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Importin-Mediated Pathological Tau Nuclear Translocation Causes Disruption of the Nuclear Lamina, TDP-43 Mislocalization and Cell Death
Tau is a cytosolic protein that has also been observed in the nucleus, where it has multiple proposed functions that are regulated by phosphorylation. However, the mechanism underlying the nuclear import of tau is unclear, as is the contribution of nuclear tau to the pathology of tauopathies. We hav...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9113199/ https://www.ncbi.nlm.nih.gov/pubmed/35592115 http://dx.doi.org/10.3389/fnmol.2022.888420 |
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author | Candia, Robert F. Cohen, Leah S. Morozova, Viktoriya Corbo, Christopher Alonso, Alejandra D. |
author_facet | Candia, Robert F. Cohen, Leah S. Morozova, Viktoriya Corbo, Christopher Alonso, Alejandra D. |
author_sort | Candia, Robert F. |
collection | PubMed |
description | Tau is a cytosolic protein that has also been observed in the nucleus, where it has multiple proposed functions that are regulated by phosphorylation. However, the mechanism underlying the nuclear import of tau is unclear, as is the contribution of nuclear tau to the pathology of tauopathies. We have previously generated a pathological form of tau, PH-tau (pseudophosphorylation mutants S199E, T212E, T231E, and S262E) that mimics AD pathological behavior in cells, Drosophila, and a mouse model. Here, we demonstrated that PH-tau translocates into the nucleus of transiently transfected HEK-293 cells, but wildtype tau does not. We identified a putative importin binding site in the tau sequence, and showed that disruption of this site prevents tau from entering the nucleus. We further showed that this nuclear translocation is prevented by inhibitors of both importin-α and importin-β. In addition, expression of PH-tau resulted in an enlarged population of dying cells, which is prevented by blocking its entry into the nucleus. PH-tau-expressing cells also exhibited disruption of the nuclear lamina and mislocalization of TDP-43 to the cytoplasm. We found that PH-tau does not bundle microtubules, and this effect is independent of nuclear translocation. These results demonstrate that tau translocates into the nucleus through the importin-α/β pathway, and that PH-tau exhibits toxicity after its nuclear translocation. We propose a model where hyperphosphorylated tau not only disrupts the microtubule network, but also translocates into the nucleus and interferes with cellular functions, such as nucleocytoplasmic transport, inducing mislocalization of proteins like TDP-43 and, ultimately, cell death. |
format | Online Article Text |
id | pubmed-9113199 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-91131992022-05-18 Importin-Mediated Pathological Tau Nuclear Translocation Causes Disruption of the Nuclear Lamina, TDP-43 Mislocalization and Cell Death Candia, Robert F. Cohen, Leah S. Morozova, Viktoriya Corbo, Christopher Alonso, Alejandra D. Front Mol Neurosci Neuroscience Tau is a cytosolic protein that has also been observed in the nucleus, where it has multiple proposed functions that are regulated by phosphorylation. However, the mechanism underlying the nuclear import of tau is unclear, as is the contribution of nuclear tau to the pathology of tauopathies. We have previously generated a pathological form of tau, PH-tau (pseudophosphorylation mutants S199E, T212E, T231E, and S262E) that mimics AD pathological behavior in cells, Drosophila, and a mouse model. Here, we demonstrated that PH-tau translocates into the nucleus of transiently transfected HEK-293 cells, but wildtype tau does not. We identified a putative importin binding site in the tau sequence, and showed that disruption of this site prevents tau from entering the nucleus. We further showed that this nuclear translocation is prevented by inhibitors of both importin-α and importin-β. In addition, expression of PH-tau resulted in an enlarged population of dying cells, which is prevented by blocking its entry into the nucleus. PH-tau-expressing cells also exhibited disruption of the nuclear lamina and mislocalization of TDP-43 to the cytoplasm. We found that PH-tau does not bundle microtubules, and this effect is independent of nuclear translocation. These results demonstrate that tau translocates into the nucleus through the importin-α/β pathway, and that PH-tau exhibits toxicity after its nuclear translocation. We propose a model where hyperphosphorylated tau not only disrupts the microtubule network, but also translocates into the nucleus and interferes with cellular functions, such as nucleocytoplasmic transport, inducing mislocalization of proteins like TDP-43 and, ultimately, cell death. Frontiers Media S.A. 2022-05-03 /pmc/articles/PMC9113199/ /pubmed/35592115 http://dx.doi.org/10.3389/fnmol.2022.888420 Text en Copyright © 2022 Candia, Cohen, Morozova, Corbo and Alonso. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Candia, Robert F. Cohen, Leah S. Morozova, Viktoriya Corbo, Christopher Alonso, Alejandra D. Importin-Mediated Pathological Tau Nuclear Translocation Causes Disruption of the Nuclear Lamina, TDP-43 Mislocalization and Cell Death |
title | Importin-Mediated Pathological Tau Nuclear Translocation Causes Disruption of the Nuclear Lamina, TDP-43 Mislocalization and Cell Death |
title_full | Importin-Mediated Pathological Tau Nuclear Translocation Causes Disruption of the Nuclear Lamina, TDP-43 Mislocalization and Cell Death |
title_fullStr | Importin-Mediated Pathological Tau Nuclear Translocation Causes Disruption of the Nuclear Lamina, TDP-43 Mislocalization and Cell Death |
title_full_unstemmed | Importin-Mediated Pathological Tau Nuclear Translocation Causes Disruption of the Nuclear Lamina, TDP-43 Mislocalization and Cell Death |
title_short | Importin-Mediated Pathological Tau Nuclear Translocation Causes Disruption of the Nuclear Lamina, TDP-43 Mislocalization and Cell Death |
title_sort | importin-mediated pathological tau nuclear translocation causes disruption of the nuclear lamina, tdp-43 mislocalization and cell death |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9113199/ https://www.ncbi.nlm.nih.gov/pubmed/35592115 http://dx.doi.org/10.3389/fnmol.2022.888420 |
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