A novel pathway regulates memory and plasticity via SIRT1 and miR-134.
A novel pathway regulates memory and plasticity via SIRT1 and miR-134.
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一条通过 SIRT1 和 miR-134 调节记忆和可塑性的新途径
作者：
NAD依赖性脱乙酰基酶Sir 2最初被鉴定为芽殖酵母中复制寿命的介质，随后被证明可以调节蠕虫和苍蝇的寿命。它的哺乳动物同源物SIRT 1似乎在心脏功能、DNA修复和基因组稳定性中进化出复杂的系统性作用。最近的研究表明SIRT 1在正常脑生理和神经系统疾病中的功能相关性。然而，目前尚不清楚SIRT 1是否在高级大脑功能中发挥作用。我们报道SIRT 1通过microRNA介导的机制调节突触可塑性和记忆形成。SIRT 1的激活增强了突触可塑性，而其功能丧失则损害了突触可塑性。令人惊讶的是，这些作用是通过脑特异性microRNA miR-134对CREB表达的转录后调节介导的。SIRT 1通常通过含有转录因子YY 1的阻遏物复合物来限制miR-134的表达，并且SIRT 1缺陷后未受抑制的miR-134表达导致CREB和BDNF的表达下调，从而损害突触可塑性。这些发现证明了SIRT 1在认知中的新作用以及SIRT 1调节这些过程的先前未知的基于microRNA的机制。此外，这些结果描述了SIRT 1信号传导的一个单独的分支，其中SIRT 1以与其细胞存活功能不同的方式在调节正常脑功能中具有直接作用，证明了其作为治疗CNS疾病的潜在治疗靶点的价值。
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 flies. Its mammalian homologue, SIRT1, appears 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 plays 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, while its loss-of-function impairs, synaptic plasticity. Surprisingly, these effects were mediated via post-transcriptional regulation of 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 down-regulated expression of CREB and BDNF, thereby impairing synaptic plasticity. These findings demonstrate a novel 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 signaling, 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 CNS disorders.
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