Nuclear Receptor 4A2
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The nuclear receptor 4A2 (NR4A2) (nuclear receptor subfamily 4 group A member 2) also known as nuclear receptor related 1 protein (NURR1) is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''NR4A2''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. NR4A2 is a member of the
nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the ex ...
family of
intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
s. NR4A2 plays a key role in the maintenance of the
dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...
system of the brain. Mutations in this gene have been associated with disorders related to dopaminergic dysfunction, including
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
and
schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
. Misregulation of this gene may be associated with
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...
. 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. This protein is thought to be critical to development of the dopaminergic phenotype in the midbrain, as mice without NR4A2 are lacking expression of this phenotype. This is further confirmed by studies showing that forced NR4A2 expression in naïve precursor cells leads to complete dopaminergic phenotype gene expression. While NR4A2 is a key protein in inducing this phenotype, there are other factors required, as expressing NR4A2 in isolation fails to produce it. One of these suggested factors is winged-helix transcription factor 2 (Foxa2). Studies have found these two factors to be within the same region of developing dopaminergic neurons, and both were required to have expression for the dopaminergic phenotype.


Structure

One investigation conducted research on the structure and found that NR4A2 does not contain a ligand-binding cavity but a patch filled with hydrophobic side chains. Non-polar amino acid residues of NR4A2’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.


Clinical significance


Role in disease

Mutations in NR4A2 have been associated with various disorders, including Parkinson's disease, schizophrenia, manic depression, and
autism Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing d ...
. De novo gene deletions that affect NR4A2 have been identified in some individuals with intellectual disability and language impairment, some of whom meet
DSM-5 The ''Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition'' (DSM-5), is the 2013 update to the '' Diagnostic and Statistical Manual of Mental Disorders'', the taxonomic and diagnostic tool published by the American Psychiat ...
criteria for an autism diagnosis.


Inflammation

Research has been conducted on NR4A2’s role in
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
, and may provide important information in treating disorders caused by dopaminergic neuron disease. Inflammation in the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
can result from activated
microglia Microglia are a type of glia, glial cell located throughout the brain and spinal cord of the central nervous system (CNS). Microglia account for about around 5–10% of cells found within the brain. As the resident macrophage cells, they act as t ...
(
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
analogs for the central nervous system) and other pro-inflammatory factors, such as bacterial lipopolysaccharide (LPS). LPS binds to
toll-like receptors Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane protein, single-spanning receptor (biochemistry), receptors usually expressed on sentinel cells such as macrophages ...
(TLR), which induces inflammatory gene expression by promoting signal-dependent
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
s. To determine which cells are dopaminergic, experiments measured the enzyme
tyrosine hydroxylase Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and ...
(TH), which is needed for dopamine synthesis. It has been shown that NR4A2 protects dopaminergic neurons from LPS-induced inflammation by reducing inflammatory gene expression in microglia and
astrocyte Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of en ...
s. When a short hairpin RNA for NR4A2 was expressed in microglia and astrocytes, these cells produced inflammatory mediators such as TNF-alpha, nitric oxide synthase, and interleukin-1 beta (IL-1β), supporting the conclusion that reduced NR4A2 promotes inflammation and leads to cell death of dopaminergic neurons. NR4A2 interacts with the transcription factor complex NF-κB-p65 on the inflammatory gene promoters. However, NR4A2 is dependent on other factors to be able to participate in these interactions. NR4A2 needs to be sumoylated and its co-regulating factor, glycogen synthase kinase 3, needs to be phosphorylated for these interactions to occur. Sumolyated NR4A2 recruits CoREST, a complex made of several proteins that assembles
chromatin remodeling Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out ...
enzymes. The NR4A2/CoREST complex inhibits transcription of inflammatory genes.


Applications

NR4A2 induces
tyrosine hydroxylase Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and ...
(TH) expression, which eventually leads to differentiation into dopaminergic neurons. NR4A2 has been demonstrated to induce differentiation in CNS precursor cells in vitro but they require additional factors to reach full maturity and dopaminergic differentiation. Therefore, NR4A2 modulation may be promising for generation of dopaminergic neurons for Parkinson's disease research, yet implantation of these induced cells as therapy treatments, has had limited results. NR4A2
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
may be a useful biomarker for Parkinson's disease in combination with inflammatory cytokines.


Knockout studies

Studies have shown that heterozygous knockout mice for the NR4A2 gene demonstrate reduced dopamine release. Initially this was compensated for by a decrease in the rate of dopamine reuptake; however, over time this reuptake could not make up for the reduced amount of dopamine being released. Coupled with the loss of dopamine receptor neurons, this can result in the onset of symptoms for Parkinson's disease.


Interactions

NR4A2 has been shown to interact with: *
Beta-catenin Catenin beta-1, also known as β-catenin (''beta''-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. β-Catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcrip ...
, * Pituitary homeobox 3, * Retinoic acid receptor alpha, and * Retinoic acid receptor beta.


References


Further reading

* * * * * * * * * * * * * * * * * * *


External links

* {{Transcription factors, g2 Intracellular receptors Transcription factors