SIRT6-CBP-dependent nuclear Tau accumulation and its role in protein synthesis
| Autor: | Daniel Stein, Alfredo Garcia-Venzor, Monica Einav, Zeev Slobodnik, Debra Toiber, Uwe Ueberham, Shai Kaluski, Adam Zaretsky, Miguel Portillo, Martina K. Brückner, Ekaterina Eremenko, Lior Onn, Thomas Arendt |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
SIRT6 Nucleolus Chemistry DNA damage Neurodegeneration tau Proteins medicine.disease General Biochemistry Genetics and Molecular Biology Cell biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Alzheimer Disease Protein Biosynthesis mental disorders Gene expression medicine Protein biosynthesis Humans Sirtuins Phosphorylation Nucleolin 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports. 35:109035 |
| ISSN: | 2211-1247 |
| Popis: | Several neurodegenerative diseases present Tau accumulation as the main pathological marker. Tau post-translational modifications such as phosphorylation and acetylation are increased in neurodegeneration. 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 results in nuclear Tau-K174ac accumulation. Once there, it induces global changes in gene expression, affecting protein translation, synthesis, and energy production. Concomitantly, Alzheimer's disease (AD) case subjects show increased nucleolin and a decrease in SIRT6 levels. AD case subjects present increased levels of nuclear Tau, particularly Tau-K174ac. Our results suggest that increased Tau-K174ac in AD case subjects 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. |
| Databáze: | OpenAIRE |
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