The microRNA miR-7a-5p ameliorates ischemic brain damage by repressing α-synuclein
The microRNA miR-7a-5p ameliorates ischemic brain damage by repressing α-synuclein
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DOI：
10.1126/scisignal.aat4285
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发表时间：
2018-12-11
影响因子：
7.3
通讯作者：
Vemuganti, Raghu
中科院分区：
文献类型：
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作者：
Kim, TaeHee;Mehta, Suresh L.;Vemuganti, Raghu
缺血性中风是由阻止血液流向大脑的血块引起的，可能会严重致残，有时甚至是致命的。我们先前的研究表明，短暂性大鼠局灶性脑缺血后，脑内microRNAs的表达发生广泛的时间变化，miR-7a-5p(miR-7)的丰度持续下降。在这里，我们根据卒中治疗学术行业圆桌会议(STAIR)标准评估了一种miR-7模拟寡核苷酸在啮齿动物脑缺血后的治疗效果。在短暂性大脑中动脉闭塞前或闭塞后，局部或全身注射模拟miR-7。脑缺血后，无论青年还是老年大鼠，miR-7的表达均降低。在所研究的性别和年龄中，用miR-7模拟缺血前或缺血后治疗均可减少病变体积。此外，在脑缺血后30分钟(而不是2小时)向小鼠全身注射miR-7可显著减少损伤体积，促进运动和认知功能的恢复，外周毒性最小。MiR-7模拟处理大大减少了缺血后α-突触核蛋白(α-Syn)的诱导，α-突触核蛋白是一种诱导线粒体碎裂、氧化应激和自噬的蛋白质，从而促进神经细胞死亡。编码α-Syn基因的缺失取消了对miR-7模拟依赖的神经保护和年轻雄性小鼠的功能恢复。进一步分析证实，编码α-Syn的转录本被miR-7结合和抑制。我们的发现表明，miR-7模拟物可能在治疗上将中风引起的脑损伤和残疾降至最低。
Ischemic stroke, which is caused by a clot that blocks blood flow to the brain, can be severely disabling and sometimes fatal. We previously showed that transient focal ischemia in a rat model induces extensive temporal changes in the expression of cerebral microRNAs, with a sustained decrease in the abundance of miR-7a-5p (miR-7). Here, we evaluated the therapeutic efficacy of a miR-7 mimic oligonucleotide after cerebral ischemia in rodents according to the Stroke Treatment Academic Industry Roundtable (STAIR) criteria. Rodents were injected locally or systemically with miR-7 mimic before or after transient middle cerebral artery occlusion. Decreased miR-7 expression was observed in both young and aged rats of both sexes after cerebral ischemia. Pre- or postischemic treatment with miR-7 mimic decreased the lesion volume in both sexes and ages studied. Furthermore, systemic injection of miR-7 mimic into mice at 30 min (but not 2 hours) after cerebral ischemia substantially decreased the lesion volume and improved motor and cognitive functional recovery with minimal peripheral toxicity. The miR-7 mimic treatment substantially reduced the postischemic induction of alpha-synuclein (alpha-Syn), a protein that induces mitochondrial fragmentation, oxidative stress, and autophagy that promote neuronal cell death. Deletion of the gene encoding alpha-Syn abolished miR-7 mimic-dependent neuroprotection and functional recovery in young male mice. Further analysis confirmed that the transcript encoding alpha-Syn was bound and repressed by miR-7. Our findings suggest that miR-7 mimics may therapeutically minimize stroke-induced brain damage and disability.