Objective: DJ-1, also known as Parkinson’s disease protein 7 (PARK7), is a multifunctional protein that is important in regulating oxidative stress and neuroprotection.

Background: The imbalance of neuronal-microglia “crosstalk” participates in the pathogenesis of Parkinson’s disease (PD), in which CX3CL1/CX3CR1 axis plays an important role. However, the specific regulatory mechanism of CX3CL1 and its role in microglia polarization remains elusive. The aim of this study was to explore the regulatory mechanisms of DJ-1 on CX3CL1/CX3CR1 to further investigate its relationship with neuroinflammation.

Method: We explored the correlation between DJ-1 and CX3CL1 and their role of neuroinflammation in MPTP-induced PD mice, DJ-1 -/- mice primary microglia, primary mesencephalic neurons, SH-SY5Y and BV-2 cell lines. We also explored the molecular mechanisms of these interactions and the signaling processes involved in neuroinflammation.

Results: We confirmed the positive correlation between DJ-1 and CX3CL1 in the serum of PD patients and MPTP PD models. With DJ-1 downregulation, CX3CL1 could inhibit the microglial activation, promote the M1 to M2 phenotype conversion, and reduce the inflammatory factors release. In addition, DJ-1 mediated CX3CL1 regulation by interfering with the shedding and maturation of ADAM10 at endoplasmic reticulum (ER) sites on neurons.

Conclusion: Our study suggests that reduced DJ-1 expression in neurons interfered with the shear maturation of ADAM10 in the ER to inhibit the membrane shear release of CX3CL1, thereby resulting in microglial activation and phenotypic transformation in a pro-inflammatory environment. This project clarifies the role of neuronal DJ-1 in regulating the CX3CL1/CX3CR1 axis and thus directly regulating microglia polarization to provide a new target for immune intervention in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neuronal-dj-1-regulates-microglia-activation-via-adam10-mediated-cx3cl1-secretion/