Summary

Dysregulated microglia are intimately involved in neurodegeneration, including Alzheimer’s disease (AD) pathogenesis, but the mechanisms controlling pathogenic microglial gene expression remain poorly understood. The transcription factor CCAAT/enhancer binding protein beta (c/EBPβ) regulates pro-inflammatory genes in microglia and is upregulated in AD. We show expression of c/EBPβ in microglia is regulated post-translationally by the ubiquitin ligase COP1 (also called RFWD2). In the absence of COP1, c/EBPβ accumulates rapidly and drives a potent pro-inflammatory and neurodegeneration-related gene program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures. Antibody blocking studies reveal that neurotoxicity is almost entirely attributable to complement. Remarkably, loss of a single allele of Cebpb prevented the pro-inflammatory phenotype. COP1-deficient microglia markedly accelerated tau-mediated neurodegeneration in a mouse model where activated microglia play a deleterious role. Thus, COP1 is an important suppressor of pathogenic c/EBPβ-dependent gene expression programs in microglia.

中文翻译：

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泛素连接酶COP1通过降解小胶质细胞中的c /EBPβ来抑制神经炎症。

概要

小胶质细胞失调与神经变性密切相关，包括阿尔茨海默氏病（AD）发病机理，但控制病原性小胶质细胞基因表达的机制仍知之甚少。转录因子CCAAT /增强子结合蛋白β（c /EBPβ）调节小胶质细胞中的促炎基因，并在AD中上调。我们显示小胶质细胞中c /EBPβ的表达受泛素连接酶COP1（也称为RFWD2）的翻译后调控。在没有COP1的情况下，c /EBPβ迅速积累并驱动有效的促炎性和神经退行性相关基因程序，这在小胶质细胞-神经元共培养物中增加了神经毒性。抗体阻断研究表明，神经毒性几乎完全归因于补体。值得注意的是，Cebpb的一个等位基因缺失预防了促炎表型。缺乏COP1的小胶质细胞在激活的小胶质细胞起有害作用的小鼠模型中显着加速了tau介导的神经变性。因此，COP1是小胶质细胞中致病性c /EBPβ依赖性基因表达程序的重要抑制剂。