Tau drives translational selectivity by interacting with ribosomal proteins.
Shon A. Koren,Matthew Hamm,Shelby E. Meier,Blaine E. Weiss,Grant K. Nation,Emad Chishti,Juan Pablo Arango,Jing Chen,Haining Zhu,Eric M. Blalock,Jose F. Abisambra,Jose F. Abisambra +11 more
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TLDR
It is established that tau expression differentially shifts both the transcriptome and the nascent proteome, and that the synthesis of ribosomal proteins is reversibly dependent on tau levels, which establishes tau as a driver of RNA translation selectivity.Abstract:
There is a fundamental gap in understanding the consequences of tau-ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in transgenic mice, in cells, and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. First, we performed microarrays and nascent proteomics to measure changes in protein synthesis. Using regulatable rTg4510 tau transgenic mice, we determined that tau expression differentially shifts both the transcriptome and the nascent proteome, and that the synthesis of ribosomal proteins is reversibly dependent on tau levels. We further extended these results to human brains and found that tau pathologically interacts with ribosomal protein S6 (rpS6 or S6), a crucial regulator of translation. Consequently, protein synthesis under translational control of rpS6 was reduced under tauopathic conditions in Alzheimer's disease brains. Our data establish tau as a driver of RNA translation selectivity. Moreover, since regulation of protein synthesis is critical for learning and memory, aberrant tau-ribosome interactions in disease could explain the linkage between tauopathies and cognitive impairment.read more
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Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy
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TL;DR: In this paper, the authors used Cry2-based optogenetics to induce tau oligomers (oTau-c), which elicits tau phosphorylation, aggregation, and reduced protein synthesis.
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FRET-based Tau seeding assay does not represent prion-like templated assembly of Tau filaments.
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TL;DR: Observations argue against the hypothesis that the propagation of Tau pathology in AD is caused by the prion-like templated aggregation of Tau protein, transmitted via cell-to-cell spreading of Tau.
Journal ArticleDOI
Integrated analysis of the aging brain transcriptome and proteome in tauopathy
Carl Grant Mangleburg,Timothy Wu,Hari Krishna Yalamanchili,Caiwei Guo,Yi-Chen Hsieh,Duc M. Duong,Eric B. Dammer,Philip L. De Jager,Philip L. De Jager,Nicholas T. Seyfried,Zhandong Liu,Zhandong Liu,Joshua M. Shulman +12 more
TL;DR: The 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.
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