Nuclear pore complex dysfunction drives TDP-43 pathology in ALS
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-10-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725003374 |
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| author | O. Ramírez-Núñez S. Rico-Ríos P. Torres V. Ayala A. Fernàndez-Bernal M. Ceron-Codorniu P. Andrés-Benito A. Vinyals S. Maqsood I. Ferrer R. Pamplona M. Portero-Otin |
| author_facet | O. Ramírez-Núñez S. Rico-Ríos P. Torres V. Ayala A. Fernàndez-Bernal M. Ceron-Codorniu P. Andrés-Benito A. Vinyals S. Maqsood I. Ferrer R. Pamplona M. Portero-Otin |
| author_sort | O. Ramírez-Núñez |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-690ce178fa8547b98f88280fc4a230be |
| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-690ce178fa8547b98f88280fc4a230be2025-08-20T03:44:06ZengElsevierRedox Biology2213-23172025-10-018610382410.1016/j.redox.2025.103824Nuclear pore complex dysfunction drives TDP-43 pathology in ALSO. Ramírez-Núñez0S. Rico-Ríos1P. Torres2V. Ayala3A. Fernàndez-Bernal4M. Ceron-Codorniu5P. Andrés-Benito6A. Vinyals7S. Maqsood8I. Ferrer9R. Pamplona10M. Portero-Otin11Metabolic Pathophysiology Research Group, Dept of Experimental Medicine, University of Lleida-IRBLleida, Avda Rovira Roure, 80 E25196, Lleida, Spain; Corresponding author.Metabolic Pathophysiology Research Group, Dept of Experimental Medicine, University of Lleida-IRBLleida, Avda Rovira Roure, 80 E25196, Lleida, SpainMetabolic Pathophysiology Research Group, Dept of Experimental Medicine, University of Lleida-IRBLleida, Avda Rovira Roure, 80 E25196, Lleida, SpainMetabolic Pathophysiology Research Group, Dept of Experimental Medicine, University of Lleida-IRBLleida, Avda Rovira Roure, 80 E25196, Lleida, SpainMetabolic Pathophysiology Research Group, Dept of Experimental Medicine, University of Lleida-IRBLleida, Avda Rovira Roure, 80 E25196, Lleida, SpainMetabolic Pathophysiology Research Group, Dept of Experimental Medicine, University of Lleida-IRBLleida, Avda Rovira Roure, 80 E25196, Lleida, SpainCognition and Behaviour Research Group, IRBLleida, Avda Rovira Roure, 80, Lleida, E-25196, Spain; Network Centre of Biomedical Research of Neurodegenerative Diseases (CIBERNED), Institute of Health Carlos III, L'Hospitalet de Llobregat, 08907, Barcelona, SpainNeurology and Neurogenetics Group - Neuroscience Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08907, Barcelona, SpainMetabolic Pathophysiology Research Group, Dept of Experimental Medicine, University of Lleida-IRBLleida, Avda Rovira Roure, 80 E25196, Lleida, SpainDepartment of Pathology and Experimental Therapeutics, University of Barcelona, Gran Via de l'Hospitalet, 199 L'Hospitalet de Llobregat, Barcelona, 08908, Spain; Reial Academia de Medicina de Catalunya, Barcelona, SpainMetabolic Pathophysiology Research Group, Dept of Experimental Medicine, University of Lleida-IRBLleida, Avda Rovira Roure, 80 E25196, Lleida, SpainMetabolic Pathophysiology Research Group, Dept of Experimental Medicine, University of Lleida-IRBLleida, Avda Rovira Roure, 80 E25196, Lleida, Spain; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2213231725003374 |
| spellingShingle | O. Ramírez-Núñez S. Rico-Ríos P. Torres V. Ayala A. Fernàndez-Bernal M. Ceron-Codorniu P. Andrés-Benito A. Vinyals S. Maqsood I. Ferrer R. Pamplona M. Portero-Otin Nuclear pore complex dysfunction drives TDP-43 pathology in ALS Redox Biology |
| title | Nuclear pore complex dysfunction drives TDP-43 pathology in ALS |
| title_full | Nuclear pore complex dysfunction drives TDP-43 pathology in ALS |
| title_fullStr | Nuclear pore complex dysfunction drives TDP-43 pathology in ALS |
| title_full_unstemmed | Nuclear pore complex dysfunction drives TDP-43 pathology in ALS |
| title_short | Nuclear pore complex dysfunction drives TDP-43 pathology in ALS |
| title_sort | nuclear pore complex dysfunction drives tdp 43 pathology in als |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725003374 |
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