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Downregulated Wnt/β-catenin signalling in the Down syndrome hippocampus

Pathological mechanisms underlying Down syndrome (DS)/Trisomy 21, including dysregulation of essential signalling processes remain poorly understood. Combining bioinformatics with RNA and protein analysis, we identified downregulation of the Wnt/β-catenin pathway in the hippocampus of adult DS indiv...

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Autores principales: Granno, Simone, Nixon-Abell, Jonathon, Berwick, Daniel C., Tosh, Justin, Heaton, George, Almudimeegh, Sultan, Nagda, Zenisha, Rain, Jean-Christophe, Zanda, Manuela, Plagnol, Vincent, Tybulewicz, Victor L. J., Cleverley, Karen, Wiseman, Frances K., Fisher, Elizabeth M. C., Harvey, Kirsten
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513850/
https://www.ncbi.nlm.nih.gov/pubmed/31086297
http://dx.doi.org/10.1038/s41598-019-43820-4
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author Granno, Simone
Nixon-Abell, Jonathon
Berwick, Daniel C.
Tosh, Justin
Heaton, George
Almudimeegh, Sultan
Nagda, Zenisha
Rain, Jean-Christophe
Zanda, Manuela
Plagnol, Vincent
Tybulewicz, Victor L. J.
Cleverley, Karen
Wiseman, Frances K.
Fisher, Elizabeth M. C.
Harvey, Kirsten
author_facet Granno, Simone
Nixon-Abell, Jonathon
Berwick, Daniel C.
Tosh, Justin
Heaton, George
Almudimeegh, Sultan
Nagda, Zenisha
Rain, Jean-Christophe
Zanda, Manuela
Plagnol, Vincent
Tybulewicz, Victor L. J.
Cleverley, Karen
Wiseman, Frances K.
Fisher, Elizabeth M. C.
Harvey, Kirsten
author_sort Granno, Simone
collection PubMed
description Pathological mechanisms underlying Down syndrome (DS)/Trisomy 21, including dysregulation of essential signalling processes remain poorly understood. Combining bioinformatics with RNA and protein analysis, we identified downregulation of the Wnt/β-catenin pathway in the hippocampus of adult DS individuals with Alzheimer’s disease and the ‘Tc1’ DS mouse model. Providing a potential underlying molecular pathway, we demonstrate that the chromosome 21 kinase DYRK1A regulates Wnt signalling via a novel bimodal mechanism. Under basal conditions, DYRK1A is a negative regulator of Wnt/β-catenin. Following pathway activation, however, DYRK1A exerts the opposite effect, increasing signalling activity. In summary, we identified downregulation of hippocampal Wnt/β-catenin signalling in DS, possibly mediated by a dose dependent effect of the chromosome 21-encoded kinase DYRK1A. Overall, we propose that dosage imbalance of the Hsa21 gene DYRK1A affects downstream Wnt target genes. Therefore, modulation of Wnt signalling may open unexplored avenues for DS and Alzheimer’s disease treatment.
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spelling pubmed-65138502019-05-24 Downregulated Wnt/β-catenin signalling in the Down syndrome hippocampus Granno, Simone Nixon-Abell, Jonathon Berwick, Daniel C. Tosh, Justin Heaton, George Almudimeegh, Sultan Nagda, Zenisha Rain, Jean-Christophe Zanda, Manuela Plagnol, Vincent Tybulewicz, Victor L. J. Cleverley, Karen Wiseman, Frances K. Fisher, Elizabeth M. C. Harvey, Kirsten Sci Rep Article Pathological mechanisms underlying Down syndrome (DS)/Trisomy 21, including dysregulation of essential signalling processes remain poorly understood. Combining bioinformatics with RNA and protein analysis, we identified downregulation of the Wnt/β-catenin pathway in the hippocampus of adult DS individuals with Alzheimer’s disease and the ‘Tc1’ DS mouse model. Providing a potential underlying molecular pathway, we demonstrate that the chromosome 21 kinase DYRK1A regulates Wnt signalling via a novel bimodal mechanism. Under basal conditions, DYRK1A is a negative regulator of Wnt/β-catenin. Following pathway activation, however, DYRK1A exerts the opposite effect, increasing signalling activity. In summary, we identified downregulation of hippocampal Wnt/β-catenin signalling in DS, possibly mediated by a dose dependent effect of the chromosome 21-encoded kinase DYRK1A. Overall, we propose that dosage imbalance of the Hsa21 gene DYRK1A affects downstream Wnt target genes. Therefore, modulation of Wnt signalling may open unexplored avenues for DS and Alzheimer’s disease treatment. Nature Publishing Group UK 2019-05-13 /pmc/articles/PMC6513850/ /pubmed/31086297 http://dx.doi.org/10.1038/s41598-019-43820-4 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Granno, Simone
Nixon-Abell, Jonathon
Berwick, Daniel C.
Tosh, Justin
Heaton, George
Almudimeegh, Sultan
Nagda, Zenisha
Rain, Jean-Christophe
Zanda, Manuela
Plagnol, Vincent
Tybulewicz, Victor L. J.
Cleverley, Karen
Wiseman, Frances K.
Fisher, Elizabeth M. C.
Harvey, Kirsten
Downregulated Wnt/β-catenin signalling in the Down syndrome hippocampus
title Downregulated Wnt/β-catenin signalling in the Down syndrome hippocampus
title_full Downregulated Wnt/β-catenin signalling in the Down syndrome hippocampus
title_fullStr Downregulated Wnt/β-catenin signalling in the Down syndrome hippocampus
title_full_unstemmed Downregulated Wnt/β-catenin signalling in the Down syndrome hippocampus
title_short Downregulated Wnt/β-catenin signalling in the Down syndrome hippocampus
title_sort downregulated wnt/β-catenin signalling in the down syndrome hippocampus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513850/
https://www.ncbi.nlm.nih.gov/pubmed/31086297
http://dx.doi.org/10.1038/s41598-019-43820-4
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