Prog Neurobiol 2011 Nov;95 (3): 373-95. [IF:9.966]
Protective effects and mechanisms of sirtuins in the nervous system.
Zhang F , Wang S , Gan L , Vosler PS , Gao Y , Zigmond MJ , Chen J .
State Key Laboratory of Medical Neurobiology and Institute of Brain Science, Fudan University, Shanghai 200032, China; Department of Neurology and the Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States.
复旦大学医学神经生物学国家重点实验室，美国匹兹堡大学医学中心脑血管疾病研究中心
Abstract
Silent information regulator two proteins (sirtuins or SIRTs) are a group of histone deacetylases whose activities are dependent on and regulated by nicotinamide adenine dinucleotide (NAD(+)). They suppress genome-wide transcription, yet upregulate a select set of proteins related to energy metabolism and pro-survival mechanisms, and therefore play a key role in the longevity effects elicited by calorie restriction. Recently, a neuroprotective effect of sirtuins has been reported for both acute and chronic neurological diseases. The focus of this review is to summarize the latest progress regarding the protective effects of sirtuins, with a focus on SIRT1. We first introduce the distribution of sirtuins in the brain and how their expression and activity are regulated. We then highlight their protective effects against common neurological disorders, such as cerebral ischemia, axonal injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Finally, we analyze the mechanisms underlying sirtuin-mediated neuroprotection, centering on their non-histone substrates such as DNA repair enzymes, protein kinases, transcription factors, and coactivators. Collectively, the information compiled here will serve as a comprehensive reference for the actions of sirtuins in the nervous system to date, and will hopefully help to design further experimental research and expand sirtuins as therapeutic targets in the future.
摘要：
沉默信息调节二蛋白（sirtuins或SIRTs）是一组组蛋白去乙酰化酶，它们的活性依赖于NAD+，并被NAD+所调节。它们减弱了基因组转录，但却上调了一组与能量代谢和前存活机制相关的一类严格选择的蛋白，因此在由限制热量而致的长寿效果中起着关键作用。近来，sirtuins的神经保护效应在急慢性神经疾病中均已有报道。这篇综述的重点是以SIRT1为重点，概述关于sirtuins的保护效应的最新进展。我们首先介绍sirtuins在大脑中的分布和它们是如何表达，活性是如何调节的。然后，重点概述他们针对常见神经疾病的保护效应，如脑缺血，轴突损伤，阿尔茨海默氏病，肌萎缩侧索硬化和多发性硬化等。最后，我们以它们的非组蛋白底物如DNA修复酶，蛋白激酶，转录因子和辅激活蛋白等为中心，分析sirtuin-介导的神经保护的机制。总起来讲，这里搜集的信息将为sirtuins在神经系统中的活动提供广泛的参考，并且有望为将来制定进一步的实验研究并使sirtuins扩展以作为疾病治疗的靶点提供帮助。
