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.
Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstrasse 19, 04103 Leipzig, Germany.
Cell Rep. 2021 Apr 27;35(4):109035. doi: 10.1016/j.celrep.2021.109035.
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.
几种神经退行性疾病表现出 Tau 积累作为主要的病理标志物。Tau 的翻译后修饰，如磷酸化和乙酰化，在神经退行性变中增加。在这里，我们表明 Tau 在残基 174 处的过度乙酰化增加了其自身的核存在，这是 DNA 损伤信号或 SIRT6 缺乏的结果，两者都是神经退行性变的原因。SIRT6 在核内使 Tau-K174ac 去乙酰化。然而，缺乏 SIRT6 或慢性 DNA 损伤导致核 Tau-K174ac 积累。一旦在那里，它会引起基因表达的全局变化，影响蛋白质翻译、合成和能量产生。同时，阿尔茨海默病（AD）病例患者表现出核仁素水平升高和 SIRT6 水平降低。AD 病例患者表现出核 Tau 的增加，特别是 Tau-K174ac。我们的研究结果表明，AD 病例患者 Tau-K174ac 的增加是 DNA 损伤信号和 SIRT6 耗竭的结果。我们提出 Tau-K174ac 的毒性是由于其稳定性增加、核积累和核仁功能障碍。
