Oxidation of ΔFOSB at Cys172 Controls Hippocampal Gene Targets and Learning

Lynch, H.; Anderson, D.; Hughes, B.; Aglyamova, G.; Yeh, S.-Y.; Ohnishi, Y.; Estill, M.; Granger, B.; Cates, H.; Berto, S.; Chin, J.; Nestler, E. J.; Rudenko, G.; Robison, A. J.

doi:10.1101/2025.10.14.682315

bioRxiv · 10.1101/2025.10.14.682315

Oxidation of ΔFOSB at Cys172 Controls Hippocampal Gene Targets and Learning

Lynch, H.·Anderson, D.·Hughes, B.·Aglyamova, G.·Yeh, S.-Y.·Ohnishi, Y.·Estill, M.·Granger, B.·Cates, H.·Berto, S.·Chin, J.·Nestler, E. J.·Rudenko, G.·Robison, A. J.

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Abstract

Imbalance of reduction/oxidation (redox) in the brain is associated with numerous diseases including Alzheimers disease (AD), substance abuse disorders, and stroke. Moreover, cognitive decline can be 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. It is dysregulated in many conditions including AD. We showed recently that {Delta}FOSB forms a redox-sensitive disulfide bond between cysteine 172 (C172) of {Delta}FOSB and C279 of its preferred binding partner JUND. This bond works as a redox switch to control DNA-binding, based on studies of recombinant proteins in vitro. Here, we show that this redox control of {Delta}FOSB function in vitro is conserved in vivo. We show that {Delta}FOSB C172 forms a redox-sensitive disulfide bond with JUND that regulates the stability of this AP1-transcription factor complex and its binding to DNA in cells. We also validate the formation of {Delta}FOSB-containing complexes held together via disulfide bonds in mouse brain in vivo. We show that exogenous oxidative stress reduces {Delta}FOSB binding to gene targets in mouse brain and that Fosb C172S knock-in mice, which lack a functional {Delta}FOSB redox switch, are insensitive to this oxidation-dependent reduction in target gene binding, demonstrating that {Delta}FOSB is regulated by a redox switch that modulates binding to target genes in the hippocampus. Finally, we demonstrate that FosB C172S knock-in mice are less sensitive to cognitive dysfunction induced by oxidative stress. This evidence supports {Delta}FOSB as an important mediator of oxidative stress-driven changes in gene expression and cognition and implicates {Delta}FOSB as a possible therapeutic target for diseases associated with oxidative stress in the brain, including AD.

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Lynch, H., Anderson, D., Hughes, B., Aglyamova, G., Yeh, S.-Y., Ohnishi, Y., Estill, M., Granger, B., Cates, H., Berto, S., Chin, J., Nestler, E. J., Rudenko, G., Robison, A. J.. 2025-10-15. Oxidation of ΔFOSB at Cys172 Controls Hippocampal Gene Targets and Learning. https://doi.org/10.1101/2025.10.14.682315

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