MLKL inhibition attenuates hypoxia-ischemia induced neuronal damage in developing brain
MLKL inhibition attenuates hypoxia-ischemia induced neuronal damage in developing brain
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MLKL 抑制可减轻发育中大脑中缺氧缺血引起的神经元损伤
DOI：
10.1016/j.expneurol.2016.03.011
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发表时间：
2016-05-01
影响因子：
5.3
通讯作者：
Mu, Dezhi
中科院分区：
文献类型：
--
作者：
Qu, Yi;Shi, Jing;Mu, Dezhi
混合谱系蛋白样蛋白(MLKL)是介导细胞坏死性下垂的重要分子。然而，它在脑损伤中的作用仍然不清楚。我们首先研究了MLKL在缺氧缺血后发育脑神经元损伤中的作用及其机制。用氧糖剥夺(OGD)加caspase抑制剂zVAD治疗(OGD/zVAD)诱导神经元性坏死性下垂。我们发现，受体相互作用蛋白1和3(RIP1，RIP3)这两个重要的坏死性下垂相关蛋白表达上调。此外，RIP1-RIP3与MLKL的相互作用增强。通过siRNA抑制MLKL可减弱RIP1-RIP3-MLKL相互作用，减轻OGD/zVAD诱导的神经元死亡。寡聚化的MLKL移位至神经细胞膜，导致细胞膜损伤，可能是神经元性坏死性下垂的新机制。用新生大鼠进行的动物实验进一步证明，MLKL抑制可减轻缺氧缺血所致的脑损伤。这些发现表明MLKL是减轻发育中脑损伤的靶点。(C)2016 Elsevier Inc.保留所有权利。
Mixed lineage kinase domain-like protein (MLKL) is a critical molecule mediating cell necroptosis. However, its role in brain injury remains obscure. We first investigated the functions and mechanisms of MLKL in mediating neuronal damage in developing brain after hypoxia-ischemia. Neuronal necroptosis was induced by oxygen glucose deprivation (OGD) plus caspase inhibitor zVAD treatment (OGD/zVAD). We found that two important necroptosis related proteins, receptor-interacting protein 1 and 3 (RIP1, RIP3) were upregulated. Furthermore, the interaction of RIP1-RIP3 with MLKL increased. Inhibition of MLKL through siRNA diminished RIP1-RIP3-MLKL interaction and attenuated neuronal death induced by OGD/zVAD. The translocation of oligomerized MLKL to the neuronal membrane leading to the injury of cellular membrane is the possible new mechanism of neuronal necroptosis. Animal experiment with neonatal rats further proved that MLKL inhibition attenuated brain damage induced by hypoxia-ischemia. These findings suggest that MLKL is a target to attenuate brain damage in developing brain. (C) 2016 Elsevier Inc All rights reserved.