A novel compound alleviates oxidative stress via PKA/CREB1‐mediated DJ‐1 upregulation

Oxidative stress is one of the major culprits causing dopaminergic neuron loss in Parkinson's disease (PD). DJ‐1 is a protein with multiple actions against oxidative stress, apoptosis, neuroinflammation, etc. DJ‐1 expression is decreased in sporadic PD, therefore increasing DJ‐1 expression might be beneficial in PD treatment. However, drugs known to upregulate DJ‐1 are still lacking. In this study, we identified a novel DJ‐1‐elevating compound called ChemJ through luciferase assay‐based high‐throughput compound screening in SH‐SY5Y cells and confirmed that ChemJ upregulated DJ‐1 in SH‐SY5Y cell line and primary cortical neurons. DJ‐1 upregulation by ChemJ alleviated MPP + ‐induced oxidative stress. In exploring the underlying mechanisms, we found that the transcription factor CREB1 bound to DJ‐1 promoter and positively regulated its expression under both unstressed and 1‐methyl‐4‐phenylpyridinium‐induced oxidative stress conditions and that ChemJ promoted DJ‐1 expression via activating PKA/CREB1 pathway in SH‐SY5Y cells. Our results demonstrated that ChemJ alleviated the MPP + ‐induced oxidative stress through a PKA/CREB1‐mediated regulation of DJ‐1 expression, thus offering a novel and promising avenue for PD treatment.