α-Synuclein disrupts the anti-inflammatory role of Drd2 via interfering β-arrestin2-TAB1 interaction in astrocytes

Background: alpha-Synuclein (alpha-Syn)-induced neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Dopamine D2 receptor (Drd2) has been regarded as a potential anti-inflammatory target in the therapy of neurodegenerative diseases. However, the effect of astrocytic Drd2 in alpha-Syn-induced neuroinflammation remains unclear. Methods: The effect of Drd2 on neuroinflammation was examined in mouse primary astrocyte in vitro and A53T transgenic mice in vivo. The inflammatory responses of astrocyte were detected using immunofluorescence, ELISA, and qRT-PCR. The details of molecular mechanism were assessed using Western blotting and protein-protein interaction assays. Results: We showed that the selective Drd2 agonist quinpirole suppressed inflammation in the midbrain of wild-type mice, but not in alpha-Syn-overexpressed mice. We also found that Drd2 agonists significantly alleviated LPS-induced inflammatory response in astrocytes, but failed to suppress alpha-Syn-induced inflammatory response. The anti-inflammation effect of Drd2 was dependent on beta-arrestin2-mediated signaling, but not classical G protein pathway. alpha-Syn reduced the expression of beta-arrestin2 in astrocytes. Increased the beta-arrestin2 expression restored in the anti-inflammation of Drd2 in alpha-Syn-induced inflammation. Furthermore, we demonstrated that alpha-Syn disrupted the anti-inflammation of Drd2 via inhibiting the association of beta-arrestin2 with transforming growth factor-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1) and promoting TAK1-TAB1 interaction in astrocytes. Conclusions: Our study illustrates that astrocytic Drd2 inhibits neuroinflammation through a beta-arrestin2-dependent mechanism and provides a new strategy for treatment of PD. Our findings also reveal that alpha-Syn disrupts the function of beta-arrestin2 and inflammatory pathways in the pathogenesis of PD.