PDF(Pubmed)
Abstract：
Rett syndrome (RTT) is a devastating neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (Mecp2) gene. Here, we found that inhibition of Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) kinase ameliorated progression of motor dysfunction after onset and prolonged the survival of Mecp2-null mice. Microglia were activated early in myeloid Mecp2-deficient mice, which was inhibited upon inactivation of RIPK1 kinase. RIPK1 inhibition in Mecp2-deficient microglia reduced oxidative stress, cytokines production and induction of SLC7A11, SLC38A1, and GLS, which mediate the release of glutamate. Mecp2-deficient microglia release high levels of glutamate to impair glutamate-mediated excitatory neurotransmission and promote increased levels of GluA1 and GluA2/3 proteins in vivo, which was reduced upon RIPK1 inhibition. Thus, activation of RIPK1 kinase in Mecp2-deficient microglia may be involved both in the onset and progression of RTT.
摘要：
Rett综合征（RTT）是一种破坏性的神经发育障碍，主要由甲基-CpG结合蛋白2（Mecp2）基因突变引起。这里,我们发现,抑制受体相互作用的丝氨酸/苏氨酸-蛋白激酶1(RIPK1)激酶可改善Mecp2-null小鼠发病后运动功能障碍的进展,并延长存活时间.在髓样Mecp2缺陷小鼠中，小胶质细胞早期被激活，RIPK1激酶失活后被抑制。Mecp2缺陷型小胶质细胞中的RIPK1抑制降低了氧化应激，细胞因子的产生和SLC7A11，SLC38A1和GLS的诱导，介导谷氨酸的释放。Mecp2缺陷的小胶质细胞释放高水平的谷氨酸，以损害谷氨酸介导的兴奋性神经传递，并促进体内GluA1和GluA2/3蛋白水平的增加，RIPK1抑制后降低。因此，Mecp2缺陷型小胶质细胞中RIPK1激酶的激活可能参与RTT的发生和进展。
