MicroRNA-124 protects against focal cerebral ischemia via mechanisms involving Usp14-dependent REST degradation
MicroRNA-124 protects against focal cerebral ischemia via mechanisms involving Usp14-dependent REST degradation
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DOI：
10.1007/s00401-013-1142-5
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发表时间：
2013-08-01
影响因子：
12.7
通讯作者：
Michel, Uwe
中科院分区：
文献类型：
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作者：
Doeppner, Thorsten R.;Doehring, Maria;Michel, Uwe
微小RNA（microRNAs，miRNAs）是一类高度保守的非编码RNA，通过与mRNA结合调节基因表达。最近的研究表明，miRNA参与心血管疾病，包括中风。因此，脑丰富的miR-124及其转录抑制因子RE 1沉默转录因子（REST）不仅在发育和成人脑中具有基本作用，而且在脑缺血时改变表达。然而，miR-124对中风的治疗潜力及其相关机制仍然难以捉摸。在这里，我们分析了异位miR-124对中风的治疗潜力及其与miR-124和REST之间相互作用的潜在机制。我们的研究结果表明，病毒载体介导的miR-124递送增加了体外培养的氧-葡萄糖剥夺皮质神经元的阻力，并减少了大脑中动脉闭塞小鼠的脑损伤和功能障碍。同样，miR-124诱导增强的神经血管重塑，导致中风后8周血管神经发生增加。虽然REST丰度在中风后增加，但这种增加被miR-124阻止，尽管miR-124和REST之间存在迄今未知的负反馈环。相反，miR-124降低了去泛素化酶Usp 14的表达，Usp 14在其mRNA的3 'UTR中具有两个保守的miR-124结合位点，从而介导了REST水平的降低。Usp 14抑制剂IU-1也模拟了miR-124对REST的下调，表明miR-124通过Usp 14依赖性REST降解促进缺血条件下的神经元存活。因此，异位miR-124表达似乎是中风治疗中一种有吸引力的新工具，通过迄今为止未知的机制介导神经保护作用，该机制涉及Usp 14依赖性REST降解。
MicroRNAs (miRNAs) are highly conserved non-coding RNAs modulating gene expression via mRNA binding. Recent work suggests an involvement of miRNAs in cardiovascular diseases including stroke. As such, the brain-abundant miR-124 and its transcriptional repressor RE1-silencing transcription factor (REST) do not only have elementary roles in the developing and the adult brain, but also alter expression upon cerebral ischemia. However, the therapeutic potential of miR-124 against stroke and the mechanisms involved remain elusive. Here, we analyzed the therapeutic potential of ectopic miR-124 against stroke and its underlying mechanisms with regard to the interaction between miR-124 and REST. Our results show that viral vector-mediated miR-124 delivery increased the resistance of cultured oxygen-glucose-deprived cortical neurons in vitro and reduced brain injury as well as functional impairment in mice submitted to middle cerebral artery occlusion. Likewise, miR-124 induced enhanced neurovascular remodeling leading to increased angioneurogenesis 8 weeks post-stroke. While REST abundance increased upon stroke, the increase was prevented by miR-124 despite a so far unknown negative feedback loop between miR-124 and REST. Rather, miR-124 decreased the expression of the deubiquitinating enzyme Usp14, which has two conserved miR-124-binding sites in the 3'UTR of its mRNA, and thereby mediated reduced REST levels. The down-regulation of REST by miR-124 was also mimicked by the Usp14 inhibitor IU-1, suggesting that miR-124 promotes neuronal survival under ischemic conditions via Usp14-dependent REST degradation. Ectopic miR-124 expression, therefore, appears as an attractive and novel tool in stroke treatment, mediating neuroprotection via a hitherto unknown mechanism that involves Usp14-dependent REST degradation.