SIRT1是在DNA修复和基因组稳定性中所涉及的一种脱乙酰酶，最初是在非哺乳动物模型系统中作为寿命的一个调控因子被识别出的。虽然人们认为它在正常脑生理中发挥功能，但过去并不知道SIRT1是否参与高等脑功能。现在，Gao等人演示了SIRT1的这样一个作用：其激发能增强突触强度和记忆形成。这些依赖于SIRT1的效应是通过一个“转录后”机制调控的，该机制涉及CREB激发和miR-134生成。SIRT1激发、 miR-134水平和突触蛋白之间的这种互动构成弹性调控的一个以前未被识别出的机制，并且表明，SIRT1激发对于涉及认知损伤的神经退行性疾病可能具有治疗潜力
推荐原文出处：
Nature doi:10.1038/nature09271
A novel pathway regulates memory and plasticity via SIRT1 and miR-134
Jun Gao,Wen-Yuan Wang,Ying-Wei Mao,Johannes Gr?ff,Ji-Song Guan,Ling Pan,Gloria Mak,Dohoon Kim,Susan C. Su" Li-Huei Tsai
The NAD-dependent deacetylase Sir2 was initially identified as a mediator of replicative lifespan in budding yeast and was subsequently shown to modulate longevity in worms and flies1, 2. Its mammalian homologue, SIRT1, seems to have evolved complex systemic roles in cardiac function, DNA repair and genomic stability. Recent studies suggest a functional relevance of SIRT1 in normal brain physiology and neurological disorders. However, it is unknown if SIRT1 has a role in higher-order brain functions. We report that SIRT1 modulates synaptic plasticity and memory formation via a microRNA-mediated mechanism. Activation of SIRT1 enhances, whereas its loss-of-function impairs, synaptic plasticity. Surprisingly, these effects were mediated via post-transcriptional regulation of cAMP response binding protein (CREB) expression by a brain-specific microRNA, miR-134. SIRT1 normally functions to limit expression of miR-134 via a repressor complex containing the transcription factor YY1, and unchecked miR-134 expression following SIRT1 deficiency results in the downregulated expression of CREB and brain-derived neurotrophic factor (BDNF), thereby impairing synaptic plasticity. These findings demonstrate a new role for SIRT1 in cognition and a previously unknown microRNA-based mechanism by which SIRT1 regulates these processes. Furthermore, these results describe a separate branch of SIRT1 signalling, in which SIRT1 has a direct role in regulating normal brain function in a manner that is disparate from its cell survival functions, demonstrating its value as a potential therapeutic target for the treatment of central nervous system disorders.
