocytoplasmic transport machinery and TDP-43 localisation. DPRs impaired the structural integrity of the nucleus, causing nuclear membrane disruption and misshapen nuclei. Ran and RanGAP, two proteins required for nucleocytoplasmic transport, were also mislocalised in DPR-expressing cells. Furthermore, DPRs triggered mislocalisation of TDP-43 to the cytoplasm, and this occurred in the same cells as Ran and RanGAP mislocalisation, suggesting a potential link between DPRs, nucleocytoplasmic transport impairments and TDP-43 pathology.
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