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

Alzheimer Disease / genetics Humans Protein Biosynthesis / genetics Sirtuins / genetics tau Proteins / metabolism
Alzheimer’s disease CBP DNA damage SIRT6 Tau acetylation nuclear translocation nucleoli protein translation

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
27 04 2021
Historique:
received: 26 07 2020
revised: 06 03 2021
accepted: 06 04 2021
entrez: 28 4 2021
pubmed: 29 4 2021
medline: 9 2 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.celrep.2021.109035 PMID: 33910019
pubmed: 33910019
pii: S2211-1247(21)00351-X
doi: 10.1016/j.celrep.2021.109035
pii:
doi:

Substances chimiques

tau Proteins 0
SIRT6 protein, human EC 3.5.1.-
Sirtuins EC 3.5.1.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

109035

Informations de copyright

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

Auteurs

Miguel Portillo (M)

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.

Ekaterina Eremenko (E)

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.

Shai Kaluski (S)

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.

Alfredo Garcia-Venzor (A)

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.

Lior Onn (L)

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.

Daniel Stein (D)

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.

Zeev Slobodnik (Z)

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.

Adam Zaretsky (A)

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.

Uwe Ueberham (U)

Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstrasse 19, 04103 Leipzig, Germany.

Monica Einav (M)

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.

Martina K Brückner (MK)

Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstrasse 19, 04103 Leipzig, Germany.

Thomas Arendt (T)

Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstrasse 19, 04103 Leipzig, Germany.

Debra Toiber (D)

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel. Electronic address: toiber@bgu.ac.il.

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Classifications MeSH

questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Maladie d'Alzheimer › SIRT6-CBP-dependent nuclear Tau accumulation...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › SIRT6-CBP-dependent nuclear Tau accumulation...
questionsmedicales.fr › Phénomènes génétiques › Expression des gènes › Biosynthèse des protéines › SIRT6-CBP-dependent nuclear Tau accumulation...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Sirtuines › SIRT6-CBP-dependent nuclear Tau accumulation...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de tissu nerveux › Protéines associées aux microtubules › Protéines tau › SIRT6-CBP-dependent nuclear Tau accumulation...