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PATHOLOGICAL TAU ABORTS CELL CYCLE ACTIVATION BY MIMICKING EPITHELIAL-MESENCHYMAL-TRANSITION IN NEURONS
Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder which is characterized by neurofibrillary tau tangles and amyloid-ß plaques. Our laboratory uses tau transgenic Drosophila to rapidly test hypotheses along with human brain samples in order to ensure that our work is relevant to...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6846030/ http://dx.doi.org/10.1093/geroni/igz038.3075 |
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author | Phan, Roseann V Beckmann, Adrian Frost, Bess E |
author_facet | Phan, Roseann V Beckmann, Adrian Frost, Bess E |
author_sort | Phan, Roseann V |
collection | PubMed |
description | Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder which is characterized by neurofibrillary tau tangles and amyloid-ß plaques. Our laboratory uses tau transgenic Drosophila to rapidly test hypotheses along with human brain samples in order to ensure that our work is relevant to clinical endeavors. Using this approach, we identified a neurodegenerative pathway whereby pathological tau over-stabilizes filamentous actin (f-actin), leading to disrupting aberrant nuclear pleomorphisms and decondensation of heterochromatic DNA. Due to the neuronal phenotypes observed in tau-transgenic Drosophila and reentry of post-mitotic neurons into the cell cycle, we hypothesized that tau perturbs the cellular program that maintains terminal neuronal differentiation. Based on RNA-sequencing, we identified prospero as the most differentially expressed and downregulated transcript in tau transgenic flies. Prospero regulates genes that promote and maintain terminal neuronal differentiation. At the protein level, prospero is significantly reduced in tau transgenic flies at 10 days old. We find that over stabilization of f-actin or over-expression of moesin, a cytoskeletal protein known to participate in tumor progression and metastasis, depletes prospero. Using genetically manipulated prospero target genes we find a connection to neurodegeneration. These targets include a PKC, tep4, and knot-suggesting that broad cellular processes are affected by this reduction. Overall, our findings suggest that pathological tau causes cell cycle re-entry by disrupting transcription factors governing terminal neuronal differentiation as well as over-stabilization of f-actin being the driving loss of terminal neuronal differentiation and casually associated with neuronal death. |
format | Online Article Text |
id | pubmed-6846030 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-68460302019-11-18 PATHOLOGICAL TAU ABORTS CELL CYCLE ACTIVATION BY MIMICKING EPITHELIAL-MESENCHYMAL-TRANSITION IN NEURONS Phan, Roseann V Beckmann, Adrian Frost, Bess E Innov Aging Session Lb935 (Late Breaking Poster) Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder which is characterized by neurofibrillary tau tangles and amyloid-ß plaques. Our laboratory uses tau transgenic Drosophila to rapidly test hypotheses along with human brain samples in order to ensure that our work is relevant to clinical endeavors. Using this approach, we identified a neurodegenerative pathway whereby pathological tau over-stabilizes filamentous actin (f-actin), leading to disrupting aberrant nuclear pleomorphisms and decondensation of heterochromatic DNA. Due to the neuronal phenotypes observed in tau-transgenic Drosophila and reentry of post-mitotic neurons into the cell cycle, we hypothesized that tau perturbs the cellular program that maintains terminal neuronal differentiation. Based on RNA-sequencing, we identified prospero as the most differentially expressed and downregulated transcript in tau transgenic flies. Prospero regulates genes that promote and maintain terminal neuronal differentiation. At the protein level, prospero is significantly reduced in tau transgenic flies at 10 days old. We find that over stabilization of f-actin or over-expression of moesin, a cytoskeletal protein known to participate in tumor progression and metastasis, depletes prospero. Using genetically manipulated prospero target genes we find a connection to neurodegeneration. These targets include a PKC, tep4, and knot-suggesting that broad cellular processes are affected by this reduction. Overall, our findings suggest that pathological tau causes cell cycle re-entry by disrupting transcription factors governing terminal neuronal differentiation as well as over-stabilization of f-actin being the driving loss of terminal neuronal differentiation and casually associated with neuronal death. Oxford University Press 2019-11-08 /pmc/articles/PMC6846030/ http://dx.doi.org/10.1093/geroni/igz038.3075 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Session Lb935 (Late Breaking Poster) Phan, Roseann V Beckmann, Adrian Frost, Bess E PATHOLOGICAL TAU ABORTS CELL CYCLE ACTIVATION BY MIMICKING EPITHELIAL-MESENCHYMAL-TRANSITION IN NEURONS |
title | PATHOLOGICAL TAU ABORTS CELL CYCLE ACTIVATION BY MIMICKING EPITHELIAL-MESENCHYMAL-TRANSITION IN NEURONS |
title_full | PATHOLOGICAL TAU ABORTS CELL CYCLE ACTIVATION BY MIMICKING EPITHELIAL-MESENCHYMAL-TRANSITION IN NEURONS |
title_fullStr | PATHOLOGICAL TAU ABORTS CELL CYCLE ACTIVATION BY MIMICKING EPITHELIAL-MESENCHYMAL-TRANSITION IN NEURONS |
title_full_unstemmed | PATHOLOGICAL TAU ABORTS CELL CYCLE ACTIVATION BY MIMICKING EPITHELIAL-MESENCHYMAL-TRANSITION IN NEURONS |
title_short | PATHOLOGICAL TAU ABORTS CELL CYCLE ACTIVATION BY MIMICKING EPITHELIAL-MESENCHYMAL-TRANSITION IN NEURONS |
title_sort | pathological tau aborts cell cycle activation by mimicking epithelial-mesenchymal-transition in neurons |
topic | Session Lb935 (Late Breaking Poster) |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6846030/ http://dx.doi.org/10.1093/geroni/igz038.3075 |
work_keys_str_mv | AT phanroseannv pathologicaltauabortscellcycleactivationbymimickingepithelialmesenchymaltransitioninneurons AT beckmannadrian pathologicaltauabortscellcycleactivationbymimickingepithelialmesenchymaltransitioninneurons AT frostbesse pathologicaltauabortscellcycleactivationbymimickingepithelialmesenchymaltransitioninneurons |