Long term effects of COP1 deletion in microglia in vivo
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA607246 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11100862.fastq.gz | Fastqsanger.gz | |||
| SRR11100863.fastq.gz | Fastqsanger.gz | |||
| SRR11100864.fastq.gz | Fastqsanger.gz | |||
| SRR11100865.fastq.gz | Fastqsanger.gz | |||
| SRR11100866.fastq.gz | Fastqsanger.gz |
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Project description:The realization in the last decade that dysregulated microglia are intimately involved in Alzheimer’s 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/EBPß is highly expressed in microglia and is known to regulate expression of pro-inflammatory genes. Notably, c/EBPß 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/EBPß for ubiquitination and subsequent proteasomal mediated degradation. In the absence of Cop1, C/EBPß 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/EBPß, 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/EBPß as a potential therapeutic target for inflammation-driven neurodegeneration as the heterozygote animal is otherwise normal.
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Project description:Effects of COP1 deletion in microglia in vivo
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Project description:The realization in the last decade that dysregulated microglia are intimately involved in Alzheimer’s 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/EBPß is highly expressed in microglia and is known to regulate expression of pro-inflammatory genes. Notably, c/EBPß 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/EBPß for ubiquitination and subsequent proteasomal mediated degradation. In the absence of Cop1, C/EBPß 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/EBPß, 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/EBPß as a potential therapeutic target for inflammation-driven neurodegeneration as the heterozygote animal is otherwise normal.
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Project description: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/EBPß) regulates pro-inflammatory genes in microglia and is upregulated in AD. We show expression of c/EBPß in microglia is regulated post-translationally by the ubiquitin ligase COP1 (also called RFWD2). Ubiquitination of c/EBPß by COP1 targets it for proteasomal degradation. In the absence of COP1, c/EBPß accumulates rapidly and drives a potent pro-inflammatory and ApoE gene-expression 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 elevated ApoE plays a deleterious role. Collectively, these results identify c/EBPß as a potential therapeutic target for inflammation-driven neurodegeneration.
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Project description:The realization in the last decade that dysregulated microglia are intimately involved in Alzheimer’s 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/EBPß is highly expressed in microglia and is known to regulate expression of pro-inflammatory genes. Notably, c/EBPß 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/EBPß for ubiquitination and subsequent proteasomal mediated degradation. In the absence of Cop1, C/EBPß 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/EBPß, 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/EBPß as a potential therapeutic target for inflammation-driven neurodegeneration as the heterozygote animal is otherwise normal.
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Project description:The realization in the last decade that dysregulated microglia are intimately involved in Alzheimer’s 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/EBPß is highly expressed in microglia and is known to regulate expression of pro-inflammatory genes. Notably, c/EBPß 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 amounts 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/EBPß for ubiquitination and subsequent proteasomal mediated degradation. In the absence of Cop1, c/EBPß 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/EBPß, rescued the pro-inflammatory phenotype underscoring a significant gene dosage effect. We also found that Cop1 deletion accelerated disease progression in a mouse model of tau-mediated neurodegeneration where elevated ApoE plays a deleterious role. Taken together these results point to c/EBPß as a potential therapeutic target for inflammation-driven neurodegeneration as the heterozygote animal is otherwise normal.
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Project description:Ubiquitin ligase COP1 suppresses microglia-mediated inflammation
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Project description:The realization in the last decade that dysregulated microglia are intimately involved in Alzheimer’s 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/EBPß is highly expressed in microglia and is known to regulate expression of pro-inflammatory genes. Notably, c/EBPß 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 amounts 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/EBPß for ubiquitination and subsequent proteasomal mediated degradation. In the absence of Cop1, c/EBPß 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/EBPß, rescued the pro-inflammatory phenotype underscoring a significant gene dosage effect. We also found that Cop1 deletion accelerated disease progression in a mouse model of tau-mediated neurodegeneration where elevated ApoE plays a deleterious role. Taken together these results point to c/EBPß as a potential therapeutic target for inflammation-driven neurodegeneration as the heterozygote animal is otherwise normal.
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Project description:The realization in the last decade that dysregulated microglia are intimately involved in Alzheimer’s 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/EBPß is highly expressed in microglia and is known to regulate expression of pro-inflammatory genes. Notably, c/EBPß 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 amounts 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/EBPß for ubiquitination and subsequent proteasomal mediated degradation. In the absence of Cop1, c/EBPß 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/EBPß, rescued the pro-inflammatory phenotype underscoring a significant gene dosage effect. We also found that Cop1 deletion accelerated disease progression in a mouse model of tau-mediated neurodegeneration where elevated ApoE plays a deleterious role. Taken together these results point to c/EBPß as a potential therapeutic target for inflammation-driven neurodegeneration as the heterozygote animal is otherwise normal.
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