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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2018

Open Access 01-12-2018 | Research

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

Authors: Ren-Hong Du, Yan Zhou, Mei-Ling Xia, Ming Lu, Jian-Hua Ding, Gang Hu

Published in: Journal of Neuroinflammation | Issue 1/2018

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Abstract

Background

α-Synuclein (α-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 α-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 α-Syn-overexpressed mice. We also found that Drd2 agonists significantly alleviated LPS-induced inflammatory response in astrocytes, but failed to suppress α-Syn-induced inflammatory response. The anti-inflammation effect of Drd2 was dependent on β-arrestin2-mediated signaling, but not classical G protein pathway. α-Syn reduced the expression of β-arrestin2 in astrocytes. Increased the β-arrestin2 expression restored in the anti-inflammation of Drd2 in α-Syn-induced inflammation. Furthermore, we demonstrated that α-Syn disrupted the anti-inflammation of Drd2 via inhibiting the association of β-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 β-arrestin2-dependent mechanism and provides a new strategy for treatment of PD. Our findings also reveal that α-Syn disrupts the function of β-arrestin2 and inflammatory pathways in the pathogenesis of PD.
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Metadata
Title
α-Synuclein disrupts the anti-inflammatory role of Drd2 via interfering β-arrestin2-TAB1 interaction in astrocytes
Authors
Ren-Hong Du
Yan Zhou
Mei-Ling Xia
Ming Lu
Jian-Hua Ding
Gang Hu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-018-1302-6

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