Ramírez Núñez, OmarRico-Rios, SantiagoTorres, PascualAyala, VictòriaFernández-Bernal, AnnaCeron-Codorniu, MiriamAndrés-Benito, PolVinyals, A.Maqsood, S.Ferrer, IsidroPamplona, ReinaldPortero-Otin, Manuel2025-10-162025-10-162025-08-152213-2317https://hdl.handle.net/2445/223689Amyotrophic 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.15 p.application/pdfengcc-by (c) Ramírez Núñez, Omar et al., 2025http://creativecommons.org/licenses/by/3.0/es/Patologia cel·lularMalalties neurodegenerativesEsclerosi lateral amiotròficaCellular pathologyNeurodegenerative DiseasesAmyotrophic lateral sclerosisinfo:eu-repo/semantics/article2025-10-15info:eu-repo/semantics/openAccess40819564