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

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.

α-Synuclein Up-regulates Monoamine Oxidase A Expression and Activity via Trans-Acting Transcription Factor 1

“…We previously found that α-SYN is located in both the nucleus and cytoplasm (Jia et al, 2020a ). MAOA is mainly expressed on the outer membrane of mitochondria (Green and Youdim, 1975 ).…”

“…As for the biosynthesis of DA, L-tyrosine is hydroxylated by tyrosine hydroxylase (TH) to generate L-DOPA and then decarboxylated by aromatic acid decarboxylase (AADC) to form DA (Daubner et al, 2011;Monzani et al, 2019). Our previous study showed that α-SYN down-regulated the expression levels of TH and AADC via suppressing Nurr1 gene expression (Jia et al, 2020a), indicating an impact of α-SYN on DA biosynthesis through Nurr1-related mechanisms. In this study, we further explored the potential impacts and molecular mechanism of α-SYN on DA degradation.…”

“…Total RNA was extracted and used to synthesize cDNA according to the manufacturer’s instructions (TransGen Biotechnology, Beijing, China). The primers sequences and analysis methods used in the present study were described previously (Jia et al, 2020a , b ).…”

“…The obtained complexes were purified with a DNA purification kit (Beyotime) and then detected with Real-time PCR. The methods of analyzed values were described previously (Jia et al, 2020a , b ).…”

“…Mutations of α-SYN can form toxic protofibril or fibril (Giasson et al, 2002 ), affecting the functions of DA neurons and inducing neurodegeneration (Dev et al, 2003 ). Previous studies have shown that α-SYN affects the expressions of DA-related genes via Nurr1, a key factor involved in the development and functional maintenance of DA neurons (Saucedo-Cardenas et al, 1998 ; Jankovic et al, 2005 ; Jia et al, 2020a ). Besides, α-SYN accumulation is also associated with tau spreading synaptic vesicles, autophagy, mitochondria, endoplasmic reticulum and Golgi complex, nucleus, cell-to-cell propagation, and neuroinflammation related functions (Wong and Krainc, 2017 ; Bassil et al, 2021 ).…”