α-Synuclein Negatively Regulates Nurr1 Expression Through NF-κB-Related Mechanism.

Congcong Jia,Sheng Chen,Hongqian Qi,Zhaofei Yang,Cheng Cheng,Xuefei Wu,Weidong Le,Huaibin Cai

doi:10.3389/fnmol.2020.00064

Abstract

The nuclear receptor-related 1 protein (Nurr1) is critical for the development and survival of midbrain dopamine neurons that are predominantly affected and progressively degenerated in Parkinson’s disease (PD). The expression level of Nurr1 has been proposed to be modulated by α-synuclein (α-SYN), an important pathological hallmark of PD. However, the underlying molecular mechanisms of α-SYN-Nurr1 interaction are still rarely explored. In this study, we investigated the effect and mechanism of α-SYN on the transcription level of Nurr1. Our results showed that overexpression of α-SYN (WT or A53T) reduced Nurr1 and its downstream gene expressions. α-SYN neither affected the mRNA stability nor bound with the promoter of Nurr1, but modulated the transcription activity of Nurr1 promoter region ranging from −605 bp to −418 bp, which contains the binding site of nuclear factor-kappa B (NF-κB). Moreover, overexpression of α-SYN (WT or A53T) down-regulated NF-κB expression level, thereby inhibiting the transcription factor activity of NF-κB and decreasing the binding quantity of NF-κB with Nurr1 promoter. These findings may give us new insights to better understand the molecular mechanisms underlying the α-SYN-regulated Nurr1 function, which may fascinate the investigation of dopamine neuron degeneration in PD pathogenesis.

Highlights

Parkinson’s disease (PD) is pathologically characterized by the progressive loss of dopamine (DA) neurons in the substantia nigra and the presence of intracellular inclusions in the remaining nigral neurons, named Lewy bodies (LBs; Lees et al, 2009). α-Synuclein (α-SYN) and its aggregates have been found as the main components of LBs (Spillantini et al, 1997; Dong et al, 2016)
We explored the mechanism of α-SYN on nuclear receptor-related 1 protein (Nurr1) transcription level, by investigating the effects of α-SYN on Nurr1 mRNA stability, and screening the potential Nurr1 promoter region affected by α-SYN
The results showed that Nurr1 expressions in α-SYNWT and α-SYNA53T overexpressed cells were significantly decreased to 57% and 53% compared with the vector control group, respectively (p < 0.01; Figure 1A)

Summary

INTRODUCTION

Parkinson’s disease (PD) is pathologically characterized by the progressive loss of dopamine (DA) neurons in the substantia nigra and the presence of intracellular inclusions in the remaining nigral neurons, named Lewy bodies (LBs; Lees et al, 2009). α-Synuclein (α-SYN) and its aggregates have been found as the main components of LBs (Spillantini et al, 1997; Dong et al, 2016). Inflammatory mediators can enhance NF-κB-binding activity with the Nurr promoter, which in turn promote Nurr transcription and markedly elevate Nurr mRNA and protein levels (McEvoy et al, 2002) All these findings may suggest the potential involvement of NF-κB in α-SYN-regulated Nurr expression. We identified NF-κB, the highest score transcription factor of Nurr, by analyzing α-SYN-regulated Nurr promoter region with JASPER database, and detected the binding quantity of NF-κB with this region in α-SYN overexpressed cells showing that α-SYN regulated Nurr expression via affecting the binding quantity of NF-κB with Nurr promoter region Taken together, these results demonstrate a NF-κB-related mechanism underlying the regulating effect of α-SYN on Nurr expression

MATERIALS AND METHODS

RESULTS

DISCUSSION

Findings

DATA AVAILABILITY STATEMENT