Accumulation of TDP-43 causes karyopherin-α4 pathology that characterises amyotrophic lateral sclerosis
Cytoplasmic mislocalisation and nuclear depletion of TDP-43 are pathological hallmarks of amyotrophic lateral sclerosis (ALS), including mutations in the C9ORF72 gene that characterise the most common genetic form of ALS (C9ALS). Studies in human cells and animal models have associated cytoplasmic m...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2025.1558227/full |
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| author | Manpreet Singh Atwal Jerneja Nimac Jerneja Nimac Urša Čerček Urša Čerček Sarah Ricarda Goesch Hannah Rebecca Goesch Paraskevi Tziortzouda Tiziana Ercolani Anna Zatorska Terouz Pasha Ivo Carre Jacqueline Mitchell Claire Troakes Bart Tummers Vera Župunski Boris Rogelj Boris Rogelj Tibor Hortobágyi Tibor Hortobágyi Frank Hirth |
| author_facet | Manpreet Singh Atwal Jerneja Nimac Jerneja Nimac Urša Čerček Urša Čerček Sarah Ricarda Goesch Hannah Rebecca Goesch Paraskevi Tziortzouda Tiziana Ercolani Anna Zatorska Terouz Pasha Ivo Carre Jacqueline Mitchell Claire Troakes Bart Tummers Vera Župunski Boris Rogelj Boris Rogelj Tibor Hortobágyi Tibor Hortobágyi Frank Hirth |
| author_sort | Manpreet Singh Atwal |
| collection | DOAJ |
| description | Cytoplasmic mislocalisation and nuclear depletion of TDP-43 are pathological hallmarks of amyotrophic lateral sclerosis (ALS), including mutations in the C9ORF72 gene that characterise the most common genetic form of ALS (C9ALS). Studies in human cells and animal models have associated cytoplasmic mislocalisation of TDP-43 with abnormalities in nuclear transport receptors, referred to as karyopherins, that mediate the nucleocytoplasmic shuttling of TDP-43. Yet the relationship between karyopherin abnormalities and TDP-43 pathology are unclear. Here we report karyopherin-α4 (KPNA4) pathology in the spinal cord of TDP-43-positive sporadic ALS and C9ALS patients. Structural analyses revealed the selective interaction between KPNA subtypes, especially KPNA4, with the nuclear localisation signal (NLS) of TDP-43. Targeted cytoplasmic mislocalisation and nuclear depletion of TDP-43 caused KPNA4 pathology in human cells. Similar phenotypes were observed in Drosophila whereby cytoplasmic accumulation of the TDP-43 homolog, TBPH, caused the nuclear decrease and cytosolic mislocalisation of the KPNA4 homolog, Importin-α3 (Impα3). In contrast, induced accumulation of Impα3 was not sufficient to cause TBPH mislocalisation. Instead, targeted gain of Impα3 in the presence of accumulating cytosolic TBPH, restored Impα3 localisation and partially rescued nuclear TBPH. These results demonstrate that cytoplasmic accumulation of TDP-43 causes karyopherin pathology that characterises ALS spinal cord. Together with earlier reports, our findings establish KPNA4 abnormalities as a molecular signature of TDP-43 proteinopathies and identify it as a potential therapeutic target to sustain nuclear TDP-43 essential for cellular homeostasis affected in ALS and frontotemporal dementia. |
| format | Article |
| id | doaj-art-54d0aaf01b124b4ab409cb1c1ce36731 |
| institution | Kabale University |
| issn | 1662-453X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj-art-54d0aaf01b124b4ab409cb1c1ce367312025-08-20T03:25:27ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2025-07-011910.3389/fnins.2025.15582271558227Accumulation of TDP-43 causes karyopherin-α4 pathology that characterises amyotrophic lateral sclerosisManpreet Singh Atwal0Jerneja Nimac1Jerneja Nimac2Urša Čerček3Urša Čerček4Sarah Ricarda Goesch5Hannah Rebecca Goesch6Paraskevi Tziortzouda7Tiziana Ercolani8Anna Zatorska9Terouz Pasha10Ivo Carre11Jacqueline Mitchell12Claire Troakes13Bart Tummers14Vera Župunski15Boris Rogelj16Boris Rogelj17Tibor Hortobágyi18Tibor Hortobágyi19Frank Hirth20Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United KingdomDepartment of Biotechnology, Jozef Stefan Institute, Ljubljana, SloveniaGraduate School of Biomedicine, Faculty of Medicine, University of Ljubljana, Ljubljana, SloveniaDepartment of Biotechnology, Jozef Stefan Institute, Ljubljana, SloveniaGraduate School of Biomedicine, Faculty of Medicine, University of Ljubljana, Ljubljana, SloveniaDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United KingdomDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United KingdomDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United KingdomDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United KingdomDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United KingdomDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United KingdomDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United KingdomDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United KingdomLondon Neurodegenerative Diseases Brain Bank, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United KingdomCentre for Inflammation Biology and Cancer Immunology, King’s College London, London, United KingdomFaculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, SloveniaDepartment of Biotechnology, Jozef Stefan Institute, Ljubljana, SloveniaFaculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, SloveniaDepartment of Neurology, University of Debrecen, Debrecen, HungaryCentre for Healthy Brain Ageing, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United KingdomDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United KingdomCytoplasmic mislocalisation and nuclear depletion of TDP-43 are pathological hallmarks of amyotrophic lateral sclerosis (ALS), including mutations in the C9ORF72 gene that characterise the most common genetic form of ALS (C9ALS). Studies in human cells and animal models have associated cytoplasmic mislocalisation of TDP-43 with abnormalities in nuclear transport receptors, referred to as karyopherins, that mediate the nucleocytoplasmic shuttling of TDP-43. Yet the relationship between karyopherin abnormalities and TDP-43 pathology are unclear. Here we report karyopherin-α4 (KPNA4) pathology in the spinal cord of TDP-43-positive sporadic ALS and C9ALS patients. Structural analyses revealed the selective interaction between KPNA subtypes, especially KPNA4, with the nuclear localisation signal (NLS) of TDP-43. Targeted cytoplasmic mislocalisation and nuclear depletion of TDP-43 caused KPNA4 pathology in human cells. Similar phenotypes were observed in Drosophila whereby cytoplasmic accumulation of the TDP-43 homolog, TBPH, caused the nuclear decrease and cytosolic mislocalisation of the KPNA4 homolog, Importin-α3 (Impα3). In contrast, induced accumulation of Impα3 was not sufficient to cause TBPH mislocalisation. Instead, targeted gain of Impα3 in the presence of accumulating cytosolic TBPH, restored Impα3 localisation and partially rescued nuclear TBPH. These results demonstrate that cytoplasmic accumulation of TDP-43 causes karyopherin pathology that characterises ALS spinal cord. Together with earlier reports, our findings establish KPNA4 abnormalities as a molecular signature of TDP-43 proteinopathies and identify it as a potential therapeutic target to sustain nuclear TDP-43 essential for cellular homeostasis affected in ALS and frontotemporal dementia.https://www.frontiersin.org/articles/10.3389/fnins.2025.1558227/fullamyotrophic lateral sclerosisTDP-43C9ORF72karyopherinKPNA4nuclear import |
| spellingShingle | Manpreet Singh Atwal Jerneja Nimac Jerneja Nimac Urša Čerček Urša Čerček Sarah Ricarda Goesch Hannah Rebecca Goesch Paraskevi Tziortzouda Tiziana Ercolani Anna Zatorska Terouz Pasha Ivo Carre Jacqueline Mitchell Claire Troakes Bart Tummers Vera Župunski Boris Rogelj Boris Rogelj Tibor Hortobágyi Tibor Hortobágyi Frank Hirth Accumulation of TDP-43 causes karyopherin-α4 pathology that characterises amyotrophic lateral sclerosis Frontiers in Neuroscience amyotrophic lateral sclerosis TDP-43 C9ORF72 karyopherin KPNA4 nuclear import |
| title | Accumulation of TDP-43 causes karyopherin-α4 pathology that characterises amyotrophic lateral sclerosis |
| title_full | Accumulation of TDP-43 causes karyopherin-α4 pathology that characterises amyotrophic lateral sclerosis |
| title_fullStr | Accumulation of TDP-43 causes karyopherin-α4 pathology that characterises amyotrophic lateral sclerosis |
| title_full_unstemmed | Accumulation of TDP-43 causes karyopherin-α4 pathology that characterises amyotrophic lateral sclerosis |
| title_short | Accumulation of TDP-43 causes karyopherin-α4 pathology that characterises amyotrophic lateral sclerosis |
| title_sort | accumulation of tdp 43 causes karyopherin α4 pathology that characterises amyotrophic lateral sclerosis |
| topic | amyotrophic lateral sclerosis TDP-43 C9ORF72 karyopherin KPNA4 nuclear import |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2025.1558227/full |
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