miR-142-5p Disrupts Neuronal Morphogenesis Underlying Porcine Hemagglutinating Encephalomyelitis Virus Infection by Targeting Ulk1.
miR-142-5p Disrupts Neuronal Morphogenesis Underlying Porcine Hemagglutinating Encephalomyelitis Virus Infection by Targeting Ulk1.
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miR-142-5p 通过靶向 Ulk1 破坏猪血凝性脑脊髓炎病毒感染的神经元形态发生
DOI：
10.3389/fcimb.2017.00155
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发表时间：
2017
影响因子：
5.7
通讯作者：
He W
中科院分区：
文献类型：
--
作者：
Li Z;Lan Y;Zhao K;Lv X;Ding N;Lu H;Zhang J;Yue H;Shi J;Song D;Gao F;He W
猪血凝性脑脊髓炎病毒（Porcine hemagglutinating encephalomyelitis virus，PHEV）可侵入哺乳仔猪中枢神经系统（central nervous system，CNS），引起中枢神经系统退行性疾病，但其神经致病性的研究还很有限。在这里，我们报告说，miR-142- 5 p是本地化的神经元和负调控神经元的形态发生在猪血凝性脑脊髓炎（PHE）。这种表型是由miR-142- 5 p抑制编码unc-51样激酶1（Ulk 1）的mRNA介导的，该激酶1控制轴突生长和树突形成。通过microRNA模拟物或抑制剂调节miR-142- 5 p活性诱导神经变性，包括发育不良的轴突伸长、不稳定的树突棘形成以及神经突中的不规则肿胀和断开。通过miR-142- 5 p引物或编码Ulk 1的复制缺陷型腺病毒（Ad 5-Ulk 1）缓解原代皮层神经元中Ulk 1 mRNA的抑制，这改善了对神经损伤的挽救，限制了病毒复制，并增加了PHEV感染小鼠的存活率。相反，在表达RNAi的神经元中破坏Ulk 1主要导致轴突延长显著缩短和/或异常大量的分支树突。总之，我们证明PHEV感染引起的异常神经元形态发生主要是由miR-142- 5 p靶点Ulk 1的功能性mRNA抑制引起的。我们的数据显示，PHEV适应于利用宿主microRNA的时空控制来侵入CNS，并为病毒相关的神经功能障碍微环境提供了新的见解。
Porcine hemagglutinating encephalomyelitis virus (PHEV) invades the central nervous system (CNS) and causes neurodegenerative disease in suckling piglets, but the understanding of its neuropathogenicity for neurological dysfunction remains limited. Here, we report that miR-142-5p is localized to neurons and negatively regulates neuronal morphogenesis in porcine hemagglutinating encephalomyelitis (PHE). This phenotype was mediated by miR-142-5p inhibition of an mRNA encoding unc-51-like-kinase1 (Ulk1), which controls axon outgrowth and dendrite formation. Modulating miR-142-5p activity by microRNA mimics or inhibitors induced neurodegeneration, including stunted axon elongation, unstable dendritic spine formation, and irregular swelling and disconnection in neurites. Relieving Ulk1 mRNA repression in primary cortical neurons by miR-142-5p antagomirs or replication-deficient adenoviruses encoding Ulk1 (Ad5-Ulk1), which improved rescue of nerve injury, restricted viral replication, and increased survival rate in mice underlying PHEV infection. In contrast, disrupting Ulk1 in RNAi-expressing neurons mostly led to significantly shortened axon elongation and/or an abnormally large number of branched dendrites. Taken together, we demonstrated that the abnormal neuronal morphogenesis underlying PHEV infection was mainly caused by functional mRNA repression of the miR-142-5p target Ulk1. Our data revealed that PHEV adapted to use spatiotemporal control of host microRNAs to invade CNS, and provided new insights into the virus-associated neurological dysfunction microenvironment.