Neuronal DJ-1 regulates microglial activation in Parkinson’s disease

DJ-1, also known as Parkinson's disease protein 7 (PARK7), is a multifunctional protein that plays an important role in oxidative stress regulation and neuroprotection. Previous studies have shown that DJ-1 affects early-onset Parkinson's disease by regulating neuroinflammation, but its specific mechanism remains unclear. The study investigated the role of DJ-1 in mediating microglia-neuron communication to identify potential therapeutic targets for neuroinflammation in Parkinson's disease. In this study, we observed a significant decrease in the levels of C-X3-C motif chemokine ligand 1 (CX3CL1) in Park7 knockout mice and SH-SY5Y cells with Park7 knockdown. Protein microarray analysis and validation using GEO datasets confirmed that knockout of the Park7 gene led to downregulation of CX3CL1 and two other chemokines, namely monocyte chemoattractant protein-1 and interleukin-8. Further investigation revealed that Park7 deficiency reduced the processing of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in the neuronal endoplasmic reticulum of both mice and SH-SY5Y cells, thereby decreasing CX3CL1 secretion. This subsequently led to abnormal microglial activation, with a shift toward the proinflammatory M1 phenotype, exacerbating neuroinflammatory responses. These effects were mitigated by exogenous CX3CL1 administration. Concurrently, exogenous CX3CL1 improved motor function in Parkinson's disease model mice with the Park7 knockout, promoting survival of tyrosine hydroxylase-positive neurons in the substantia nigra and reducing Iba-1-positive microglial activation. These findings demonstrate that DJ-1 exerts neuroprotective effects on dopaminergic neurons by suppressing microglial activation through CX3CL1 regulation, suggesting that targeting the DJ-1/CX3CL1 axis may represent a novel therapeutic strategy for modulating neuroinflammation and protecting dopaminergic neurons.