PLX152882

GSE145445: Effects of COP1 deletion in microglia in vivo

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

The realization in the last decade that dysregulated microglia are intimately involved in Alzheimers disease (AD) pathogenesis has been a major advance. The precise mechanisms controlling pathogenic programs of microglia gene expression, however, remain poorly understood. The transcription factor (TF) c/EBP is highly expressed in microglia and is known to regulate expression of pro-inflammatory genes. Notably, c/EBP is upregulated in AD. Despite mounting evidence that the levels of this pivotal pro-inflammatory TF are tightly regulated, how this is achieved is unclear as alterations in its levels are not reflected in transcript levels. Remarkably, we find that this TF is primarily regulated post-translationally. Here we show that the ubiquitin ligase Cop1 functions as a brake on microglial activation by targeting C/EBP for ubiquitination and subsequent proteasomal mediated degradation. In the absence of Cop1, C/EBP protein rapidly and dramatically accumulates leading to engagement of a potent pro-inflammatory and ApoE gene-expression program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures. Antibody blocking studies revealed that the neurotoxicity was almost entirely attributable to complement. Unexpectedly, loss of a single allele of C/EBP, rescued the pro-inflammatory phenotype underscoring a significant gene dosage effect. We also found that Cop1 deletion accelerated a mouse model of tau-mediated neurodegeneration where elevated ApoE plays a deleterious role. Taken together these results point to C/EBP as a potential therapeutic target for inflammation-driven neurodegeneration as the heterozygote animal is otherwise normal. SOURCE: Rohit Reja (rejar@gene.com) - Genentech