The Cavβ4 subunit of Cav1.2 channels antagonizes isoproterenol-induced hypertrophy in rat cardiac muscle cells by down-regulating miR-183-5p.
Carrillo ED, Galicia E, García MC, Sánchez JA
The Cavβ4 protein protects heart cells from stress-induced enlargement by suppressing a microRNA that normally reduces NR4A2 levels. This mechanism increases NR4A2 abundance, which helps counteract harmful growth signals in cardiac tissue.
- Cavβ4 prevents heart cell enlargement caused by stress hormones like isoproterenol.
- Cavβ4 lowers levels of miR-183-5p, a microRNA that targets NR4A2.
- Reduced miR-183-5p leads to higher NR4A2 protein levels in heart cells.
- NR4A2 and FOXO1 proteins help stop excessive heart muscle growth.
Mesenchymal stem cell-derived exosome NR4A2 inhibits fracture healing in aged rat by blocking NELL2-mediated osteogenic differentiation.
Ye P, Bai R, Ding X, Chen H, Bai Z, Wu L
Exosomes from aged bone cells carry NR4A2, which blocks the NELL2 gene and prevents new bone formation, leading to slower fracture healing. This mechanism shows how NR4A2 interferes with the signaling pathways required for osteogenic differentiation.
- NR4A2 in exosomes suppresses NELL2 gene transcription in recipient cells.
- NELL2 is essential for activating FAK/AKT signaling during bone repair.
- Blocking this pathway impairs osteogenesis and delays fracture healing in aged models.
Transcriptomic profiling of subpopulations of mouse embryonic subplate neurons.
Achiwa H, Hara Y, Kawaji H, Oshima M, Kaneko N, Morioka A, Hoerder-Suabedissen A, Molnár Z, Ohtaka-Maruyama C
This study maps the genetic activity of early-developing brain neurons in mice, confirming that the NR4A2 gene is a specific marker for these cells. It identifies distinct subgroups of these neurons and tracks how their gene expression changes rapidly during embryonic development. These findings help define the molecular identity of transient neural populations involved in early brain circuit formation.
- NR4A2 serves as a key genetic marker for specific subplate neuron subtypes in the developing mouse cortex.
- Researchers identified ten distinct clusters of these neurons using single-cell sequencing and spatial mapping.
- Gene expression profiles shift significantly between embryonic days 15 and 17, indicating rapid developmental changes.
- The study provides a molecular framework for classifying early-born neurons based on their unique genetic signatures.
Vidofludimus calcium for the treatment of multiple sclerosis: development rationale, mechanism of action, and early trial data.
Ondrus M, Fox RJ, Peelen E, Fonseca J, Sciacca V, Sanchez-Gomez I, Arend J, Herrmann A, Samcova M, Gege C, Havrylova L, Kohlhof H, Tardio J, Vitt D, Muehler A
Vidofludimus calcium is an oral medication that activates Nurr1, a protein closely related to NR4A2, to reduce inflammation and neurodegeneration in the central nervous system. Early clinical trials show it significantly reduces brain lesions in relapsing-remitting multiple sclerosis and shows promise for slowing disability progression in progressive forms of the disease.
- Vidofludimus calcium directly activates Nurr1, a protein structurally similar to NR4A2.
- It targets both inflammatory processes and neurodegeneration in the central nervous system.
- Phase 2 trials show reduced brain lesions in relapsing-remitting multiple sclerosis patients.
- Preliminary data suggest potential benefits for slowing disability progression in progressive MS.
- The drug is generally well-tolerated with ongoing phase 3 trials underway.
Correction: Nurr1 deficiency orchestrates a coupled liver-gut pathological axis revealed by multi-omics and deep-learning histopathology.
Faisal S, Ullah I, Kambey PA, Malik A, Ejaz MA, Shah SA, Li YX
Nurr1 deficiency disrupts the communication between the liver and gut, creating a pathological cycle that affects both organs. This study identifies specific molecular and tissue changes driven by this deficiency using advanced imaging and multi-omics analysis.
- Nurr1 loss triggers a coupled disease axis linking liver and gut dysfunction.
- Multi-omics and deep-learning histopathology reveal the underlying mechanisms of this interaction.
- The findings highlight systemic effects of Nurr1 deficiency beyond just the brain.
Xifeng Zhichou decoction mitigates tic disorder on juvenile rats by regulating neuroinflammation and neurotransmitter homeostasis: dual modulation of Nr4a2 and gut microbiota.
Wu R, Peng J, Zhang M, He Q, Luo J, Long Q, Xiao X, Li S, Wan L
A Chinese herbal formula reduces tic-like behaviors in juvenile rats by calming brain inflammation and balancing neurotransmitters. This effect relies on regulating the NR4A2 gene and restoring healthy gut bacteria levels.
- The herbal decoction significantly reduced tics and abnormal movements in rat models.
- Treatment lowered neuroinflammation and restored balance of key brain chemicals.
- NR4A2 gene regulation is central to the drug's protective effects on neurons.
- Gut bacteria changes correlate with improved metabolic and neurological outcomes.
1,25-Dihydroxyvitamin D Induces a NURR1-Tyrosine Hydroxylase Transcriptional Axis Modulated by Rexinoid/RXR Signaling in Parkinson's Disease-Relevant Human Neural Cell Models.
Sausedo MA, Mallick S, Sabir ZL, Livingston S, Nguyen QT, Doost ME, Wagner CE, Marshall PA, Haussler CA, Haussler MR, Jurutka PW
Vitamin D directly increases NURR1 levels, which then boosts tyrosine hydroxylase, a key enzyme for dopamine production in human neural cells. Retinoid drugs enhance this effect further by stimulating both NURR1 and tyrosine hydroxylase expression.
- Vitamin D significantly raises NURR1 and tyrosine hydroxylase mRNA in human neural cells.
- NURR1 acts as a bridge, linking Vitamin D signaling to dopamine-related gene activation.
- Retinoid drugs amplify this pathway by independently increasing NURR1 and tyrosine hydroxylase levels.
- This mechanism offers a potential therapeutic target for restoring dopaminergic function in NR4A2-related conditions.
Molecular links between reelin downregulation, topoisomerase IIβ alterations, and proteins involved in Alzheimer pathology in human SH-SY5Y neuroblastoma cell line.
Terzioglu-Usak S, Zaim M, Beker M, Isik S, Elibol B
Downregulating reelin in human nerve cells reduces levels of proteins involved in brain development and increases proteins linked to Alzheimer's disease, suggesting a potential mechanism by which reelin deficiency could contribute to neurodegeneration.
- Reelin downregulation reduces topo IIβ, Psen1, and BACE1 expression
- Reelin downregulation increases tau and APP expression, linked to Alzheimer's pathology
- Reelin silencing decreases Nurr1 protein, a factor important for dopamine neuron health
- The study uses human neuroblastoma cells, relevant to human brain biology
- Post-transcriptional regulation may explain unchanged full-length reelin protein levels
Genetic and epigenetic complexity of Parkinson's disease: From dopamine pathways to estrogen interplay.
Deena K, Nathish L, Fenwick EA, Karthi M, Sivasamy R
This review explains how genetic and epigenetic factors, including changes to the NR4A2 gene, contribute to Parkinson's disease by affecting dopamine production and cell survival. It highlights that these biological mechanisms interact with environmental factors and sex hormones, offering potential targets for future therapies.
- NR4A2 epigenetic changes influence Parkinson's disease susceptibility and progression.
- Genetic mutations disrupt cellular cleanup processes, leading to neuron death.
- Estrogen may protect dopamine neurons, explaining differences between men and women.
- Research links specific genes to inflammation and mitochondrial stress in the brain.
Nurr1 deficiency orchestrates a coupled liver-gut pathological axis revealed by multi-omics and deep-learning histopathology.
Faisal S, Ullah I, Kambey PA, Malik A, Ejaz MA, Shah SA, Li YX
Nurr1 deficiency in mice causes a severe, lethal disorder affecting both the liver and gut, with clear changes in gene activity, inflammation, and gut bacteria that can be detected using AI on tissue samples. Human liver disease data show similar gene changes, suggesting the findings may apply to people with NR4A2-related conditions.
- Nurr1 deficiency causes liver and gut disease in mice
- AI can detect disease patterns in tissue images with high accuracy
- Gene changes in mice match those seen in human liver disease
- The study links Nurr1 to liver-gut communication
- Multi-omics and AI provide a new way to classify disease
Development of a Brain-Penetrant Nurr1 Agonist Tool.
Vietor J, Stiller T, Gege C, Saeb W, López-García Ú, Kohlhof H, Vitt D, Merk D
Researchers developed a new drug-like molecule that activates the Nurr1 protein in the brain, which may help protect neurons and treat neurodegenerative diseases.
- A new brain-penetrant Nurr1 agonist was created to study its effects in the central nervous system.
- The molecule was designed to cross the blood-brain barrier and activate Nurr1 effectively.
- This compound could be used to test potential therapies for diseases linked to Nurr1 dysfunction.
Comparative analysis of gene expression in mammalian claustrum subdivisions.
Fang C, Li M, Li L, Liang F, Huang J, Lu L, Lu Z, Wang H, Naumann RK
This study compares gene expression patterns in the claustrum across several mammalian species to identify evolutionarily conserved subdivisions, including the gene Nurr1, which is relevant to NR4A2-related syndromes.
- The study compares claustrum gene expression across mammals to find conserved brain regions.
- Genes like Nurr1, Oprk1, Lxn, and Cdh8 are used to define claustrum subregions.
- The research helps clarify how the claustrum is organized in primates and other mammals.
- Nurr1 is a key gene studied, which is linked to NR4A2 and related neurodevelopmental conditions.
Isoginkgetin stabilizes atherosclerotic plaques by targeting NR4A2 to modulate the PPAR signaling pathway and reprogram ceramide metabolism, thereby inhibiting vascular smooth muscle cell phenotypic transformation.
Wei D, Zhong Z, Li H, Qi J, Liu Y, Cao H, Ma Y, Li Z, Yang G, Jiang Y, Zhang Z
Isoginkgetin stabilizes atherosclerotic plaques by boosting NR4A2, which activates PPAR signaling and reduces harmful ceramide buildup, preventing vascular smooth muscle cells from changing into unstable, inflammatory forms.
- Isoginkgetin reduces plaque instability in atherosclerosis.
- It works by increasing NR4A2, which activates PPAR signaling.
- It lowers harmful ceramides by boosting their breakdown.
- It prevents vascular smooth muscle cells from becoming inflammatory.
- These effects suggest potential for treating atherosclerosis.
Genetic Variants and Clinical Characteristics of Young-Onset Parkinson's Disease in the Hakka Population of Western Fujian.
Pan LY, Guo F, Zheng C, Hu XH, Chen YG, Lin RR
This study found that genetic variants in genes like ATXN2, PRKN, VPS13C, and SNCA are linked to young-onset Parkinson's disease in the Hakka population of western Fujian, with some variants classified as likely pathogenic and others as uncertain significance. Many patients also carried risk variants in susceptibility genes, including NR4A2, suggesting a genetic predisposition even without clear pathogenic mutations.
- ATXN2 repeat expansions were found in two patients
- NR4A2 variants were among risk factors identified
- Several variants in PRKN and VPS13C were uncertain significance
- LRRK2 variants were common in this cohort
- Genetic testing improves diagnosis accuracy
Early-Life Rotenone Exposure Enhances Nigrostriatal Vulnerability and Parkinsonian Neurodegeneration in Aging Rats.
Gómez-Chavarín M, Morales-Gómez R, Padilla-Mendoza JR, Padilla P, Torres-Saldaña I, Vergara-Aragón P, Silva-Lucero MD, Galindo-Solano N
Exposure to the pesticide rotenone during early development causes lasting brain changes in rats, making them more vulnerable to Parkinson's-like neurodegeneration later in life, even after the toxin is gone.
- Early-life rotenone exposure leads to worse motor and brain function in aging rats.
- It causes greater loss of dopamine neurons and reduced Nurr1 expression in the brain.
- The damage includes brain cell aging, structural changes in neurons, and buildup of toxic proteins.
- Even low levels of rotenone during development can cause long-term brain changes.
- This suggests early environmental toxins may increase Parkinson's risk later in life.
Differential Expression Profiles of Orphan Nuclear Receptors (NR4A) and N-myc Downstream-Regulated Gene Family (NDRG) in Patients with Inflammatory Bowel Disease.
Fonseca-Camarillo G, Furuzawa-Carballeda J, Aguilar-León D, Barreto-Zuñiga R, Martínez-Benítez B, Yamamoto-Furusho JK
This study found that levels of NDRG and NR4A proteins differ between people with ulcerative colitis and Crohn's disease, and that these differences may affect how inflammation is controlled, suggesting potential new treatment targets for inflammatory bowel disease.
- NDRG and NR4A proteins are altered in the colon of people with ulcerative colitis.
- NR4A2 levels are lower in active disease and linked to higher inflammation markers.
- These changes may affect NF-κB signaling, a key driver of inflammation.
- The differences between ulcerative colitis and Crohn's disease suggest distinct disease mechanisms.
A53T α-Synuclein Expression is Associated with Altered Dopaminergic-Like Differentiation and Reduced DNA Topoisomerase IIβ Levels in an In Vitro Model of Parkinson's Disease.
Selim A, Avşar T, Neğiş Y, Işık S
Mutant A53T alpha-synuclein disrupts the development of dopamine-producing neurons in a lab model, reducing levels of key protective genes like NR4A2 and DNA topoisomerase IIβ, which may contribute to early brain changes seen in Parkinson’s disease.
- A53T alpha-synuclein impairs dopamine neuron development
- NR4A2 and topoisomerase IIβ levels drop in affected cells
- Reduced NR4A2 may weaken protective brain pathways
- Topo IIβ loss may link to early neurodevelopmental issues
- These changes mirror early Parkinson’s disease features
Identifying novel gene dysregulation associated with opioid overdose death: a meta-analysis of differential gene expression in human prefrontal cortex.
Carter JK, Quach BC, Willis C, Minto MS, Hancock DB, Montalvo-Ortiz J, Corradin O, Logan RW, Walss-Bass C, Maher BS, PGC-SUD Epigenetics Working Group, Johnson EO
Opioid overdose death is linked to widespread changes in gene activity in the brain's prefrontal cortex, including newly identified genes like NR4A2, which is involved in brain development and function. These changes affect key pathways related to neuron flexibility and signaling, particularly through the orexin and tyrosine kinase systems.
- NR4A2 is newly linked to opioid overdose in human brain tissue
- Gene changes affect brain plasticity and signaling pathways
- Findings may help explain neurological impacts of opioid overdose
- No strong genetic causes found for gene expression differences
- MEK/ERK/MAPK and orexin pathways are central to the changes
Multi-Target Antioxidant Potential of Tricin Against Parkinson's Disease- Linked Oxidative Stress.
Giri S, Chandra P
Tricin is a natural compound that shows strong potential to protect brain cells in Parkinson's disease by targeting multiple pathways involved in oxidative stress, including those linked to NURR1 and other key proteins. It effectively binds to and may regulate several disease-related targets, reducing harmful free radicals in lab tests.
- Tricin targets NURR1 and other Parkinson's-related proteins
- It reduces oxidative stress in lab tests
- Tricin may protect dopamine neurons by multiple mechanisms
- Binding strength suggests strong biological activity
- Natural compound with multitarget antioxidant effects
Therapeutic Effects of Cinnamaldehyde on Neuromuscular Function in Rat Parkinson's Model Induced by Rotenone.
Buyukakilli B, Balli E, Arslan M, Demirbag HO
Cinnamaldehyde improved motor function and protected brain cells in a rat model of Parkinson's disease by reducing oxidative stress and boosting dopamine levels. The treatment helped preserve nerve cells in brain regions critical for movement.
- Cinnamaldehyde reduced brain cell damage in Parkinson's rats
- It improved muscle function and nerve signaling
- It lowered oxidative stress and increased dopamine
- Effects seen in both brain and muscle tissues
- Suggests potential for protecting neurons in movement disorders
Towards a unified molecular mechanism for ligand-dependent activation of NR4A-RXR heterodimers.
Yu X, He Y, Kamenecka TM, Kojetin DJ
Some NR4A nuclear receptors team up with RXR to control gene activity, and certain drugs that activate RXR can turn on these pairs in unexpected ways. The study shows that for one such pair (Nur77-RXRγ), both classic drug action and a newly discovered mechanism involving the breakup of the protein pair contribute to activation, but only specific drugs reveal the full picture.
- NR4A-RXR pairs can be activated by RXR drugs through two mechanisms
- One mechanism involves the proteins splitting apart when a drug binds
- Only certain selective drugs reveal the split-protein mechanism
- This may apply to other NR4A-RXR pairs linked to brain and immune diseases
- Better drug testing requires diverse ligand sets to uncover true activation paths
Gestational and Lactational Atrazine Exposure Potentially Mediates Behavioral and Dopaminergic Alterations in Rat Offspring: Insights into Nurr1-Related ceRNA Regulation.
Ma Y, Sun T, Pan M, Zheng Z, Wei J, Yuan X, Wan J, Zhou Y, Sun Y
Exposure to the pesticide atrazine during pregnancy and breastfeeding harms brain development in rat offspring, disrupting dopamine systems and causing behavioral issues. The study identifies a specific molecular pathway involving Elavl4, miR-301a-5p, and Nurr1 that may explain how atrazine reduces Nurr1, a key protein linked to NR4A2-related disorders. Boosting Elavl4 reversed some of the damage in lab models, suggesting a potential therapeutic target.
- Atrazine exposure harms dopamine systems in offspring
- Nurr1 levels drop, linked to NR4A2-related syndromes
- Elavl4/miR-301a-5p/Nurr1 pathway is disrupted
- Boosting Elavl4 reduced Nurr1 loss in lab tests
- Findings suggest new treatment strategies
NR4A2-driven metabolic reprogramming in the heart: from adaptive response to maladaptive remodeling.
Stujanna EN, Yoshioka J
This study shows that NR4A2 controls metabolic changes in heart cells, helping the heart adapt under stress but contributing to heart damage when these changes become excessive. The findings suggest NR4A2 could be a target for treating heart conditions.
- NR4A2 regulates energy use in heart cells
- It helps the heart adapt to stress initially
- Overactive NR4A2 leads to heart damage
- Targeting NR4A2 may improve heart health
Dysregulation of astrocytic DNAJC6 contributes to sporadic Parkinson's disease pathogenesis.
Darsono WHW, Hwang Y, Valencia E, Gunawan LT, Hyeon SJ, Ryu H, Stein TD, Chang MY, Wulansari N, Lee SH
DNAJC6, a protein linked to Parkinson's disease, is underactive in both neurons and astrocytes in sporadic Parkinson's, contributing to brain cell damage and inflammation. Restoring DNAJC6 in brain cells improved symptoms and pathology in a mouse model, suggesting a potential treatment strategy.
- DNAJC6 is reduced in Parkinson's patients' brains
- Low DNAJC6 harms astrocytes and worsens brain cell damage
- Fixing DNAJC6 in mice improved Parkinson's symptoms
- Both neurons and astrocytes are affected by DNAJC6 loss
- Targeting DNAJC6 may slow or stop disease progression
Downregulated transcription in chromosomal domains of midbrain dopamine neurons linked to schizophrenia.
Singh S, Iskhakova M, Lambert TY, Valada A, Shokrian N, Evans V, Bendl J, Auluck PK, Marenco S, Wang M, Zhang B, Hoffman GE, Girdhar K, Roussos P, Akbarian S
In people with schizophrenia, the genes in midbrain dopamine neurons are less active, especially those in tightly organized chromosomal regions that control brain cell connections. This reduced activity affects key genes linked to brain development and function, including NR4A2 (NURR1), and may explain some of the disorder’s core symptoms.
- Schizophrenia reduces gene activity in dopamine neurons
- Affected genes are in organized chromosomal regions
- NR4A2 (NURR1) and other key genes are downregulated
- This disruption impacts brain connectivity and development
- Changes are specific to dopamine neurons, not general
Cytokine armored CAR T cells for cancer immunotherapy.
Sek K, Yap KM, Hong WX, Darcy PK
This study develops enhanced CAR T cells that produce specific cytokines to boost cancer immunotherapy, using engineered receptors or tumor-responsive promoters to improve effectiveness and safety. The approach aims to make CAR T cells more durable and better at recruiting the body’s own immune system to fight tumors.
- CAR T cells engineered to produce IL-15 or IL-9 for better survival and function
- Tumor-targeted cytokine release via IL-36γ or IL-12 boosts immune response
- NR4A2 promoter used to limit cytokine release to tumor sites only
- Reduces harmful side effects by avoiding systemic cytokine exposure
- Improves CAR T cell persistence and anti-tumor activity in models
Valsartan promotes neuroprotection in Parkinson's disease via epigenetic modulation and activation of the ASCL1/Nurr1 pathway.
Gowied HG, El-Mezayen NS, Afify EA
Valsartan improved motor function and protected dopamine-producing neurons in a rat model of Parkinson's disease by boosting the Nurr1 pathway and altering gene regulation through epigenetic changes. These effects suggest valsartan may slow or reverse neurodegeneration, not just ease symptoms.
- Valsartan improved movement and neuron health in Parkinson's rats
- It boosted Nurr1 and related genes linked to dopamine neuron survival
- Valsartan changed gene activity via epigenetic mechanisms
- Blocking Nurr1 reduced but did not eliminate valsartan’s benefits
- Results suggest valsartan could be a disease-modifying treatment
Aberrant immune regulation and enrichment of stem-like CD8+ T cells in the pancreatic lymph node during type 1 diabetes development.
Peters LD, Seay HR, Smith J, Posgai AL, Berkowitz R, Wasserfall CH, Atkinson MA, Bacher R, Brusko MA, Brusko TM
In type 1 diabetes, CD8+ T cells in the pancreatic lymph nodes show abnormal immune behavior, including a buildup of stem-like cells that are prone to becoming destructive, and reduced levels of NR4A2, a gene linked to immune exhaustion. These cells are more active and less regulated, with signs of inflammation and potential for attacking insulin-producing cells. The findings suggest that boosting NR4A2 or targeting related pathways could help restore immune balance.
- NR4A2 levels are reduced in CD8+ T cells in T1D
- Stem-like CD8+ T cells are enriched in pancreatic lymph nodes
- These cells show signs of being overactive and not properly exhausted
- IL-15 signaling may drive this abnormal immune state
- T cells in the pancreas show stronger attack-ready traits than in lymph nodes
miR-19a-3p and miR-19b-3p repress Nurr1 and Nur77 to promote microglial inflammation after spinal cord injury.
Sahebdel F, Zia A, Quintá HR, Stucky A, Morse LR, Olson JK, Battaglino RA
miR-19a-3p and miR-19b-3p reduce levels of the Nurr1 and Nur77 proteins in microglia, worsening inflammation and neuropathic pain after spinal cord injury. Blocking these miRNAs may reduce inflammation and pain, offering a potential treatment strategy.
- miR-19a/b reduce Nurr1 and Nur77 in microglia
- Higher miR-19a/b levels link to pain after spinal injury
- These miRNAs drive harmful brain inflammation
- Blocking them may reduce pain and inflammation
- Nurr1 and Nur77 are key protective proteins
Janus kinase 2 regulates Nurr1 protein stability in dopaminergic neurons of the aging midbrain.
Jang Y, Kim YH, Jeon J, Cha Y, Lopes C, Jung JH, Oh E, Park Y, Ko C, Hyeon B, Leblanc P, Kim KS
JAK2 stabilizes the Nurr1 protein in dopamine-producing brain cells, helping protect them from aging-related damage. This stabilization happens without changing Nurr1's gene activity and may explain how some neurons survive longer in older brains.
- JAK2 boosts Nurr1 protein stability in aging brain cells
- JAK2 protects dopamine neurons from oxidative stress
- This effect happens without altering Nurr1 gene expression
- The mechanism is independent of common signaling pathways
- Targeting JAK2 could help maintain Nurr1 in NR4A2-related conditions