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

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 alpha-synuclein (alpha-SYN), an important pathological hallmark of PD. However, the underlying molecular mechanisms of alpha-SYN-Nurr1 interaction are still rarely explored. In this study, we investigated the effect and mechanism of alpha-SYN on the transcription level of Nurr1. Our results showed that overexpression of alpha-SYN (WT or A53T) reduced Nurr1 and its downstream gene expressions. alpha-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-kappa B). Moreover, overexpression of alpha-SYN (WT or A53T) down-regulated NF-kappa B expression level, thereby inhibiting the transcription factor activity of NF-kappa B and decreasing the binding quantity of NF-kappa B with Nurr1 promoter. These findings may give us new insights to better understand the molecular mechanisms underlying the alpha-SYN-regulated Nurr1 function, which may fascinate the investigation of dopamine neuron degeneration in PD pathogenesis.