Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite

Bruning, John M.; Wang, Yan; Oltrabella, Francesca; Tian, Boxue; Kholodar, Svetlana A.; Liu, Harrison; Bhattacharya, Paulomi; Guo, Su; Holton, James M.; Fletterick, Robert J.; Jacobson, Matthew P.; England, Pamela M.

doi:10.1016/j.chembiol.2019.02.002

Cited by 45 publications

(84 citation statements)

References 112 publications

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“…We also found that the mutations in the first exon of NURR1 gene (−291Tdel and −245T → G) are associated with human familial PD (Le et al, 2003). Therefore, Nurr1 has been regarded as a potential susceptibility gene for PD (Bruning et al, 2019). This gene may also serve as a master downstream molecular target for α-SYN-induced neuron toxicity (Decressac et al, 2012).…”

Section: Introductionmentioning

confidence: 81%

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

Jia

Cheng

et al. 2020

Front. Mol. Neurosci.

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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.

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Section: Introductionmentioning

confidence: 81%

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

Jia

Cheng

et al. 2020

Front. Mol. Neurosci.

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“…Several compounds have been reported in the literature to interact with the Nurr1 LBD. Unsaturated fatty acids, amodiaquine, and chloroquine appear to bind to the Nurr1 orthosteric ligand-binding pocket (4,5,11), whereas the endogenous dopamine metabolite 5,6-dihydroxyindole (DHI) covalently binds to noncanonical site via covalent attachment to a surface-exposed cysteine residue in the Nurr1 LBD (7).…”

Section: Discussionmentioning

confidence: 99%

“…Crystal structures of the Nur77 and Nurr1 ligand-binding domains (LBDs) show a collapsed orthosteric pocket that is filled with residues containing bulky hydrophobic sidechains suggesting these receptors may function independent of binding ligand within an orthosteric pocket (2,3). Furthermore, contributing to their status as orphan receptors, it remains unclear if the NR4As are regulated by binding physiological or endogenous ligands, although unsaturated fatty acids (4)(5)(6) and dopamine metabolites (7) have been shown to interaction with the Nur77 and/or Nurr1 LBDs.…”

Section: Introductionmentioning

confidence: 99%

Assessment of NR4A Ligands that Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1

Munoz-Tello

Lin

Khan

et al. 2020

Preprint

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Nurr1/NR4A2 is an orphan nuclear receptor transcription factor implicated as a potential drug target for neurological disorders including Alzheimer’s and Parkinson’s diseases. Previous studies identified small molecule modulators of NR4A nuclear receptors including Nurr1 and Nur77/NR4A1; it remains unclear whether these ligands affect Nurr1 through direct binding or indirect non-binding mechanisms. We assessed a panel of twelve ligands reported to affect NR4A activity for Nurr1-dependent and Nurr1-independent transcriptional effects and binding to the Nurr1 ligand-binding domain (LBD). Most of the NR4A ligands show Nurr1-independent effects on transcription in a cell type-specific manner, suggesting they may function through binding to effector proteins whose downstream activities influence Nurr1 function. Protein NMR spectroscopy structural footprinting data show that 4-amino-7-chloroquinoline derivatives (amodiaquine and chloroquine) and cytosporone B directly bind the Nurr1 LBD. In contrast, other NR4A ligands including commercially available compounds such as C-DIM12, celastrol, camptothecin, IP7e, isoalantolactone, and TMPA do not bind the Nurr1 LBD. Interestingly, previous crystal structures indicate that cytosporone B analogs bind to surface pockets in the Nur77 LBD, but protein NMR data indicate cytosporone B likely binds to the Nurr1 orthosteric pocket. These findings should influence medicinal chemistry efforts that desire to optimize Nurr1-binding ligands as opposed to ligands that function through binding to Nurr1 effector proteins.

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“…A number of studies have demonstrated the protective role and correlation of Nurr1 in cell death by oxidative stress, but the detailed molecular mechanism of Nurr1 against oxidative stress remains unclear [17,19,20,60,[81][82][83]. Interestingly, a contemporary study reporting the direct binding of dopamine metabolite on Nurr1 and its stimulation of Nurr1 activity may provide an evidence for mechanism underlying the role of Nurr1 in sensing and responding the oxidative stress [84]. Moreover, Jo et al…”

Section: Neuroprotective Effects Of Nurr1mentioning

confidence: 99%

The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer’s Disease-related Pathogenesis

et al. 2020

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Several studies have revealed that the transcription factor nuclear receptor related 1 (Nurr1) plays several roles not only in the regulation of gene expression related to dopamine synthesis, but also in alternative splicing, and miRNA targeting. Moreover, it regulates cognitive functions and protects against inflammationinduced neuronal death. In particular, the role of Nurr1 in the pathogenesis of Parkinson's disease (PD) has been well investigated; for example, it has been shown that it restores behavioral and histological impairments in PD models. Although many studies have evaluated the connection between Nurr1 and PD pathogenesis, the role of Nurr1 in Alzheimer's disease (AD) remain to be studied. There have been several studies describing Nurr1 protein expression in the AD brain. However, only a few studies have examined the role of Nurr1 in the context of AD. Therefore, in this review, we highlight the overall effects of Nurr1 under the neuropathologic conditions related to AD. Furthermore, we suggest the possibility of using Nurr1 as a therapeutic target for AD or other neurodegenerative disorders.

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Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite

Cited by 45 publications

References 112 publications

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

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

Assessment of NR4A Ligands that Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1

The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer’s Disease-related Pathogenesis

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