NR4A2 genetic variation and Parkinson's disease: Evidence from a systematic review and meta-analysis.
Liu H, Liu H, Li T, Cui J, Fu Y, Ren J, Sun X, Jiang P, Yu S, Li C
The NR4A2 gene variant rs35479735 is linked to a slightly increased risk of Parkinson's disease, especially in people with sporadic cases, but overall evidence does not strongly support NR4A2 as a major risk factor. More research is needed to confirm its role.
- rs35479735 variant increases PD risk slightly
- Strongest link seen in sporadic Parkinson's cases
- No clear link found for other NR4A2 variants
- Results not strong enough to confirm NR4A2 as major PD risk factor
Developmental Vitamin D (DVD) Deficiency Reduces Nurr1 and TH Expression in Post-mitotic Dopamine Neurons in Rat Mesencephalon.
Luan W, Hammond LA, Cotter E, Osborne GW, Alexander SA, Nink V, Cui X, Eyles DW
Vitamin D deficiency in developing rats reduces Nurr1 and dopamine-related proteins without killing the neurons. This suggests environmental factors can alter brain chemistry before birth, potentially influencing behavior later in life.
- Rat study on developmental vitamin D deficiency effects.
- Neuron numbers remain normal despite chemical changes.
- Nurr1 and dopamine markers decrease in specific brain regions.
- Links prenatal environment to future behavioral risks.
Evaluation of a Novel Difficulty of Smoking Cessation Phenotype Based on Number of Quit Attempts.
Stevens VL, Jacobs EJ, Gapstur SM, Carter BD, Gaudet MM, Westmaas JL, Patel AV
This study found that certain genetic variants, including one in the NR4A2 gene, are linked to difficulty quitting smoking, especially in people who need many attempts. A genetic risk score based on these variants can predict who may struggle more with quitting.
- NR4A2 gene variant linked to smoking cessation difficulty
- Genetic risk score predicts quitting challenges
- Findings may help develop better smoking cessation treatments
- Focus on number of quit attempts improves genetic discovery
A study of the age-related effects of lactational atrazine exposure.
Sun Y, Li YS, Li B, Ma K, Li BX
Exposure to the herbicide atrazine during early development harms dopamine neurons in rats, leading to reduced dopamine levels and increased neuron damage over time, especially as the animals age. This damage is linked to reduced levels of a key brain protein called Nurr1, which controls genes involved in dopamine storage and recycling.
- Atrazine exposure during development harms dopamine neurons
- Nurr1 protein levels drop, affecting dopamine regulation
- Dopamine storage and recycling become impaired
- Neuron damage worsens with age
- Aging makes atrazine-related harm worse
In vivo expression of Nurr1/Nr4a2a in developing retinal amacrine subtypes in zebrafish Tg(nr4a2a:eGFP) transgenics.
Goodings L, He J, Wood AJ, Harris WA, Currie PD, Jusuf PR
This study maps when and where the NR4A2 gene is active in developing zebrafish retinal neurons, identifying it as a marker for specific amacrine cell subtypes. The findings provide detailed developmental lineage data that may help refine future regenerative strategies targeting these cells.
- Researchers created a transgenic zebrafish line to visualize NR4A2 expression in real-time during eye development.
- NR4A2 marks approximately 25% of all amacrine interneurons, including dopaminergic and GABAergic subtypes.
- The gene is active in postmitotic neurons derived from a specific progenitor lineage involving Atoh7 and Ptf1a.
- This model serves as a tool to study gene interactions and potential regenerative therapies for retinal cells.
PCK1 expression is correlated with the plasma glucose level in the duck.
Chen L, Zeng T, Li GQ, Liu R, Tian Y, Li QH, Lu LZ
PCK1 is a key gene that helps maintain blood sugar levels during fasting in ducks, and its activity affects fat and sugar levels in the blood. Domestic ducks have lower PCK1 levels than wild ducks, which may explain differences in metabolism between them.
- PCK1 helps control blood sugar during fasting in ducks
- Domestic ducks have lower PCK1 than wild ducks
- PCK1 affects blood fat and sugar levels
- PCK1 upregulation maintains stable fat levels during fasting
- NR4A2 was not found to regulate PCK1 in ducks
NR4A Receptors Differentially Regulate NF-κB Signaling in Myeloid Cells.
McEvoy C, de Gaetano M, Giffney HE, Bahar B, Cummins EP, Brennan EP, Barry M, Belton O, Godson CG, Murphy EP, Crean D
This study shows that NR4A2 regulates inflammatory responses in immune cells by simultaneously enhancing and suppressing specific genes controlled by NF-κB. It identifies a mechanism where NR4A2 influences inflammation without needing to bind directly to DNA, involving the Relb protein.
- NR4A2 acts as a positive regulator for MIP-3α expression in myeloid cells.
- Altered NR4A activity suppresses LPS-induced MCP-1 gene and protein expression.
- NR4A2 modulates NF-κB target genes concurrently, enhancing some while repressing others.
- NR4A2 does not require DNA-binding capacity to regulate these inflammatory targets.
- Relb is identified as a novel NR4A target gene involved in MIP-3α regulation.
Role of miR-34a-5p in Hematopoietic Progenitor Cells Proliferation and Fate Decision: Novel Insights into the Pathogenesis of Primary Myelofibrosis.
Bianchi E, Ruberti S, Rontauroli S, Guglielmelli P, Salati S, Rossi C, Zini R, Tagliafico E, Vannucchi AM, Manfredini R
This study found that elevated levels of miR-34a-5p in blood cell precursors contribute to the abnormal development of megakaryocytes and immune cells in primary myelofibrosis, a blood disorder involving bone marrow scarring. The gene NR4A2 is suppressed by miR-34a-5p, and reducing NR4A2 mimics the same effects, suggesting it plays a key role in the disease process.
- miR-34a-5p is increased in blood cell precursors in myelofibrosis
- miR-34a-5p reduces cell growth and favors megakaryocyte/immune cell development
- NR4A2 is a target of miR-34a-5p and its loss mimics disease effects
- Lower NR4A2 may drive abnormal blood cell development in myelofibrosis
- This pathway may contribute to bone marrow scarring in patients
The NR4A subfamily of nuclear receptors: potential new therapeutic targets for the treatment of inflammatory diseases.
Rodríguez-Calvo R, Tajes M, Vázquez-Carrera M
This review discusses how NR4A2 helps regulate inflammation by acting as a negative feedback mechanism to resolve inflammatory responses. It highlights the molecular mechanisms of this process but notes that specific target genes and pathways are not yet fully understood.
- NR4A2 acts as a regulator to help resolve chronic inflammation.
- The paper reviews molecular transrepression mechanisms in immune cells.
- It suggests NR4A receptors are potential targets for inflammatory diseases.
- Current understanding of specific target genes remains incomplete.
Cellular Model of Alzheimer's Disease: Aβ1-42 Peptide Induces Amyloid Deposition and a Decrease in Topo Isomerase IIβ and Nurr1 Expression.
Terzioglu-Usak S, Negis Y, Karabulut DS, Zaim M, Isik S
This study shows that Alzheimer's-like conditions cause a drop in Nurr1 levels in rat brain cells and human stem cells. The research demonstrates that another protein, topo IIβ, regulates Nurr1 expression in these cell models.
- Alzheimer's peptide Aβ1-42 reduces both topo IIβ and Nurr1 in rat neurons.
- Reducing topo IIβ lowers Nurr1 levels in human stem cells.
- Increasing topo IIβ restores Nurr1 expression in human stem cells.
- The study uses cell cultures, not living animals or humans.
Transcriptional Regulation of DJ-1.
Takahashi-Niki K, Niki T, Iguchi-Ariga SMM, Ariga H
This review describes how the DJ-1 protein interacts with various transcription factors, including Nurr1 (NR4A2), to regulate cell growth and dopamine synthesis. It highlights that DJ-1 acts as a co-regulator for these proteins without binding DNA directly, influencing oxidative stress responses and metabolic functions.
- DJ-1 regulates dopamine synthesis by interacting with transcription factors like Nurr1.
- The protein's activation depends on the oxidation state of cysteine residue 106.
- DJ-1 influences cell growth, death, and oxidative stress responses via multiple pathways.
- This is a general review of DJ-1 biology, not specific to NR4A2 syndrome.
Daphnane and Phorbol Diterpenes, Anti-neuroinflammatory Compounds with Nurr1 Activation from the Roots and Stems of Daphne genkwa.
Han BS, Minh NV, Choi HY, Byun JS, Kim WG
Compounds isolated from the Daphne genkwa plant activate Nurr1 and strongly reduce neuroinflammation in cell cultures. These natural diterpenes inhibit inflammatory markers significantly more potently than the standard drug minocycline in microglial cells. This work identifies specific plant-derived molecules that modulate Nurr1 activity and inflammation pathways.
- Four daphnane-type and two phorbol-type diterpenes activate Nurr1 in vitro.
- Selected compounds reduce inflammatory cytokine expression in microglial cells.
- Anti-inflammatory potency is 15-30 times higher than minocycline.
- Study uses cell culture models, not human or animal subjects.
- No clinical data or treatment protocols for humans are presented.
Effects of Feeder Cells on Dopaminergic Differentiation of Human Embryonic Stem Cells.
Zhao Z, Ma Y, Chen Z, Liu Q, Li Q, Kong D, Yuan K, Hu L, Wang T, Chen X, Peng Y, Jiang W, Yu Y, Liu X
This study compares how two different types of feeder cells influence the creation of dopamine-producing neurons from human embryonic stem cells in a laboratory setting. It finds that using human foreskin fibroblasts results in a higher yield of functional dopamine neurons with better electrical properties than using mouse fibroblasts or a mix of both.
- Human feeder cells produce more functional dopamine neurons than mouse feeders.
- Neurons grown on human feeders show higher electrical excitability.
- The study uses standard lab protocols for stem cell differentiation.
- No human patients or genetic variants are involved in this research.
Transcriptomic Analysis Shows Decreased Cortical Expression of NR4A1, NR4A2 and RXRB in Schizophrenia and Provides Evidence for Nuclear Receptor Dysregulation.
Corley SM, Tsai SY, Wilkins MR, Shannon Weickert C
This study finds that NR4A2 mRNA levels are lower in the brain tissue of people with schizophrenia compared to healthy controls. The reduction correlates with antipsychotic drug exposure, suggesting medication may influence these gene levels.
- NR4A2 expression decreases in the prefrontal cortex of individuals with schizophrenia.
- NR4A1 and KLF4 mRNA levels also show significant downregulation in this tissue.
- Lower NR4A2 levels correlate with higher lifetime antipsychotic exposure.
- Females with schizophrenia show decreased RARG and NR4A2 mRNA specifically.
MK-801 (Dizocilpine) Regulates Multiple Steps of Adult Hippocampal Neurogenesis and Alters Psychological Symptoms via Wnt/β-Catenin Signaling in Parkinsonian Rats.
Singh S, Mishra A, Srivastava N, Shukla S
MK-801, an NMDA receptor antagonist, improves motor function and reduces anxiety-like behaviors in a rat model of Parkinson's disease by protecting dopaminergic neurons and enhancing hippocampal neurogenesis. The drug achieves these effects by activating the Wnt/β-catenin signaling pathway, which increases the expression of key transcription factors including Nurr-1 (NR4A2) and Pitx-3.
- MK-801 protects dopaminergic neurons in a rat Parkinson's model.
- Treatment increases NR4A2 (Nurr-1) and Pitx-3 expression in the brain.
- The drug reduces anxiety and depression-like behaviors in affected rats.
- Mechanisms involve Wnt/β-catenin signaling activation and neurogenesis enhancement.
- MK-801 is a known NMDA antagonist with significant side effect profiles.
Orphan nuclear receptor Nurr1 as a potential novel marker for progression in human pancreatic ductal adenocarcinoma.
Ji L, Gong C, Ge L, Song L, Chen F, Jin C, Zhu H, Zhou G
Nurr1 is highly expressed in pancreatic cancer and is linked to more aggressive disease and worse survival. Lowering Nurr1 levels reduces cancer cell growth and spread, suggesting it could be a target for treatment.
- Nurr1 is elevated in pancreatic cancer tissues
- High Nurr1 correlates with advanced cancer stage and poor survival
- Reducing Nurr1 slows cancer cell growth and spread
- Nurr1 may be a target for new pancreatic cancer treatments
Maternal Separation Impairs Cocaine-Induced Behavioural Sensitization in Adolescent Mice.
Gracia-Rubio I, Martinez-Laorden E, Moscoso-Castro M, Milanés MV, Laorden ML, Valverde O
Early-life stress in mice alters dopamine system proteins and reduces sensitivity to cocaine's behavioral effects. These findings describe basic neurobiological mechanisms of stress response with no direct application to NR4A2-related syndromes.
- Maternal separation in mice reduces cocaine-induced behavioral sensitization.
- Stress exposure changes dopamine receptor and transporter protein levels.
- Nurr1 protein levels increase after early-life stress but decrease with cocaine treatment.
- The study uses animal models of addiction, not human genetic conditions.
- No clinical relevance or treatment implications for NR4A2 syndrome are identified.
Glucose regulates the intrinsic inflammatory response of the heart to surgically induced hypothermic ischemic arrest and reperfusion.
Bux AS, Lindsey ML, Vasquez HG, Taegtmeyer H, Harmancey R
This study examines how glucose levels influence heart inflammation during cardiac surgery using rat models. It identifies NR4A2 as one of several genes upregulated in response to surgical stress and reperfusion, highlighting its role in metabolic reprogramming within the heart.
- The study uses isolated rat hearts to mimic human open-heart surgery conditions.
- Surgical stress triggers inflammation and cell proliferation gene expression in the heart.
- NR4A2 is upregulated alongside other master regulators like MYC and NR4A1.
- Glucose levels affect macrophage polarization, a process linked to tissue repair.
- Insulin resistance alters this glucose-dependent inflammatory response in the heart.
Context and Auditory Fear are Differentially Regulated by HDAC3 Activity in the Lateral and Basal Subnuclei of the Amygdala.
Kwapis JL, Alaghband Y, López AJ, White AO, Campbell RR, Dang RT, Rhee D, Tran AV, Carl AE, Matheos DP, Wood MA
Blocking HDAC3 enzyme activity in specific amygdala regions enhances fear memory formation in mice, demonstrating that this epigenetic regulator negatively controls fear learning. This study identifies a mechanism by which chromatin modification influences behavioral responses to fear contexts and tones.
- HDAC3 enzymatic activity suppresses fear memory formation in mouse amygdala subregions.
- Blocking HDAC3 enhances context fear when inhibited in the basal nucleus.
- Blocking HDAC3 enhances tone fear when inhibited in the lateral nucleus.
- The study uses viral vectors to deliver mutant HDAC3 in mice, not humans.
- Findings relate to general fear circuitry, not NR4A2-specific genetic syndromes.
Mapping of a FEB3 homologous febrile seizure locus on mouse chromosome 2 containing candidate genes Scn1a and Scn3a.
Hessel EV, van Lith HA, Wolterink-Donselaar IG, de Wit M, Groot Koerkamp MJ, Holstege FC, Kas MJ, Fernandes C, de Graan PN
This study maps a genetic region in mice associated with febrile seizures and identifies the NR4A2 gene as one of several candidates located within that locus. It does not provide clinical data on human NR4A2-related syndromes or evidence for treatments applicable to your child.
- The research focuses on mouse models of febrile seizures, not human neurodevelopmental disorders.
- NR4A2 is listed as a candidate gene within a broader seizure susceptibility locus in mice.
- No clinical outcomes, patient phenotypes, or therapeutic interventions are reported.
- The findings do not directly inform management or prognosis for NR4A2 syndrome.
In vivo and in silico studies to identify mechanisms associated with Nurr1 modulation following early life exposure to permethrin in rats.
Fedeli D, Montani M, Bordoni L, Galeazzi R, Nasuti C, Correia-Sá L, Domingues VF, Jayant M, Brahmachari V, Massaccesi L, Laudadio E, Gabbianelli R
Early-life exposure to the pesticide permethrin alters Nurr1-related pathways in rat brains, potentially affecting dopamine neuron health. These changes involve increased protein aggregation and enzyme levels that shift as the animals age.
- Permethrin exposure during neonatal development causes long-term accumulation in rat brains.
- Adolescent rats show increased DNA methyltransferases and alpha-synuclein in the striatum.
- Adult rats exhibit enhanced DNMT3b levels and alpha-synuclein aggregation.
- In silico models confirm permethrin binds directly to the Nurr1 protein.
- Nurr1 modulation depends on age-related adaptive responses in the animal model.
Transcriptional modulation of regulatory T cell development by novel regulators NR4As.
Won HY, Hwang ES
This review describes how NR4A proteins, including Nurr1, regulate immune cells called regulatory T cells to control inflammation and potentially treat immune disorders. It does not provide information on the neurological symptoms, development, or treatment of NR4A2-related syndromes in children.
- NR4A proteins help develop regulatory T cells that suppress immune responses.
- The paper focuses on treating inflammation and cancer via immune modulation.
- No data is presented regarding neurodevelopmental phenotypes or motor symptoms.
- This is a review of immunology, not clinical genetics or neurology.
Efficient induction of neural precursor cells from fibroblasts using stromal cell-derived inducing activity.
Lim MS, Kim SM, Lee EH, Park CH
Researchers demonstrate a method to convert rat skin cells into neural precursor cells and then into dopamine-producing neurons using specific genetic factors and stromal cell support. The study confirms that overexpressing Nurr1 (NR4A2) and Foxa2 effectively drives these induced cells toward the dopaminergic lineage in vitro. This provides a technical protocol for generating human-relevant neuronal models but does not involve human patients or clinical treatments.
- The study uses rat fibroblasts, not human cells or patient samples.
- It establishes an efficient lab method to create dopamine neurons from skin cells.
- Nurr1 (NR4A2) is used as a tool to direct cell fate in culture.
- No clinical data, human trials, or therapeutic outcomes are reported.
- The work is purely preclinical methodology for disease modeling.
Protective effects of a herbal extract combination of Bupleurum falcatum, Paeonia suffruticosa, and Angelica dahurica against MPTP-induced neurotoxicity via regulation of nuclear receptor-related 1 protein.
Sim Y, Park G, Eo H, Huh E, Gu PS, Hong SP, Pak YK, Oh MS
A herbal extract combination protects dopaminergic neurons and improves movement in mice with Parkinson's-like symptoms by increasing Nurr1 levels. The treatment prevents dopamine depletion and restores key dopamine-related proteins through the ERK signaling pathway.
- The herbal mix improved movement impairments in a mouse model of Parkinson's disease.
- Treatment prevented the loss of dopaminergic neurons and dopamine depletion in the brain.
- The extract increased Nurr1 expression, which regulates essential dopamine synthesis proteins.
- Mechanisms involve ERK phosphorylation leading to higher levels of TH, VMAT2, and DAT.
Nurr1 expression is modified by inflammation in microglia.
Lallier SW, Graf AE, Waidyarante GR, Rogers LK
Inflammation alters Nurr1 expression in brain cells, with levels rising in whole-brain tissue but falling in isolated microglia. This complex regulation suggests Nurr1 helps control brain inflammation, which may inform future therapeutic strategies for neurological conditions.
- Nurr1 protein increases in whole-brain tissue after inflammation and hyperoxia exposure.
- Nurr1 message decreases in isolated microglia under similar inflammatory conditions.
- The study uses mouse models and cell lines to observe these changes.
- Findings suggest Nurr1 plays a role in regulating brain inflammation.
Opposite effects of acute and chronic amphetamine on Nurr1 and NF-κB p65 in the rat ventral tegmental area.
Arredondo C, González M, Andrés ME, Gysling K
This rat study shows that chronic amphetamine exposure reduces Nurr1 levels in dopamine neurons, while acute exposure increases them. It also demonstrates that the inflammatory factor NF-κB p65 directly suppresses Nurr1's ability to activate genes.
- Chronic amphetamine decreases Nurr1 protein in rat dopamine neurons.
- Acute amphetamine increases Nurr1 and TH protein levels.
- NF-κB p65 represses Nurr1 transcriptional activity in cell assays.
- Nurr1 regulates dopamine production genes like tyrosine hydroxylase.
Integrated analysis of DNA methylation and RNA‑sequencing data in Down syndrome.
Zhang J, Zhou W, Liu Y, Li N
This study identifies NR4A2 as part of a protein interaction network involved in Down syndrome pathogenesis, based on DNA methylation and RNA sequencing data from human samples. It does not provide evidence regarding NR4A2-related syndrome or offer any clinical insights for treatment.
- The research focuses exclusively on Down syndrome mechanisms, not NR4A2-related syndrome.
- NR4A2 appears only as an incidental node in a protein interaction network.
- No clinical data, patient phenotypes, or therapeutic strategies are presented.
- Findings relate to general transcriptional regulation in trisomy 21.
Adenovirus-mediated expression of orphan nuclear receptor NR4A2 targeting hepatic stellate cell attenuates liver fibrosis in rats.
Chen P, Li J, Huo Y, Lu J, Wan L, Yang Q, Huang J, Gan R, Guo C
This study shows that increasing NR4A2 levels reduces liver scarring in rats by stopping specific liver cells from activating. The findings are limited to animal models and do not provide evidence for human treatments or insights into NR4A2-related neurological syndromes.
- NR4A2 overexpression stops liver stellate cells from producing scar tissue in rat models.
- The study uses adenovirus to deliver NR4A2, which significantly improves liver fibrosis in rats.
- Results are preclinical and do not apply to human neurological conditions or NR4A2 syndromes.
BMP2 promotes the differentiation of neural stem cells into dopaminergic neurons in vitro via miR-145-mediated upregulation of Nurr1 expression.
Yan W, Chen ZY, Chen JQ, Chen HM
This study shows that BMP2 stimulates neural stem cells to become dopamine-producing neurons in a lab dish by suppressing miR-145, which allows Nurr1 levels to rise. While Nurr1 is the same protein affected in NR4A2 syndrome, this work only demonstrates a molecular pathway in cell cultures and does not test any treatments in humans or animal models.
- BMP2 increases dopamine neuron formation from stem cells in vitro.
- BMP2 works by reducing miR-145 levels via DNA methylation.
- Lower miR-145 allows Nurr1 expression to increase.
- Nurr1 directly binds to and is regulated by miR-145.
- The study uses only cell cultures, not living animals or humans.
Comparative DNA Methylation Profiling Reveals an Immunoepigenetic Signature of HIV-related Cognitive Impairment.
Corley MJ, Dye C, D'Antoni ML, Byron MM, Yo KL, Lum-Jones A, Nakamoto B, Valcour V, SahBandar I, Shikuma CM, Ndhlovu LC, Maunakea AK
This study found that immune cells in people with HIV-related cognitive impairment have distinct DNA methylation patterns linked to brain function and HIV, including changes in the NR4A2 gene, which may help explain cognitive issues and could lead to better diagnostics or treatments.
- DNA methylation changes in immune cells are linked to HIV-related cognitive problems
- NR4A2 gene methylation changes correlate with cognitive performance
- These patterns may help diagnose or treat cognitive impairment in HIV
- Changes affect genes involved in brain function and HIV activity
- A specific epigenetic signature could guide future therapies
Fructose overfeeding in first-degree relatives of type 2 diabetic patients impacts energy metabolism and mitochondrial functions in skeletal muscle.
Seyssel K, Meugnier E, Lê KA, Durand C, Disse E, Blond E, Pays L, Nataf S, Brozek J, Vidal H, Tappy L, Laville M
Eating too much fructose for just one week changes how muscle cells produce energy in people with a family history of type 2 diabetes, turning down genes needed for burning fat and running mitochondria efficiently. This shift may increase the risk of metabolic problems over time.
- Fructose reduces fat-burning genes in muscle within 7 days
- Mitochondrial energy production is impaired by high fructose
- NR4A2 is linked to gene changes in response to fructose
- Changes happen even without high lactate or uric acid
- Family history of diabetes makes muscle more sensitive to fructose