The Nuclear receptor related 1 protein (NURR1) also known as NR4A2 (nuclear receptor subfamily 4, group A, member 2) is a protein that in humans is encoded by the NR4A2 gene.[1] NURR1 is a member of the nuclear receptor family of intracellular transcription factors.
NURR1 plays a key role in the maintenance of the dopaminergic system of the brain.[2] Mutations in this gene have been associated with disorders related to dopaminergic dysfunction, including Parkinson's disease, schizophrenia, and manic depression. Misregulation of this gene may be associated with rheumatoid arthritis. Four transcript variants encoding four distinct isoforms have been identified for this gene. Additional alternate splice variants may exist, but their full length nature has not been determined.[3]
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Research has been conducted on Nurr1’s role in inflammation, and may provide important information in treating disorders caused by dopaminergic neuron disease. Inflammation in the CNS can result from activated microglia (macrophage analogs for the central nervous system) and other pro-inflammatory factors, such as bacterial lipopolysaccharide (LPS). LPS binds to toll like receptors (TLR), which induces inflammatory gene expression by promoting signal dependant transcription factors. To determine which cells are dopaminegenic, experiments measure the enzyme tyrosine hydroxylase, since this enzyme is need to synthesize dopamine. It has been shown that Nurr1 protects dopamengeric neurons from LPS induced inflammation, by reducing the inflammatory gene expression in microglial and asterocytes. When a short hairpin for Nurr1 was expressed in microglial and astrocytes, they produced inflammatory mediators, such as TNFa, NO synthase and ILβ. Supporting the conclusion that reduced Nurr1 promotes inflammation and leads to cell death of dopamenergetic neurons. Nurr1 interacts with a transcription factor complex NF-κB-p65 on the inflammatory gene promoters. However, for Nurr1 is dependant on other factors to be able to participate in these interactions. Nurr1 needs to be sumoylated and its co-regulating factor; glycogen synthase kinase 3 needs to be phorphorylated for these interactions to occur. Sumolyated Nurr1 recruits CoREST, a complex made of several proteins that assembles chromatin-modifying enzymes. The Nurr1/CoREST complex inhibits transcription of inflammatory genes[4].
One investigation conducted research on the structure and found that Nurr1 does not contain a ligand binding cavity but an patch filled with hydrophobic side chains. Non-polar amino acid residues of Nurr1’s co-regulators, SMRT and NCoR, bind to this hydrophobic patch. Analysis of tertiary structure has shown that the binding surface of the ligand-binding domain is located on the grooves of the 11th and 12th alpha helices. This study also found essential structural components of this hydrophobic patch, to be the three amino acids residues, F574, F592, L593; mutation of any these three inhibits LBD activity[5].
Nurr1 induces tyrosine hydroxylase (TH) expression, which eventually leads to differentiation into dopaminergic neurons. Nurr1 has been demonstrated to induce differentiation in CNS precursor cells in vitro but they require additional factors for these induced dopaminergic to reach full maturity.[6] This is promising for generation of dopaminergic neurons for Parkinson’s disease research, yet implantation of these induced cells as therapy treatments, has had limited results.
Nuclear receptor related 1 protein has been shown to interact with:
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