Thiazolidinediones inhibit TNFalpha induction of PAI-1 independent of PPARgamma activation.
Liu HB, Hu YS, Medcalf RL, Simpson RW, Dear AE
Thiazolidinediones reduce PAI-1 levels in endothelial cells by blocking TNFalpha's effects through a pathway involving Nur77/Nurr1, independent of PPARgamma activation. This suggests a potential mechanism for protecting blood vessels, possibly relevant to conditions involving inflammation and clotting.
- TZDs lower PAI-1 without needing PPARgamma
- Effect involves Nur77/Nurr1 and DNA binding
- May protect blood vessels from inflammation
- Could inform treatments for vascular issues
Neurochemical characterization of dopaminergic neurons in human striatum.
Cossette M, Lévesque D, Parent A
Dopamine-producing neurons in the human striatum are a distinct group of mature interneurons that also make GABA, a key neurotransmitter. These neurons are not part of the main projection pathways but function as local circuit regulators in the brain.
- Striatal dopamine neurons are mature and not immature
- They produce both dopamine and GABA
- They are a unique interneuron type, not part of major brain pathways
- They express Nurr1 and DAT, confirming dopaminergic identity
- Most do not match other known striatal neuron markers
In search of genes involved in neurodegenerative disorders.
Pardo LM, van Duijn CM
This paper reviews known genes linked to Alzheimer's and Parkinson's diseases, including NR4A2, which is associated with early-onset Parkinson's. It discusses ongoing efforts to find new genes that contribute to the more common forms of these diseases.
- NR4A2 is one of seven genes linked to Parkinson's disease
- These genes mostly explain early-onset cases, not common late-onset forms
- Research aims to find new genes behind the most frequent cases of Parkinson's and Alzheimer's
- Two main genetic theories guide the search: common variants and rare variants
- No direct treatment implications are presented in this review
Parathyroid hormone induces the NR4A family of nuclear orphan receptors in vivo.
Pirih FQ, Aghaloo TL, Bezouglaia O, Nervina JM, Tetradis S
Parathyroid hormone rapidly activates NR4A genes in bone and kidney tissues in living animals, suggesting these genes play a role in how PTH affects bone metabolism. The response is fast, short-lived, and depends on the cAMP-PKA signaling pathway.
- PTH activates NR4A genes in bone and kidney in live animals
- Activation happens within 30 minutes and returns to baseline quickly
- NR4A genes are turned on through the cAMP-PKA pathway
- Nur77 is the most strongly induced of the three NR4A genes
- The response matches what's seen in cell studies
Modulation of orphan nuclear receptor NURR1 expression by methotrexate in human inflammatory joint disease involves adenosine A2A receptor-mediated responses.
Ralph JA, McEvoy AN, Kane D, Bresnihan B, FitzGerald O, Murphy EP
Methotrexate reduces levels of the NURR1 protein in people with psoriatic arthritis, and this reduction is linked to improved disease symptoms. The drug works by triggering adenosine release, which activates the A2A receptor to suppress NURR1 expression.
- Methotrexate lowers NURR1 levels in arthritis patients
- Lower NURR1 matches better disease control
- Methotrexate acts via adenosine and A2A receptors
- NURR1 is a key target of methotrexate's action
- This mechanism may influence inflammation and treatment response
Analysis of global mRNA expression in human skeletal muscle during recovery from endurance exercise.
Mahoney DJ, Parise G, Melov S, Safdar A, Tarnopolsky MA
This study analyzed gene activity in human muscle after intense exercise and found changes in genes related to energy production, stress response, and muscle repair. It identified several nuclear receptor genes, including NR4A2 (Nurr1), that are activated during recovery, suggesting a role in muscle adaptation.
- NR4A2 (Nurr1) is activated after exercise in human muscle
- Exercise triggers genes for energy production and stress protection
- Changes in gene activity may support muscle recovery and adaptation
- Findings could inform therapies targeting muscle function
NR4A orphan nuclear receptor family in peripheral blood eosinophils from patients with atopic dermatitis and apoptotic eosinophils in vitro.
Kagaya S, Hashida R, Ohkura N, Tsukada T, Sugita Y, Terakawa M, Tsujimoto G, Katsunuma T, Akasawa A, Matsumoto K, Saito H
The NR4A family of genes, including Nurr1, is overactive in eosinophils from people with atopic dermatitis, and this activity is linked to the controlled death of these immune cells. This process is triggered by CD30 signaling and can be blocked by a drug that inhibits a key cellular pathway, suggesting a potential treatment target.
- NR4A genes are overactive in eosinophils of atopic dermatitis patients
- CD30 signaling boosts NR4A gene expression and eosinophil death
- A drug blocking MAPK pathway reduces NR4A activity and apoptosis
- This pathway may control harmful immune cell buildup in skin inflammation
- Could lead to new treatments targeting eosinophil survival in AD
Transcriptional regulation of tyrosine hydroxylase by estrogen: opposite effects with estrogen receptors alpha and beta and interactions with cyclic AMP.
Maharjan S, Serova L, Sabban EL
Estrogen can either increase or decrease the activity of the tyrosine hydroxylase gene depending on which estrogen receptor is present—ERalpha boosts it, while ERbeta suppresses it. This effect depends on a specific DNA region that overlaps with signals from cAMP and the Nurr1 protein, suggesting a complex interaction between hormones and brain chemical regulation.
- Estrogen boosts TH gene activity via ERalpha but reduces it via ERbeta
- A shared DNA site integrates estrogen, cAMP, and Nurr1 signals
- This site is critical for how estrogen affects dopamine production
- cAMP increases TH activity, but estrogen blocks this effect
- The findings may help explain hormone-related differences in dopamine disorders
TRAP220 is modulated by the antineoplastic agent 6-Mercaptopurine, and mediates the activation of the NR4A subgroup of nuclear receptors.
Wansa KD, Muscat GE
The drug 6-Mercaptopurine activates NR4A nuclear receptors, which are linked to neurological and psychiatric conditions, by modulating a coactivator protein called TRAP220. This interaction enhances receptor activity without changing how the drug works overall, but increases the total output of gene activation.
- 6-Mercaptopurine activates NR4A receptors linked to brain disorders
- TRAP220 coactivator boosts NR4A activity in cells
- TRAP220 works through a specific region (1-800 amino acids)
- Activation is independent of key phosphorylation sites
- Higher absolute gene activation, not increased drug response
Engineering a dopaminergic phenotype in stem/precursor cells: role of Nurr1, glia-derived signals, and Wnts.
Arenas E
This review explains how to grow dopamine-producing brain cells from stem cells, focusing on three key factors: the Nurr1 protein, signals from support brain cells (glia), and Wnt proteins. Understanding these factors helps improve stem cell therapies for Parkinson's disease.
- Nurr1 is essential for making dopamine neurons
- Support brain cells (glia) help guide dopamine neuron development
- Wnt proteins control growth and specialization of dopamine precursors
- Better understanding leads to improved stem cell therapies for Parkinson's
- These insights aim to enhance graft integration and reduce side effects
Microarray analysis identifies an aberrant expression of apoptosis and DNA damage-regulatory genes in multiple sclerosis.
Satoh J, Nakanishi M, Koike F, Miyake S, Yamamoto T, Kawai M, Kikuchi S, Nomura K, Yokoyama K, Ota K, Kanda T, Fukazawa T, Yamamura T
People with multiple sclerosis have abnormal gene activity in their immune cells, especially genes that control cell death and DNA repair. This imbalance may contribute to the immune system attacking the nervous system.
- MS patients show disrupted gene activity in immune cells
- Genes regulating cell death are both overactive and underactive
- NR4A2 (Nurr1) is increased in MS immune cells
- DNA repair and chromatin genes are downregulated
- This gene imbalance may drive MS progression
Biological effects of pramipexole on dopaminergic neuron-associated genes: relevance to neuroprotection.
Pan T, Xie W, Jankovic J, Le W
Pramipexole boosts the activity of key genes in dopamine-producing neurons, including Nurr1, DAT, and VMAT2, which may explain its protective effects in Parkinson's disease. This effect is triggered through D3 dopamine receptors and could help preserve brain function.
- Pramipexole increases Nurr1, DAT, and VMAT2 gene activity
- Nurr1 rises fastest and most dramatically after treatment
- Effect depends on D3 dopamine receptors, not D2
- May explain why dopamine neurons decline slower in patients
- Suggests pramipexole could support neuron health in NR4A2-related conditions
In vitro and in vivo analyses of human embryonic stem cell-derived dopamine neurons.
Park CH, Minn YK, Lee JY, Choi DH, Chang MY, Shim JW, Ko JY, Koh HC, Kang MJ, Kang JS, Rhie DJ, Lee YS, Son H, Moon SY, Kim KS, Lee SH
Human embryonic stem cells can be turned into dopamine neurons in the lab, which work properly in tests, but these neurons do not survive or keep their dopamine-making ability when transplanted into rat brains, limiting their use for treating Parkinson's disease.
- hES cells can become dopamine neurons in the lab
- These neurons release dopamine and function normally in dishes
- But they fail to survive or maintain dopamine traits in rat brains
- Transplanted cells don’t improve movement problems in rats
- This suggests a major hurdle for using these cells in therapy
Structural basis for the cell-specific activities of the NGFI-B and the Nurr1 ligand-binding domain.
Flaig R, Greschik H, Peluso-Iltis C, Moras D
The NGFI-B and Nurr1 proteins, which are related to NR4A2, have different abilities to turn on genes in cells, due to small differences in their structures. A key part of this difference lies in how a specific protein helix (helix 12) is positioned, which affects how the protein interacts with other molecules needed for gene activation.
- Small structural differences affect how Nurr1 and NGFI-B activate genes
- Helix 12 positioning is critical for gene activation strength
- Changes in helix 11-12 region alter protein function
- A new protein interaction surface involving helix 11 and helix 12 may explain cell-specific activity
- These findings may help design treatments targeting NR4A2-related disorders
The NR4A subfamily of nuclear receptors: new early genes regulated by growth factors in vascular cells.
Martínez-González J, Badimon L
The NR4A family of genes, including NR4A2 (Nurr1), is rapidly activated by growth factors and other signals in blood vessel cells, where it helps control cell growth and function. These genes are not regulated by traditional hormone-like molecules, making them unique and potentially important in disease processes like atherosclerosis.
- NR4A2 is part of a family of genes turned on quickly by growth signals
- These genes regulate cell growth in blood vessels without needing external ligands
- NR4A2 is highly responsive to factors like cytokines and lipoproteins
- The pathway may be relevant to vascular diseases and could be targeted therapeutically
Identification and characterization of human NR4A2 polymorphisms in attention deficit hyperactivity disorder.
Smith KM, Bauer L, Fischer M, Barkley R, Navia BA
This study found two common genetic variations in the NR4A2 gene, which is important for brain dopamine systems linked to ADHD. One variation in the gene's control region may affect how the gene works, potentially increasing ADHD risk, though more research is needed to confirm this. These findings help explain how genetic differences in NR4A2 might contribute to ADHD.
- Two NR4A2 gene variations were found linked to ADHD
- One variation affects gene activity in brain cells
- NR4A2 is key for dopamine brain circuits involved in ADHD
- These findings may guide future ADHD research and treatments
- Variations may influence how the gene turns on in the brain
Long-term expansion of human neural progenitor cells by epigenetic stimulation in vitro.
Zhang H, Zhao Y, Zhao C, Yu S, Duan D, Xu Q
This study developed a method to grow human neural progenitor cells in a lab dish for over 240 days while maintaining their ability to become neurons and support cells. The cells expressed Nurr1, a key protein linked to dopamine-producing neurons, suggesting potential for studying or treating NR4A2-related disorders. The technique could help test gene therapies or model brain development.
- Cells grew for 240 days without losing key properties
- Expressed Nurr1, relevant to NR4A2-related conditions
- Can become dopamine-producing neurons
- May support gene therapy research for brain disorders
- Uses a simple lab dish method, scalable for study
The homeodomain transcription factor Pitx3 facilitates differentiation of mouse embryonic stem cells into AHD2-expressing dopaminergic neurons.
Chung S, Hedlund E, Hwang M, Kim DW, Shin BS, Hwang DY, Kang UJ, Isacson O, Kim KS
Pitx3 helps guide stem cells to become a specific type of dopamine neuron (A9) that is most affected in Parkinson's disease, while Nurr1 boosts overall dopamine neuron production without changing the A9 type proportion. This suggests Pitx3 is key to making the right kind of neuron for potential Parkinson's cell therapies.
- Pitx3 increases A9-like dopamine neurons, which are lost in Parkinson's
- Nurr1 boosts total dopamine neurons but not the A9 subtype
- Pitx3 may help make better cells for Parkinson's transplantation therapy
- A9 neurons are most vulnerable in Parkinson's disease
- Stem cells with Pitx3 make more disease-relevant neurons
Neural cell differentiation in vitro from adult human bone marrow mesenchymal stem cells.
Long X, Olszewski M, Huang W, Kletzel M
Adult human bone marrow stem cells can be guided into becoming neural cells in the lab using a specific mix of growth factors and chemicals, including those that support nerve development and function.
- Bone marrow stem cells turn into neural cells in lab conditions
- Key growth factors include bFGF, hEGF, BDNF, and others
- Cells show early and mature neural markers
- This method may help study neurological disorders
- Not directly about NR4A2/NURR1, but relevant to neural development
Transactivation activity of Nur77 discriminates between Ca2+ and cAMP signals.
Klopotowska D, Matuszyk J, Rapak A, Gidzinska B, Cebrat M, Ziolo E, Strzadala L
Nur77, a protein linked to NR4A2-related syndrome, moves into the cell nucleus only when activated by cAMP signals, not calcium signals, which may affect how the protein controls gene activity in the brain.
- cAMP triggers Nur77 to move into the nucleus
- Calcium signals do not move Nur77 into the nucleus
- Nur77 stays in the cytoplasm with calcium activation
- This suggests cAMP and calcium affect Nur77 differently
- Nuclear movement is key to Nur77's gene-regulating role
Age-dependent dopaminergic dysfunction in Nurr1 knockout mice.
Jiang C, Wan X, He Y, Pan T, Jankovic J, Le W
Old mice with one copy of the Nurr1 gene missing show worsening movement problems, lower dopamine levels, and loss of dopamine-producing brain cells, indicating that Nurr1 is essential for keeping these neurons healthy over time. This model helps researchers understand how Parkinson’s disease might develop and test treatments that could slow or stop the damage.
- Nurr1 helps maintain dopamine neurons as mice age
- One missing Nurr1 gene leads to Parkinson-like symptoms in old mice
- Dopamine levels and neuron numbers drop with age in these mice
- The model mimics key features of Parkinson’s disease
- Could help test treatments that protect brain cells
Nurr1 co-localizes with EphB1 receptors in the developing ventral midbrain, and its expression is enhanced by the EphB1 ligand, ephrinB2.
Calò L, Spillantini M, Nicoletti F, Allen ND
EphB1 receptors and Nurr1 are found together in the developing midbrain, and activating EphB1 with its natural ligand ephrinB2 boosts Nurr1 levels, which may help brain cells become dopamine-producing neurons.
- EphB1 and Nurr1 are active in the same brain regions during early development
- EphrinB2, the natural activator of EphB1, increases Nurr1 levels
- Low doses of ephrinB2 boost Nurr1, but higher doses do not
- This process may guide the formation of dopamine-producing neurons
- Nurr1 is critical for the development of the brain's dopamine system
Induction patterns of transcription factors of the nur family (nurr1, nur77, and nor-1) by typical and atypical antipsychotics in the mouse brain: implication for their mechanism of action.
Maheux J, Ethier I, Rouillard C, Lévesque D
Antipsychotic drugs alter the activity of Nurr1, Nur77, and Nor-1—key brain transcription factors linked to dopamine signaling—in ways that differ between typical and atypical drugs. These changes occur in brain regions critical for movement, reward, and cognition, suggesting that drug effects may involve long-term gene regulation through these factors.
- Antipsychotics change Nurr1, Nur77, and Nor-1 levels in dopamine-related brain areas
- Drug effects on these genes help distinguish typical from atypical antipsychotics
- Changes correlate with D2/D3 receptor activity and drug affinity profiles
- Nurr1 increases in midbrain regions like substantia nigra and VTA
- These gene changes may underlie long-term drug effects on brain function
Protein-protein interactions and transcriptional antagonism between the subfamily of NGFI-B/Nur77 orphan nuclear receptors and glucocorticoid receptor.
Martens C, Bilodeau S, Maira M, Gauthier Y, Drouin J
Glucocorticoid receptor (GR) blocks the activity of NR4A2-related nuclear receptors (like NGFI-B) at the POMC gene promoter by directly binding to them, preventing gene activation. This interaction occurs through their DNA-binding domains and may explain how stress hormones interfere with brain pathways involved in development and behavior.
- GR directly binds NR4A2-related receptors to block gene activation
- This interaction happens at the DNA-binding domain, not through DNA or dimerization
- The mechanism may affect brain development and stress responses
- May explain how glucocorticoids disrupt normal NR4A2 function in the brain
- Suggests a pathway for potential therapeutic intervention
Dopaminergic neurons.
Chinta SJ, Andersen JK
Dopaminergic neurons in the midbrain produce dopamine and are essential for movement, mood, and reward; their loss causes Parkinson's disease. Key genes like NR4A2 (Nurr1) are critical for their development and function, and dysfunction in these neurons is central to neurodegenerative disease.
- NR4A2/Nurr1 is vital for dopaminergic neuron development
- Loss of these neurons leads to Parkinson’s disease
- The substantia nigra is a vulnerable brain region due to high iron and dopamine
- NR4A2 dysfunction may underlie neurodegeneration
- Understanding these neurons helps identify potential therapies
Presynaptic dopaminergic properties of differentiated mouse embryonic stem cells.
Nakano Y, Hirko AC, Smith AD, Oka M, Dawson R, Peris J, Terada N, Meyer EM
Differentiated mouse embryonic stem cells can develop key presynaptic functions of dopamine-producing neurons, including dopamine release and uptake, and express important dopaminergic genes like Nurr1, which is the human gene mutated in NR4A2-related syndrome.
- Mouse stem cells become dopamine-producing neurons
- They release dopamine in response to stimulation
- They express Nurr1, the gene linked to NR4A2 syndrome
- They show key features needed for dopamine regulation
- Findings may help develop stem cell therapies
Chronic lithium decreases Nurr1 expression in the rat brain and impairs spatial discrimination.
Al Banchaabouchi M, Peña de Ortíz S, Menéndez R, Ren K, Maldonado-Vlaar CS
Chronic lithium treatment reduces Nurr1 levels in the rat brain, particularly in the hippocampus, and impairs learning on a spatial memory task that relies on this brain region. This suggests lithium may negatively affect cognitive functions tied to Nurr1, a protein linked to NR4A2-related syndrome.
- Lithium lowers Nurr1 levels in the hippocampus
- Impaired spatial learning in rats on lithium
- Nurr1 reduction correlates with lithium blood levels
- Training restored Nurr1 levels in treated rats
- Lithium may affect hippocampal-dependent cognition
Nur77 family of nuclear hormone receptors.
Hsu HC, Zhou T, Mountz JD
The Nur77 family of nuclear receptors, including Nurr1 (NR4A2), plays critical roles in brain development, immune function, and cell survival, with their location in the cell determining whether they promote cell death or growth. These receptors are involved in key biological processes relevant to neurodevelopmental and inflammatory disorders.
- NR4A2 (Nurr1) is essential for brain development and function
- Its location in the cell determines if it promotes cell death or survival
- NR4A2 regulates immune responses and inflammation
- It interacts with co-factors that influence gene expression
- Targeting NR4A2 may offer new treatment strategies
Differentiation of the dopaminergic phenotype in the olfactory system of neonatal and adult mice.
Saino-Saito S, Sasaki H, Volpe BT, Kobayashi K, Berlin R, Baker H
Dopamine-producing neurons in the mouse nose develop from migrating cells that start making dopamine-related proteins early, with full maturation depending on sensory activity from smell. This process is controlled by the Nurr1 gene, which helps turn on the dopamine program in these cells.
- Dopamine neurons in the nose form from migrating cells in newborn mice
- Dopamine protein appears only after sensory input from smell
- The Nurr1 gene controls dopamine development in these cells
- Mature dopamine neurons are only in the olfactory bulb's outer layer
- This process depends on activity from the sense of smell
Fibroblast growth factor-20 promotes the differentiation of Nurr1-overexpressing neural stem cells into tyrosine hydroxylase-positive neurons.
Grothe C, Timmer M, Scholz T, Winkler C, Nikkhah G, Claus P, Itoh N, Arenas E
FGF-20 helps neural stem cells that overexpress the Nurr1 protein turn into dopamine-producing neurons, which could be useful for treating Parkinson's disease. However, these cells only grow long connections in young animals, suggesting that the adult brain may lack other needed factors.
- FGF-20 drives Nurr1-expressing stem cells to become dopamine neurons
- Cells keep dopamine-making ability after being transplanted
- Neuron connections only form in young, not adult, brains
- FGF-20 may act on dopamine neurons from nearby cells
- Adult brain may need extra signals for full neuron development
NGFI-B (Nurr77/Nr4a1) orphan nuclear receptor in rat pinealocytes: circadian expression involves an adrenergic-cyclic AMP mechanism.
Humphries A, Weller J, Klein D, Baler R, Carter DA
NGFI-B, a nuclear receptor related to NR4A2/NURR1, shows strong nighttime increases in the rat pineal gland, driven by adrenergic and cAMP signaling. This suggests a role for NR4A2-like proteins in regulating circadian gene expression, potentially relevant to neurological and sleep-related functions.
- NGFI-B levels rise at night in rat pineal cells
- Regulated by adrenergic and cAMP pathways
- Involves the transcription factor Fra-2
- May influence circadian gene control
- Relevance to NR4A2/NURR1 function in brain
The orphan nuclear receptors NURR1 and NGFI-B modulate aromatase gene expression in ovarian granulosa cells: a possible mechanism for repression of aromatase expression upon luteinizing hormone surge.
Wu Y, Ghosh S, Nishi Y, Yanase T, Nawata H, Hu Y
NURR1 and NGFI-B, two related proteins, turn down the production of aromatase in ovarian cells, which may explain why estrogen levels drop during ovulation. This regulation happens quickly after a hormone surge and involves direct binding of NURR1 to the aromatase gene's control region.
- NURR1 and NGFI-B reduce aromatase expression in ovarian cells
- This repression occurs rapidly after a hormone surge
- NURR1 binds directly to the aromatase gene's control region
- The mechanism may explain estrogen drop during ovulation
- Findings are in human ovarian cells, relevant to hormone regulation
Nuclear orphan receptor Nurr1 directly transactivates the osteocalcin gene in osteoblasts.
Pirih FQ, Tang A, Ozkurt IC, Nervina JM, Tetradis S
Nurr1 directly activates the osteocalcin gene in bone-forming cells, suggesting it plays a key role in bone development and function. This finding places Nurr1 among the main regulators of bone-related gene expression.
- Nurr1 turns on the osteocalcin gene in bone cells
- Nurr1 binds directly to a specific site in the osteocalcin gene
- This interaction is critical for bone cell gene regulation
- Nurr1 is activated by key signaling pathways in bone cells
- The process involves direct DNA binding by Nurr1 as a monomer
Expression, purification, and initial structural characterization of rat orphan nuclear receptor NOR-1 LBD domain.
Razzera G, Vernal J, Portugal RV, Calgaro MR, Fernandez P, Zakin MM, Polikarpov I, Terenzi H
This study successfully produced and characterized the rat NOR-1 protein's ligand-binding domain, which is structurally similar to Nurr1, a protein linked to NR4A2-related disorders. The protein folded correctly and showed a stable structure, enabling future studies on how it might be targeted therapeutically.
- Rat NOR-1 LBD was produced and purified at high purity
- Structure resembles Nurr1, a key protein in NR4A2-related conditions
- Protein is stable and correctly folded, suitable for further study
- No known ligands exist, but structure may guide drug design
- Findings support future work on NR4A2/Nurr1-targeted therapies
Tyrosine hydroxylase-positive neurons intrinsic to the human striatum express the transcription factor Nurr1.
Cossette M, Parent A, Lévesque D
Human striatum contains dopamine-producing neurons that closely resemble the dopamine neurons in the substantia nigra, sharing both their shape and key molecular markers, including Nurr1, which is critical for dopamine neuron development and function.
- Dopamine neurons exist in the human striatum
- These neurons match those in the substantia nigra in shape and molecular makeup
- All striatal dopamine neurons express Nurr1, a key gene for dopamine function
- Nurr1 is essential for proper dopamine neuron development and maintenance
- This supports the idea that striatal dopamine neurons are biologically significant