CircSpna2 attenuates cuproptosis by mediating ubiquitin ligase Keap1 to regulate the Nrf2-Atp7b signalling axis in depression after traumatic brain injury in a mouse model

Abstract

This study explores the role of circSpna2 in depression following traumatic brain injury (TBI). It was found that circSpna2 is significantly downregulated in TBI patients, and its expression levels correlate with depressive symptoms. In TBI mouse models, overexpression of circSpna2 alleviated depression-like behaviours, while its knockdown exacerbated these symptoms, suggesting its potential as both a biomarker and a therapeutic target for post-TBI depression. Mechanistically, circSpna2 regulates the Nrf2-Atp7b signalling pathway by binding to the DGR domain of Keap1, which prevents Nrf2 ubiquitination and enhances Nrf2 activity. This in turn promotes the transcription of Atp7b, a copper transport protein, helping to maintain copper homeostasis and mitigate copper-induced oxidative stress, a key protein of cell death (cuproptosis). The overexpression of circSpna2 also improved mitochondrial function and synaptic integrity, which are typically impaired by copper dysregulation. These findings highlight the therapeutic potential of circSpna2 in managing TBI-related depression through the regulation of oxidative stress and copper homeostasis.

Keywords

circRNAs / cuproptosis / depression / traumatic brain injury / ubiquitination

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2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.