Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China.
Shanghai Key Laboratory of Aging Studies, Shanghai 201210, China.
Proc Natl Acad Sci U S A. 2024 Feb 6;121(6):e2320383121. doi: 10.1073/pnas.2320383121. Epub 2024 Jan 30.
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.
雷特综合征（RTT）是一种严重的神经发育障碍，主要由甲基化CpG 结合蛋白 2（Mecp2）基因突变引起。在这里，我们发现抑制受体相互作用丝氨酸/苏氨酸蛋白激酶 1（RIPK1）激酶可改善发病后运动功能障碍的进展，并延长 Mecp2 缺失小鼠的存活时间。髓样 Mecp2 缺陷小鼠中的小胶质细胞被早期激活，而 RIPK1 激酶失活后则被抑制。Mecp2 缺陷小胶质细胞中 RIPK1 抑制可减少氧化应激、细胞因子产生以及 SLC7A11、SLC38A1 和 GLS 的诱导，这些都介导谷氨酸的释放。Mecp2 缺陷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 蛋白水平升高，而 RIPK1 抑制可降低其水平。因此，Mecp2 缺陷小胶质细胞中 RIPK1 激酶的激活可能参与了 RTT 的发病和进展。
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