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Tau excess impairs mitosis and kinesin-5 function, leading to aneuploidy and cell death
In neurodegenerative diseases such as Alzheimer's disease (AD), cell cycle defects and associated aneuploidy have been described. However, the importance of these defects in the physiopathology of AD and the underlying mechanistic processes are largely unknown, in particular with respect to the...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Company of Biologists Ltd
2016
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833329/ https://www.ncbi.nlm.nih.gov/pubmed/26822478 http://dx.doi.org/10.1242/dmm.022558 |
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author | Bougé, Anne-Laure Parmentier, Marie-Laure |
author_facet | Bougé, Anne-Laure Parmentier, Marie-Laure |
author_sort | Bougé, Anne-Laure |
collection | PubMed |
description | In neurodegenerative diseases such as Alzheimer's disease (AD), cell cycle defects and associated aneuploidy have been described. However, the importance of these defects in the physiopathology of AD and the underlying mechanistic processes are largely unknown, in particular with respect to the microtubule (MT)-binding protein Tau, which is found in excess in the brain and cerebrospinal fluid of affected individuals. Although it has long been known that Tau is phosphorylated during mitosis to generate a lower affinity for MTs, there is, to our knowledge, no indication that an excess of this protein could affect mitosis. Here, we studied the effect of an excess of human Tau (hTau) protein on cell mitosis in vivo. Using the Drosophila developing wing disc epithelium as a model, we show that an excess of hTau induces a mitotic arrest, with the presence of monopolar spindles. This mitotic defect leads to aneuploidy and apoptotic cell death. We studied the mechanism of action of hTau and found that the MT-binding domain of hTau is responsible for these defects. We also demonstrate that the effects of hTau occur via the inhibition of the function of the kinesin Klp61F, the Drosophila homologue of kinesin-5 (also called Eg5 or KIF11). We finally show that this deleterious effect of hTau is also found in other Drosophila cell types (neuroblasts) and tissues (the developing eye disc), as well as in human HeLa cells. By demonstrating that MT-bound Tau inhibits the Eg5 kinesin and cell mitosis, our work provides a new framework to consider the role of Tau in neurodegenerative diseases. |
format | Online Article Text |
id | pubmed-4833329 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | The Company of Biologists Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-48333292016-05-19 Tau excess impairs mitosis and kinesin-5 function, leading to aneuploidy and cell death Bougé, Anne-Laure Parmentier, Marie-Laure Dis Model Mech Research Article In neurodegenerative diseases such as Alzheimer's disease (AD), cell cycle defects and associated aneuploidy have been described. However, the importance of these defects in the physiopathology of AD and the underlying mechanistic processes are largely unknown, in particular with respect to the microtubule (MT)-binding protein Tau, which is found in excess in the brain and cerebrospinal fluid of affected individuals. Although it has long been known that Tau is phosphorylated during mitosis to generate a lower affinity for MTs, there is, to our knowledge, no indication that an excess of this protein could affect mitosis. Here, we studied the effect of an excess of human Tau (hTau) protein on cell mitosis in vivo. Using the Drosophila developing wing disc epithelium as a model, we show that an excess of hTau induces a mitotic arrest, with the presence of monopolar spindles. This mitotic defect leads to aneuploidy and apoptotic cell death. We studied the mechanism of action of hTau and found that the MT-binding domain of hTau is responsible for these defects. We also demonstrate that the effects of hTau occur via the inhibition of the function of the kinesin Klp61F, the Drosophila homologue of kinesin-5 (also called Eg5 or KIF11). We finally show that this deleterious effect of hTau is also found in other Drosophila cell types (neuroblasts) and tissues (the developing eye disc), as well as in human HeLa cells. By demonstrating that MT-bound Tau inhibits the Eg5 kinesin and cell mitosis, our work provides a new framework to consider the role of Tau in neurodegenerative diseases. The Company of Biologists Ltd 2016-03-01 /pmc/articles/PMC4833329/ /pubmed/26822478 http://dx.doi.org/10.1242/dmm.022558 Text en © 2016. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Article Bougé, Anne-Laure Parmentier, Marie-Laure Tau excess impairs mitosis and kinesin-5 function, leading to aneuploidy and cell death |
title | Tau excess impairs mitosis and kinesin-5 function, leading to aneuploidy and cell death |
title_full | Tau excess impairs mitosis and kinesin-5 function, leading to aneuploidy and cell death |
title_fullStr | Tau excess impairs mitosis and kinesin-5 function, leading to aneuploidy and cell death |
title_full_unstemmed | Tau excess impairs mitosis and kinesin-5 function, leading to aneuploidy and cell death |
title_short | Tau excess impairs mitosis and kinesin-5 function, leading to aneuploidy and cell death |
title_sort | tau excess impairs mitosis and kinesin-5 function, leading to aneuploidy and cell death |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833329/ https://www.ncbi.nlm.nih.gov/pubmed/26822478 http://dx.doi.org/10.1242/dmm.022558 |
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