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Integrated analysis of the aging brain transcriptome and proteome in tauopathy
BACKGROUND: Tau neurofibrillary tangle pathology characterizes Alzheimer’s disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau- versus age-de...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526226/ https://www.ncbi.nlm.nih.gov/pubmed/32993812 http://dx.doi.org/10.1186/s13024-020-00405-4 |
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author | Mangleburg, Carl Grant Wu, Timothy Yalamanchili, Hari K. Guo, Caiwei Hsieh, Yi-Chen Duong, Duc M. Dammer, Eric B. De Jager, Philip L. Seyfried, Nicholas T. Liu, Zhandong Shulman, Joshua M. |
author_facet | Mangleburg, Carl Grant Wu, Timothy Yalamanchili, Hari K. Guo, Caiwei Hsieh, Yi-Chen Duong, Duc M. Dammer, Eric B. De Jager, Philip L. Seyfried, Nicholas T. Liu, Zhandong Shulman, Joshua M. |
author_sort | Mangleburg, Carl Grant |
collection | PubMed |
description | BACKGROUND: Tau neurofibrillary tangle pathology characterizes Alzheimer’s disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau- versus age-dependent changes. METHODS: Paired, longitudinal RNA-sequencing and mass-spectrometry were performed in a Drosophila model of tauopathy, based on pan-neuronal expression of human wildtype Tau (Tau(WT)) or a mutant form causing frontotemporal dementia (Tau(R406W)). Tau-induced, differentially expressed transcripts and proteins were examined cross-sectionally or using linear regression and adjusting for age. Hierarchical clustering was performed to highlight network perturbations, and we examined overlaps with human brain gene expression profiles in tauopathy. RESULTS: Tau(WT) induced 1514 and 213 differentially expressed transcripts and proteins, respectively. Tau(R406W) had a substantially greater impact, causing changes in 5494 transcripts and 697 proteins. There was a ~ 70% overlap between age- and Tau-induced changes and our analyses reveal pervasive bi-directional interactions. Strikingly, 42% of Tau-induced transcripts were discordant in the proteome, showing opposite direction of change. Tau-responsive gene expression networks strongly implicate innate immune activation. Cross-species analyses pinpoint human brain gene perturbations specifically triggered by Tau pathology and/or aging, and further differentiate between disease amplifying and protective changes. CONCLUSIONS: Our results comprise a powerful, cross-species functional genomics resource for tauopathy, revealing Tau-mediated disruption of gene expression, including dynamic, age-dependent interactions between the brain transcriptome and proteome. |
format | Online Article Text |
id | pubmed-7526226 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-75262262020-09-30 Integrated analysis of the aging brain transcriptome and proteome in tauopathy Mangleburg, Carl Grant Wu, Timothy Yalamanchili, Hari K. Guo, Caiwei Hsieh, Yi-Chen Duong, Duc M. Dammer, Eric B. De Jager, Philip L. Seyfried, Nicholas T. Liu, Zhandong Shulman, Joshua M. Mol Neurodegener Research Article BACKGROUND: Tau neurofibrillary tangle pathology characterizes Alzheimer’s disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau- versus age-dependent changes. METHODS: Paired, longitudinal RNA-sequencing and mass-spectrometry were performed in a Drosophila model of tauopathy, based on pan-neuronal expression of human wildtype Tau (Tau(WT)) or a mutant form causing frontotemporal dementia (Tau(R406W)). Tau-induced, differentially expressed transcripts and proteins were examined cross-sectionally or using linear regression and adjusting for age. Hierarchical clustering was performed to highlight network perturbations, and we examined overlaps with human brain gene expression profiles in tauopathy. RESULTS: Tau(WT) induced 1514 and 213 differentially expressed transcripts and proteins, respectively. Tau(R406W) had a substantially greater impact, causing changes in 5494 transcripts and 697 proteins. There was a ~ 70% overlap between age- and Tau-induced changes and our analyses reveal pervasive bi-directional interactions. Strikingly, 42% of Tau-induced transcripts were discordant in the proteome, showing opposite direction of change. Tau-responsive gene expression networks strongly implicate innate immune activation. Cross-species analyses pinpoint human brain gene perturbations specifically triggered by Tau pathology and/or aging, and further differentiate between disease amplifying and protective changes. CONCLUSIONS: Our results comprise a powerful, cross-species functional genomics resource for tauopathy, revealing Tau-mediated disruption of gene expression, including dynamic, age-dependent interactions between the brain transcriptome and proteome. BioMed Central 2020-09-29 /pmc/articles/PMC7526226/ /pubmed/32993812 http://dx.doi.org/10.1186/s13024-020-00405-4 Text en © The Author(s) 2020 Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Mangleburg, Carl Grant Wu, Timothy Yalamanchili, Hari K. Guo, Caiwei Hsieh, Yi-Chen Duong, Duc M. Dammer, Eric B. De Jager, Philip L. Seyfried, Nicholas T. Liu, Zhandong Shulman, Joshua M. Integrated analysis of the aging brain transcriptome and proteome in tauopathy |
title | Integrated analysis of the aging brain transcriptome and proteome in tauopathy |
title_full | Integrated analysis of the aging brain transcriptome and proteome in tauopathy |
title_fullStr | Integrated analysis of the aging brain transcriptome and proteome in tauopathy |
title_full_unstemmed | Integrated analysis of the aging brain transcriptome and proteome in tauopathy |
title_short | Integrated analysis of the aging brain transcriptome and proteome in tauopathy |
title_sort | integrated analysis of the aging brain transcriptome and proteome in tauopathy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526226/ https://www.ncbi.nlm.nih.gov/pubmed/32993812 http://dx.doi.org/10.1186/s13024-020-00405-4 |
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