Qu Yi, Shi Jing, Tang Ying, Zhao Fengyan, Li Shiping, Meng Junjie, Tang Jun, Lin Xuemei, Peng Xiaodong, Mu Dezhi
Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China.
Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China.
Exp Neurol. 2016 May;279:223-231. doi: 10.1016/j.expneurol.2016.03.011. Epub 2016 Mar 12.
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.
混合谱系激酶结构域样蛋白（MLKL）是介导细胞坏死性凋亡的关键分子。然而，其在脑损伤中的作用仍不清楚。我们首先研究了MLKL在缺氧缺血后发育中的脑内介导神经元损伤的功能及机制。通过氧糖剥夺（OGD）加半胱天冬酶抑制剂zVAD处理（OGD/zVAD）诱导神经元坏死性凋亡。我们发现两种重要的与坏死性凋亡相关的蛋白，受体相互作用蛋白1和3（RIP1、RIP3）上调。此外，RIP1-RIP3与MLKL的相互作用增强。通过小干扰RNA抑制MLKL可减少RIP1-RIP3-MLKL相互作用，并减轻OGD/zVAD诱导的神经元死亡。寡聚化的MLKL转位至神经元膜导致细胞膜损伤可能是神经元坏死性凋亡的新机制。新生大鼠的动物实验进一步证明，抑制MLKL可减轻缺氧缺血诱导的脑损伤。这些发现表明，MLKL是减轻发育中脑内脑损伤的一个靶点。
