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

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

doi:10.3389/fnmol.2020.00064

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

Front Mol Neurosci. 2020 May 12:13:64. doi: 10.3389/fnmol.2020.00064. eCollection 2020.

Authors

Congcong Jia^{1

2}, Hongqian Qi^{1

2}, Cheng Cheng^{1

2}, Xuefei Wu³, Zhaofei Yang^{1

2}, Huaibin Cai⁴, Sheng Chen⁵, Weidong Le^{1

2}

Affiliations

¹ Center for Clinical Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, China.
² Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, China.
³ Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China.
⁴ Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging (NIA), National Institutes of Health, Bethesda, MD, United States.
⁵ Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

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.

Keywords: Parkinson’s disease; dopamine; nuclear factor κ B (NF-κB); nuclear receptor-related 1 protein (Nurr1); α-synuclein.