Biochemistry Section, Department of Zoology, Institute of Science, Banaras Hindu University Varanasi, 221005, India.
Biochemistry Section, Department of Zoology, Institute of Science, Banaras Hindu University Varanasi, 221005, India.
J Chem Neuroanat. 2019 Jan;95:43-53. doi: 10.1016/j.jchemneu.2017.11.009. Epub 2017 Nov 9.
Sirtuins are highly conserved NAD dependent class III histone deacetylases and catalyze deacetylation and ADP ribosylation of a number of non-histone proteins. Since, they require NAD for their activity, the cellular level of Sirtuins represents redox status of the cells and thereby serves as bona fide metabolic stress sensors. Out of seven homologues of Sirtuins identified in mammals, SIRT3, 4 & 5 have been found to be localized and active in mitochondria. During recent past, clusters of protein substrates for SIRT3 have been identified in mitochondria and thereby advocating SIRT3 as the main mitochondrial Sirtuin which could be involved in protecting stress induced mitochondrial integrity and energy metabolism. As mitochondrial dysfunction underlies the pathogenesis of almost all neurodegenerative diseases, a role of SIRT3 becomes an arguable speculation in such brain disorders. Some recent findings demonstrate that SIRT3 over expression could prevent neuronal derangements in certain in vivo and in vitro models of aging and neurodegenerative brain disorders like; Alzheimer's disease, Huntington's disease, stroke etc. Similarly, loss of SIRT3 has been found to accelerate neurodegeneration in the brain challenged with excitotoxicity. Therefore, it is argued that SIRT3 could be a relevant target to understand pathogenesis of neurodegenerative brain disorders. This review is an attempt to summarize recent findings on (1) the implication of SIRT3 in neurodegenerative brain disorders and (2) whether SIRT3 modulation could ameliorate neuropathologies in relevant models.
Sirtuins 是高度保守的 NAD 依赖性 III 类组蛋白去乙酰化酶，可催化许多非组蛋白蛋白的去乙酰化和 ADP 核糖基化。由于它们的活性需要 NAD，因此 Sirtuins 的细胞水平代表了细胞的氧化还原状态，从而成为真正的代谢应激传感器。在哺乳动物中鉴定出的 7 种 Sirtuins 同源物中，SIRT3、4 和 5 已被发现定位于线粒体并具有活性。在最近的研究中，鉴定出了线粒体中 SIRT3 的蛋白质底物簇，从而主张 SIRT3 是主要的线粒体 Sirtuin，它可能参与保护应激诱导的线粒体完整性和能量代谢。由于线粒体功能障碍是几乎所有神经退行性疾病发病机制的基础，因此 SIRT3 的作用在这些脑部疾病中成为一个有争议的推测。一些最近的研究结果表明，SIRT3 的过度表达可以预防某些衰老和神经退行性脑疾病的体内和体外模型中的神经元紊乱，如阿尔茨海默病、亨廷顿病、中风等。同样，在受到兴奋性毒性挑战的大脑中，SIRT3 的缺失已被发现加速了神经退行性变。因此，有人认为 SIRT3 可能是理解神经退行性脑疾病发病机制的一个相关靶点。这篇综述试图总结 SIRT3 在神经退行性脑疾病中的作用（1）以及 SIRT3 调节是否可以改善相关模型中的神经病理学（2）的最新发现。
