@article{ee1e8adf089f4fd6bd2226baaab64f62,
title = "SIRT6-CBP-dependent nuclear Tau accumulation and its role in protein synthesis",
abstract = "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.",
keywords = "Alzheimer's disease, CBP, DNA damage, SIRT6, Tau, acetylation, nuclear translocation, nucleoli, protein translation",
author = "Miguel Portillo and Ekaterina Eremenko and Shai Kaluski and Alfredo Garcia-Venzor and Lior Onn and Daniel Stein and Zeev Slobodnik and Adam Zaretsky and Uwe Ueberham and Monica Einav and Br{\"u}ckner, {Martina K.} and Thomas Arendt and Debra Toiber",
note = "Funding Information: This work was supported by The David and Inez Myers Foundation, Beachwood, OH, USA, by the Israel Science Foundation (ISF 188/17), and by the High-tech, Bio-tech, and Negev fellowships of Kreitman School of Advanced Research of Ben Gurion University, Israel. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation program (grant 849029), Brussels, Belgium. Conceptualization and experimental design, M.P. and D.T.; performance of experiments, M.P. E.E. S.K. A.G.-V. L.O. Z.S. A.Z. D.S. U.U. and M.B.; design and cloning of tools, M.E. and E.E.; manuscript criticism, T.A.; writing of manuscript, M.P. and D.T. The authors declare no competing interests. Funding Information: This work was supported by The David and Inez Myers Foundation , Beachwood, OH, USA, by the Israel Science Foundation ( ISF 188/17 ), and by the High-tech, Bio-tech, and Negev fellowships of Kreitman School of Advanced Research of Ben Gurion University , Israel. This project has received funding from the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 Research and Innovation program (grant 849029 ), Brussels, Belgium. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = apr,
day = "27",
doi = "10.1016/j.celrep.2021.109035",
language = "English",
volume = "35",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}