Integrated analysis of the aging brain transcriptome and proteome in tauopathy
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(2020) 15:56
RESEARCH ARTICLE
Open Access
Integrated analysis of the aging brain transcriptome and proteome in tauopathy Carl Grant Mangleburg1,2†, Timothy Wu1,2†, Hari K. Yalamanchili1†, Caiwei Guo3, Yi-Chen Hsieh1, Duc M. Duong4, Eric B. Dammer4, Philip L. De Jager5,6, Nicholas T. Seyfried4,7, Zhandong Liu8,9 and Joshua M. Shulman1,3,9,10*
Abstract 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 (TauWT) or a mutant form causing frontotemporal dementia (TauR406W). 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: TauWT induced 1514 and 213 differentially expressed transcripts and proteins, respectively. TauR406W 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. Keywords: MAPT, Tau, Alzheimer’s disease, Transcriptome, Proteome, Inflammation, Innate immunity
Background The Microtubule Associated Protein Tau (MAPT/Tau) aggregates to form neurofibrillary tangle pathology in Alzheimer’s disease (AD) and other neurodegenerative tauopathies * Correspondence: [email protected] † Carl Grant Mangleburg, Timothy Wu and Hari K. Yalamanchili are co-first authors 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA 3 Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA Full list of author information is available at the end of the article
characterized by progressive cognitive and/or motor disability, including progressive supranuclear palsy (PSP), corticobasal degeneration, chronic traumatic encephalopathy, and certain forms of frontotemporal dementia (FTD) [1, 2]. R
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