Opposing functions of β-arrestin 1 and 2 in Parkinson's disease via microglia inflammation and Nprl3

Although beta-arrestins (ARRBs) regulate diverse physiological and pathophysiological processes, their functions and regulation in Parkinson's disease (PD) remain poorly defined. In this study, we show that the expression of beta-arrestin 1 (ARRB1) and beta-arrestin 2 (ARRB2) is reciprocally regulated in PD mouse models, particularly in microglia. ARRB1 ablation ameliorates, whereas ARRB2 knockout aggravates, the pathological features of PD, including dopaminergic neuron loss, neuroinflammation and microglia activation in vivo, and microglia-mediated neuron damage in vitro. We also demonstrate that ARRB1 and ARRB2 produce adverse effects on inflammation and activation of the inflammatory STAT1 and NF-kappa B pathways in primary cultures of microglia and macrophages and that two ARRBs competitively interact with the activated form of p65, a component of the NF-kappa B pathway. We further find that ARRB1 and ARRB2 differentially regulate the expression of nitrogen permease regulator-like 3 (Nprl3), a functionally poorly characterized protein, as revealed by RNA sequencing, and that in the gain- and loss-of-function studies, Nprl3 mediates the functions of both ARRBs in microglia inflammatory responses. Collectively, these data demonstrate that two closely related ARRBs exert opposite functions in microglia-mediated inflammation and the pathogenesis of PD which are mediated at least in part through Nprl3 and provide novel insights into the understanding of the functional divergence of ARRBs in PD.

Automated summary

The study reveals the opposite roles of ARRB1 and ARRB2 in microglia-mediated inflammation and the pathogenesis of PD, partly mediated through Nprl3. This provides novel insights into the functional divergence of ARRBs in PD.