SIRT6-CBP-dependent nuclear Tau accumulation and its role in protein synthesis

Miguel Portillo, Ekaterina Eremenko, Shai Kaluski, Alfredo Garcia-Venzor, Lior Onn, Daniel Stein, Zeev Slobodnik, Adam Zaretsky, Uwe Ueberham, Monica Einav, Martina K. Brückner, Thomas Arendt, Debra Toiber

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish
Article number109035
JournalCell Reports
Volume35
Issue number4
DOIs
StatePublished - 27 Apr 2021

Keywords

  • Alzheimer's disease
  • CBP
  • DNA damage
  • SIRT6
  • Tau
  • acetylation
  • nuclear translocation
  • nucleoli
  • protein translation

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