Integrated analysis of the aging brain transcriptome and proteome in tauopathy

• Type of Material: Article
• Authors: Carl Grant Mangleburg, Baylor College of Medicine; Timothy Wu, Baylor College of Medicine; Hari K. Yalamanchili, Baylor College of Medicine; Caiwei Guo, Baylor College of Medicine; Yi-Chen Hsieh, Baylor College of Medicine; Duc M. Duong, Emory University; Eric Dammer, Emory University; Philip L. De Jager, Columbia University; Nicholas Seyfried, Emory University; Zhandong Liu, Baylor College of Medicine; Joshua M. Shulman, Baylor College of Medicine
• Language: English
• Date: 2020-09-29
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13024-020-00405-4
• Title of Journal or Parent Work: MOLECULAR NEURODEGENERATION
• Volume: 15
• Issue: 1
• Start Page: 56
• End Page: 56
• Grant/Funding Information: This study was supported by grants from the NIH (R01AG053960, R01AG050631, R01AG057339, U01AG061357, U01AG046161, R01AG057911, R01AG061800, RF1AG057471, RF1AG057470, R01AG061800, R01AG057911, R01AG057339). CMG was additionally supported by the Cullen Foundation, and both CMG and TW, by the Baylor College of Medicine Medical Scientist Training Program (MSTP). Z.L. received support from Cancer Prevention Research Institute of Texas RP170387, Houston Endowment, Huffington Foundation, and Belfer Neurodegenerative Disease Consortium. J.M.S. was additionally supported by Huffington Foundation, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, and a Career Award for Medical Scientists from the Burroughs Wellcome Fund.
• Keywords: Alzheimer's disease; Science & Technology; MUTATIONS; ALZHEIMERS-DISEASE; Inflammation; Life Sciences & Biomedicine; MODIFIERS; GENE-EXPRESSION ANALYSIS; Neurosciences & Neurology; MAPT; Innate immunity; TAU; NEURODEGENERATION; DROSOPHILA; SIGNATURES; Neurosciences; Proteome; Transcriptome; Tau; NETWORK; RISK
• Research Categories: Biology, Neuroscience; Psychology, Cognitive

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.