Delineation of Delta FosB's In Vivo Redox Sensitivity
Many neurodegenerative diseases, including Alzheimer’s disease (AD), are driven by altered reduction/oxidation (redox) balance in the brain. Moreover, cognitive decline in AD is caused by neuronal dysfunction that precedes cell death, and this dysfunction is in part produced by altered gene expressi...
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| Format: | Dissertation |
| Language: | English |
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ProQuest Dissertations & Theses
01-01-2021
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| Online Access: | Get full text |
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| Summary: | Many neurodegenerative diseases, including Alzheimer’s disease (AD), are driven by altered reduction/oxidation (redox) balance in the brain. Moreover, cognitive decline in AD is caused by neuronal dysfunction that precedes cell death, and this dysfunction is in part produced by altered gene expression. However, the mechanisms by which redox state controls gene expression in neurons are not well understood. Delta FosB is a neuronally enriched transcription factor critical for orchestrating gene expression underlying memory, mood, and motivated behaviors and is dysregulated in AD. Delta FosB regulates gene expression by dimerizing with JunD to form activator protein 1 (AP-1) which binds the promoter regions of target genes to control transcription. In controlled in vitro conditions, AP-1 complex formation and DNA binding are modulated by redox-sensitive disulfide bonds and related redox-sensitive conformational changes in Delta FosB. Here, we show that the redox-dependence of the structure-function relationship of Fos-family proteins found in vitro is also conserved in Delta FosB in cells and in the mouse brain. Under oxidizing conditions, Delta FosB cysteine residues can form disulfide bridges, including at C222 and C172, which can stabilize its interaction with a partner protein; however, these conditions reduce complex binding to AP-1 consensus sequence DNA, specifically when C172 is oxidized. We present evidence that this effect occurs in cells and in mouse brain, altering Delta FosB target gene expression during redox stress. This evidence supports Delta FosB as an important mediator of oxidative stress-driven changes in gene expression seen in neurological conditions and implicates Delta FosB as a possible therapeutic target for intervention in diseases of oxidative stress like AD. |
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| ISBN: | 9798544281719 |