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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/223689
Nuclear pore complex dysfunction drives TDP-43 pathology in ALS
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration and pathological aggregation of TDP-43. While protein misfolding and impaired autophagy are established features, accumulating evidence highlights the nuclear pore complex (NPC)as a vulnerable, redox-sensitive hub in ALS pathogenesis. Here, we show that selective loss of NPC components, particularly the scaffold proteins NUP107 and NUP93, and FG-repeat-containing components-is a consistent finding across ALS postmortem spinal cord, SOD1<^>G93A and TDP-43 mutant mouse models, and human cell systems.CRISPR-mediated depletion of NUP107 in human cells triggers hallmark features of ALS pathology, including cytoplasmic TDP-43 mislocalization, increased phosphorylation, and autophagy dysfunction. Conversely, TDP-43 knockdown perturbs NPC composition, suggesting a reciprocal regulatory loop. Crucially, we demonstrate that oxidative stress exacerbated NPC subunit mislocalization and enhanced TDP-43 aggregation. Using oxime blotting and DNPH assays, we show that FG-repeat subunits of NPC were direct targets of redox-driven carbonylation, indicating that oxidative modifications compromise NPC integrity thuspotentially affecting nucleocytoplasmic transport. Our findings established NPC dysfunction as a redox-sensitive driver of TDP-43 pathology in ALS and highlight nucleocytoplasmic transport as a promising therapeutic axis. The susceptibility of long-lived NPC proteins to oxidative damage provides a mechanistic link between redox stress, proteostasis collapse, and neurodegeneration.
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RAMÍREZ NÚÑEZ, Omar, RICO-RIOS, Santiago, TORRES, Pascual, AYALA, Victòria, FERNÁNDEZ-BERNAL, Anna, CERON-CODORNIU, Miriam, ANDRÉS-BENITO, Pol, VINYALS, A., MAQSOOD, S., FERRER, Isidro, PAMPLONA, Reinald, PORTERO-OTIN, Manuel. Nuclear pore complex dysfunction drives TDP-43 pathology in ALS. _Redox Biology_. 2025. Vol. 86, núm. 103824. [consulta: 7 de febrer de 2026]. ISSN: 2213-2317. [Disponible a: https://hdl.handle.net/2445/223689]