Tau drives translational selectivity by interacting with ribosomal proteins
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ABSTRACT:
PROVIDER: PRJNA496504 | ENA |
REPOSITORIES: ENA
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Project description: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 vivo and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. We performed microarrays and nascent proteomics to measure changes in protein synthesis using rTg4510 tau transgenic mice. We determined that tau expression differentially shifts the transcriptome and the proteome and that the synthesis of ribosomal proteins is reversibly dependent on tau levels. We further extended these results to human brains and show that tau pathologically interacts with ribosomal protein S6 (rpS6 or S6). Consequently, synthesis of ribosomal proteins coded by 5’TOP-mRNAs was reduced under tauopathic conditions in Alzheimer’s disease brains. Our data establish tau as a driver of RNA translation selectivity. Moreover, considering that regulation of protein synthesis is critical to learning and memory, aberrant tau-ribosome interactions in disease could explain the linkage between virtually every tauopathy and cognitive impairment and memory decline.
2019-03-30 | GSE121264 | GEO
Project description: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.
| S-EPMC6426815 | biostudies-literature
Project description:High resolution polysome fractionation and low-input ribosome profiling of bovine oocytes and preimplantation embryos has enabled us to define the translational landscape of early embryo development at an unprecedented level. We systematically and comparatively analyzed the transcriptome, polysome- and nonpolysome-bound RNA profiles of bovine oocytes and early embryos at 2-, 8-cell, morula, and blastocyst stage, and defined four modes of translational selectivity in bovine preimplantation embryo development: i. selective translation of non-abundant mRNAs, ii. active translating highly expressed mRNAs, iii. Translationally suppressed abundant mRNAs, and iv. Monosomaly occupied mRNAs. A strong selection towards genes involved in mitochondrial function and metabolic pathways was found throughout bovine preimplantation development. We found translatome largely follows transcriptome at oocytes, followed by a marked translational control at 8-cell embryos, which is gradually synchronized at the morula and blastocyst stage. We identified important novel cellular/embryonic functional regulators that being utilized and prioritized for translation at each developmental stage, that accompanies little-known bovine embryonic developmental programming. Together, these data reveal a unique spatiotemporal translational regulation that accompanies bovine preimplantation development.
2022-10-01 | GSE196484 | GEO
Project description:Ribosomopathies are cell-type-specific pathologies related to a ribosomal protein (RP) gene insult. The 5q- syndrome is a somatic ribosomopathy linked to RPS14 gene haploinsufficiency and characterized by a prominent erythroid hypoplasia. Using quantitative proteomic, we show that GATA1 protein expression is low in shRPS14 cells in which ribosome quantities are diminished. Here, we investigated the cause of low GATA1 protein expression in limiting ribosome availability. A global analysis of translation in RPs deficiencies highlights the rules that drive translation selectivity. We demonstrate that in addition of the transcript length, a high codon adaptation index (CAI) and a highly structured 3’UTR are the key characteristics for a selective translation. An integrated analysis of transcriptome and proteome confirms that the post-transcriptional regulations of gene expression are directly linked to the criteria governing the translational selectivity. In particular, these criteria explain GATA1 translation default with unprecedented precision. More generally, the proteins that accumulate along normal erythropoiesis share the determinants of translation selectivity revealed by the conditions of limiting ribosome availability. We performed translatome expression profiling of cells infected with shRPS14 or shSCR
2020-04-28 | GSE124800 | GEO
Project description:High-resolution Ribosome Profiling Reveals Translational Selectivity in Bovine Preimplantation Embryo Development
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Project description:The PI3K-Akt-mTOR signaling pathway is a master regulator of RNA translation. Pharmacological inhibition of this pathway preferentially and coordinately suppresses, in a 4EBP1/2-dependent manner, translation of mRNAs encoding ribosomal proteins. However, it remains unclear whether mTOR-4EBP1/2 is the exclusive translational regulator of this group of genes, and furthermore, systematic searches for novel translational modulators have been immensely challenging due to difficulties in scaling existing RNA translation profiling assays. Here, we developed a rapid and highly scalable approach for gene-specific quantitation of RNA translation, termed Targeted Profiling of RNA Translation (TPRT). We applied this technique in a chemical screen for novel translational modulators, and identified numerous preclinical and clinical therapeutic compounds, with diverse nominal targets, that preferentially suppress translation of ribosomal proteins. Surprisingly, some of these compounds act in a manner that bypasses canonical regulation by mTOR-4EBP1/2. Instead, these compounds exert their translational effects in a manner that is dependent upon GCN2-eIF2α, a central signaling axis within the integrated stress response. Furthermore, we were also able to identify metabolic perturbations that also suppress ribosomal protein translation in an mTOR-independent manner. Together, we describe a novel translational assay that is directly applicable to large-scale RNA translation studies, and that enabled us to identify a non-canonical, mTOR-independent mode for translational regulation of ribosomal proteins.
2018-09-21 | GSE118422 | GEO
Project description:Alzheimer’s disease (AD) is an age-associated neurodegenerative disease characterized by amyloidosis, tauopathy, and activation of microglia, the brain resident innate immune cells. We show that a RiboTag translational profiling approach can bypass biases due to cellular enrichment/cell sorting. In our recent study entitled “Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau”, we utilized data acquired using this approach in models of amyloidosis, tauopathy, and aging, to reveal a common set of alterations and identified a central APOE-driven network that converged on CCL3 and CCL4 across all conditions. Notably, examination of the aged female dataset demonstrated a significant exacerbation of many of these shared transcripts in this APOE network, revealing a potential mechanism for increased AD susceptibility in females. This study has broad implications for microglial transcriptomic approaches and provides new insights into microglial pathways associated with different pathological aspects of aging and AD.
2018-07-25 | GSE117646 | GEO
Project description:Ribosomal profiling in single cells reveals cell-cycle dependent translational pausing
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Project description:Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau
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Project description:Several neurodegenerative diseases present Tau accumulation as the main pathological marker. Tau post-translational modifications such as phosphorylation and acetylation are increased in neurodegenerative patients. Here, we show that Tau hyper-acetylation at residue 174 increases its own nuclear presence and is the result of DNA damage signaling or the lack of SIRT6, both causative of neurodegeneration. Tau-K174ac is deacetylated in the nucleus by SIRT6. However, lack of SIRT6 or chronic DNA damage result in nuclear Tau-K174ac accumulation. Once there, it induces global changes in gene expression affecting protein translation, synthesis and energy production. Concomitantly, AD patients showed increased Nucleolin and a decrease in SIRT6 levels. AD patients present increased levels of nuclear Tau, particularly Tau-K174ac. Our results suggest that increased Tau-K174ac in AD patients is the result of DNA damage signaling and SIRT6 depletion. We propose that Tau-K174ac toxicity is due to its increased stability, nuclear accumulation and nucleolar dysfunction.
2021-04-02 | GSE171342 | GEO