MicroRNA-223 protects neurons from degeneration in experimental autoimmune encephalomyelitis
MicroRNA-223 protects neurons from degeneration in experimental autoimmune encephalomyelitis
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DOI：
10.1093/brain/awz245
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发表时间：
2019-10-01
期刊：
影响因子：
14.5
通讯作者：
Fournier, Alyson E.
中科院分区：
文献类型：
--
作者：
Morquette, Barbara;Juzwik, Camille A.;Fournier, Alyson E.
多发性硬化症是一种慢性炎症、脱髓鞘和神经退行性疾病，影响大脑、脊髓和视神经。神经元损伤是由各种有害因素引发的，这些有害因素参与神经元中的各种信号级联;因此，保护神经元的治疗方法将需要专注于可以靶向多种生物过程的药物。因此，我们将注意力集中在microRNA上：小的非编码RNA，主要作为转录后调节因子，靶向信使RNA并抑制其翻译成蛋白质。单个microRNA可以靶向许多功能相关的信使RNA，使microRNA成为强大的表观遗传调节因子。在包括多发性硬化症在内的许多神经退行性疾病中已经描述了microRNA的失调。在这里，我们报告了两种microRNA，miR-223- 3 p和miR-27 a-3 p，在实验性自身免疫性脑脊髓炎小鼠CNS炎症模型和含有灰质的多发性硬化病变中的神经元中上调。先前的工作表明，外周血单核细胞条件培养基导致培养中神经元的亚致死变性。我们发现miR-27 a-3 p或miR-223- 3 p的过表达保护解离的皮质神经元免于条件培养基介导的变性。在小鼠视网膜神经节细胞中体内引入miR-223- 3 p保护其轴突免受实验性自身免疫性脑脊髓炎的变性。计算机模拟分析显示，参与谷氨酸受体信号传导的信使RNA富集为miR-27 a-3 p和miR-223- 3 p靶标。我们观察到，NMDA和AMPA型谷氨酸受体拮抗剂保护神经元免受条件介质依赖性变性。我们的研究结果表明，miR-2233 p和miR-27 a-3 p在炎症反应中上调，介导了一种补偿性神经保护基因表达程序，该程序通过靶向参与谷氨酸受体信号传导的信使RNA使神经元对谷氨酸脱敏。
Multiple sclerosis is a chronic inflammatory, demyelinating, and neurodegenerative disease affecting the brain, spinal cord and optic nerves. Neuronal damage is triggered by various harmful factors that engage diverse signalling cascades in neurons; thus, therapeutic approaches to protect neurons will need to focus on agents that can target multiple biological processes. We have therefore focused our attention on microRNAs: small non-coding RNAs that primarily function as post-transcriptional regulators that target messenger RNAs and repress their translation into proteins. A single microRNA can target many functionally related messenger RNAs making microRNAs powerful epigenetic regulators. Dysregulation of microRNAs has been described in many neurodegenerative diseases including multiple sclerosis. Here, we report that two microRNAs, miR-223-3p and miR-27a-3p, are upregulated in neurons in the experimental autoimmune encephalomyelitis mouse model of CNS inflammation and in grey matter-containing multiple sclerosis lesions. Prior work has shown peripheral blood mononuclear cell conditioned media causes sublethal degeneration of neurons in culture. We find overexpression of miR-27a-3p or miR-223-3p protects dissociated cortical neurons from condition media mediated degeneration. Introduction of miR-223-3p in vivo in mouse retinal ganglion cells protects their axons from degeneration in experimental autoimmune encephalomyelitis. In silico analysis revealed that messenger RNAs involved in glutamate receptor signalling are enriched as miR-27a-3p and miR-223-3p targets. We observe that antagonism of NMDA and AMPA type glutamate receptors protects neurons from condition media dependent degeneration. Our results suggest that miR-2233p and miR-27a-3p are upregulated in response to inflammation to mediate a compensatory neuroprotective gene expression program that desensitizes neurons to glutamate by targeting messenger RNAs involved in glutamate receptor signalling.