Targeting Nurr1 With Amodiaquine Preserves Dendritic Spines and Cognitive Function After Chronic Cerebral Hypoperfusion.
Zeng X, Xie X, Zhang J, Jia J, Huang L
Amodiaquine, a drug that activates the Nurr1 protein, improved memory and protected brain connections in rats with reduced brain blood flow, a condition linked to cognitive decline. The treatment preserved the structure of neurons and their tiny connections (dendritic spines) in the memory-related hippocampus.
- Amodiaquine boosts Nurr1 activity in the brain
- It protects neuron connections after poor blood flow
- Memory and learning improved in treated rats
- Benefits lasted up to 6 weeks after treatment
- Nurr1 activation may help prevent cognitive decline
Nurr1 Orchestrates Claustrum Development and Functionality.
Yan K, Newman AG, Lange P, Müller S, Foddis M, Koch SP, Böhm-Sturm P, Mantwill M, Finke C, Deng P, Long M, Schmitz D, Tarabykin V
Nurr1 is essential for the proper development and function of the claustrum, a brain region involved in coordinating cognition and consciousness. Without Nurr1, claustral cells misplace themselves and adopt incorrect genetic programs, disrupting brain connectivity and behavior.
- Nurr1 controls claustrum development and cell identity
- Nurr1 loss causes cells to migrate incorrectly into the insular cortex
- Claustrum connectivity and behavior are disrupted without Nurr1
- Nurr1 works by suppressing Gαs-PKA signaling
- Single-cell data confirms abnormal gene programs in mutant cells
Prolonged Loss of Oxidative Phosphorylation and Mitochondrial Mass Characterize CD66b+ Leukocytes from Patients with Sepsis.
Rodhouse C, Barrios EL, Zeumer-Spataro L, Balzano-Nogueira L, Wu R, Yu X, Tian G, Brant JO, Gauthier ML, Chen J, Hernandez-Rios M, Polcz VE, Wiggins W, Charles AM, Dirain ML, Ungaro R, Rincon J, Loftus T, Xiao F, Cai G, Moldawer LL, Maile R, Kladde MP, Efron PA, Mathews CE
People who have had sepsis continue to have immune cells with damaged mitochondria and reduced energy production for at least six months after their illness, even when they appear recovered. This long-term metabolic defect is linked to worse health outcomes and may be caused by the silencing of key genes, including NR4A2, that control mitochondrial health.
- Mitochondria in immune cells remain damaged for 6 months after sepsis
- NR4A2 and other genes controlling mitochondria are turned down
- This gene silencing may explain ongoing immune problems
- Reduced mitochondrial function predicts worse recovery
- Targeting metabolism could help restore immune health
The multiple mechanisms of NR4A2 in neurological disorders and advances in targeted therapy research.
Duan K, Yang C, Gao D, Li M, Chen M, Li H, Zeng W, Zhao L, Zhu M
NR4A2 is a key gene involved in brain development and function, and its dysfunction is linked to multiple neurological conditions including Parkinson's, Alzheimer's, autism, and stroke. Research shows that boosting NR4A2 activity may help treat these disorders through drugs, gene therapy, or cell replacement strategies.
- NR4A2 is critical for brain development and function
- Mutations in NR4A2 are linked to autism and other neurological disorders
- NR4A2-targeted therapies are being developed for treatment
- Agonists and gene therapy show promise in preclinical studies
- NR4A2 plays roles in both brain development and neurodegeneration
Essential function of Nr4a2 in subicular development and social novelty.
Liu XY, Tao YC, Zhang Q, Liu WT, Zhao L, Hu ZB, Zhou BY, Li ZX, Qi CC, Zhang L, Chen JY, Song NN, Ding YQ
Nr4a2 is critical for the proper development and function of neurons in the subiculum, a key part of the hippocampus involved in memory and social behavior. Without Nr4a2, these neurons lose their identity, fail to connect correctly with other brain regions, and mice show impaired social novelty recognition.
- Nr4a2 maintains subiculum neuron identity
- Loss of Nr4a2 disrupts brain circuit connections
- Nr4a2 deficiency causes social novelty deficits
- Nr4a2 directly controls key gene expression
- Findings link Nr4a2 to hippocampal-related disorders
Dual Nurr1/RXR agonism of valerenic acid and synthetic mimetics enables dimer-selective Nurr1 modulation.
Scholz K, López-García Ú, Busch R, Marschner JA, Merk D
Valerenic acid and similar compounds can selectively activate Nurr1 when it pairs with RXR, which may help treat NR4A2-related conditions by targeting specific gene pathways without disrupting other Nurr1 functions.
- Dual Nurr1/RXR activators target only the Nurr1-RXR heterodimer
- This approach preserves beneficial gene activation while blocking harmful homodimer activity
- In neurons, only a subset of Nurr1 genes were turned on, showing selectivity
- Valerenic acid and synthetic mimetics show promise for precise Nurr1 modulation
- This strategy could lead to safer, more effective treatments for NR4A2-related disorders
Monogenic defects in Russian children with autism spectrum disorders.
Suspitsin EN, Malysheva KS, Laptiev SA, Sharonova OS, Abuzova AS, Kuznitsyna AA, Melashenko TV, Efremova OV, Korzun PR, Binnatova JO, Gorgul YA, Syomina MV, Imyanitov EN
This study found that about 11% of Russian children with autism spectrum disorder have a known monogenic cause, including rare variants in genes like NR4A2, which are linked to neurodevelopmental conditions. Some children had variants in genes associated with syndromes that include autism, intellectual disability, and developmental delay.
- 11% of children had pathogenic variants in known ASD genes
- NR4A2 was among genes with rare variants found in multiple patients
- Variants in NR4A2 and other genes may explain autism and developmental delays
- Exome sequencing effectively identified genetic causes in this cohort
- Findings support genetic testing for children with autism and ID
Single-cell multi-omic landscape reveals anatomical-specific immune features in adult and pediatric sepsis.
Ye Q, Lai X, Liu Y, Zhang Z, Fu Y, Luo J, Liu C, Duan J, Ding H, Liu Y, Ao Z, Tao Y, Ai S, Huang W, Jiang L, Liu Y, Xu F, Cao J
NR4A2 is a key gene in immune cells that worsens sepsis outcomes when overactive, especially in abdominal, lung, and skin infections. Blocking NR4A2 may improve survival, suggesting a potential treatment target for severe infections.
- NR4A2+ T cells are linked to worse sepsis outcomes
- Reducing NR4A2 activity improves survival in sepsis
- NR4A2 overexpression harms recovery
- Immune responses vary by infection site and age
- NR4A2 is a promising target for sepsis therapy
Midnight darkness and evening melatonin pre-treatment reverse night-light-induced neurobehavioural disruptions in a diurnal corvid.
Buniyaadi A, Prabhat A, Bhardwaj SK, Kumar V
Exposure to dim light at night disrupts sleep, mood, and brain function in birds, but giving melatonin in the evening completely reverses these effects. The study shows melatonin protects brain genes linked to learning and mental health, suggesting it could help children with NR4A2-related disorders who have sleep and cognitive issues.
- Dim light at night harms sleep and brain function
- Melatonin given before night light fully reversed brain and behavior problems
- NR4A2 gene expression was disrupted by light at night
- Melatonin protected brain genes involved in learning and mood
- Evening melatonin may help children with NR4A2-related conditions
Similarities of neocortical deep layer Oprk1-positive neurons and claustrum neurons in connectivity and activity.
Fang C, Zhou H, Brecht M, Wang H, Naumann RK
Neurons in the deep layers of the cortex that resemble claustrum neurons in gene expression are connected to sensory areas of the brain and respond similarly to environmental changes and anesthesia, suggesting they form a parallel circuit to the claustrum that may influence brain coordination and behavior.
- Some deep cortical neurons share genes with claustrum neurons
- These neurons connect mainly to sensory brain regions
- They activate in new environments and during anesthesia
- They likely form a parallel circuit to the claustrum
- May influence brain states like sleep and seizures
The Nuclear Receptor Nurr1 Modulates the Expression and Activity of PPARγ in Human Pro-Inflammatory Macrophages.
Santana-Cisneros E, Solís-Barbosa MA, Segovia-Gamboa NC, Meraz-Ríos MA, González-Domínguez E, Hernández-Rivas R, Marrero-Rodríguez D, Sanchez-Torres C
Nurr1 boosts the activity of PPARγ in human immune cells called macrophages by stabilizing the PPARγ protein and reducing a modification that turns it off. This suggests Nurr1 helps control inflammation and may influence other pathways linked to PPARγ, such as metabolism and immune responses.
- Nurr1 increases PPARγ activity in human macrophages
- Nurr1 stabilizes PPARγ protein and reduces its inactivation
- Activating Nurr1 reduces inflammation in pro-inflammatory macrophages
- Nurr1 and PPARγ work together to regulate immune and metabolic genes
- This interaction may offer new treatment strategies for inflammatory conditions
Molecular Characterization of Hypothalamic-Pituitary-Ovarian Axis Regulation in the Manchurian Zokor (Myospalax psilurus) During Seasonal Estrus.
Nai R, Li X, Shan D, Bao S, Wang F, Lin Y, Zhang Y, Hu B, Xie Y, Man D
This study identifies key genes and pathways involved in seasonal breeding in a subterranean rodent, including NR4A2 in the pituitary, which may help explain how reproductive cycles are regulated in the absence of light. The findings highlight the neuroactive ligand-receptor interaction pathway as central to reproductive control across the hypothalamus, pituitary, and ovary.
- NR4A2 is a key gene in the pituitary during seasonal breeding
- The neuroactive ligand-receptor pathway is central to reproductive regulation
- Findings reveal how reproduction is controlled in perpetual darkness
- Gene expression changes differ across hypothalamus, pituitary, and ovary
- Results may inform understanding of human reproductive disorders
Genetic and Environmental Risk Factors for Autism Spectrum Disorder in Saudi Arabia: A Systematic Review.
Hamed NF, Alqahtani AM, Alshaibani F, Elsharif SM, Alamri SAS, Serhan A
Children with NR4A2-related syndrome may have developmental delays, movement issues, and autism-like symptoms due to mutations in the NR4A2 gene, which plays a key role in brain development and function. The condition is often linked to consanguinity and may be influenced by environmental factors like prenatal exposure to phthalates and vitamin D deficiency.
- NR4A2 loss-of-function variants are linked to autism and neurodevelopmental issues
- Consanguinity increases the risk of recessive NR4A2 mutations
- Prenatal phthalate exposure and vitamin D deficiency may worsen outcomes
- NR4A2 is involved in brain development and dopamine regulation
- Environmental and genetic factors interact in complex ways
Early α-Synuclein Pathology Induces Neuroinflammation and Decreases Topoisomerase IIβ Expression in A53T Mice.
Yeman-Kıyak B, Yurdakul T, Selim A, Elibol B, Avşar T, Neğiş Y, Sürmen MG, Şeyhali-Abutayeh R, Akbayır R, Eren MC, Öz P, Çevreli B, Işık S
Early-stage Parkinson's disease in mice with a mutant α-synuclein gene shows brain inflammation and a drop in two important proteins, Nurr1 and Topoisomerase IIβ, which may help explain how the disease starts. These changes appear before major symptoms, suggesting they could be early warning signs or targets for treatment.
- Early α-synuclein buildup triggers brain inflammation in mice
- Nurr1 and Topoisomerase IIβ drop early in disease
- Low Nurr1 and inflammation may drive early Parkinson’s changes
- Topoisomerase IIβ could be a new treatment target
Tanshinone IIA ameliorates pancreatic injury in type 2 diabetic mice by modulating inflammation and endoplasmic reticulum stress via the IL-6/JAK2/STAT3 pathway.
Li Y, Wang D, Liu Y, Liu C, Chen M, Li J, Wu Z, Wu N
Tanshinone IIA reduces pancreatic damage in type 2 diabetes mice by calming inflammation and easing cellular stress through the IL-6/JAK2/STAT3 pathway, with NR4A2 identified as a key target.
- TanIIA protects pancreatic beta cells in diabetic mice
- NR4A2 is a core target with strong binding to TanIIA
- TanIIA reduces inflammation and endoplasmic reticulum stress
- The IL-6/JAK2/STAT3 pathway is central to TanIIA's effect
- TanIIA improves insulin function and reduces cell death
Regulation of NR4A2 Gene Expression and Its Importance in Neurodegenerative and Psychiatric Diseases.
Ruiz-Sánchez E, Rojas C, Yescas Gómez P, Martínez-Rodríguez N, Ruiz-Chow ÁA, Nava-Ruiz C, Ibáñéz-Cervantes G, Arciniega-Martínez IM, Reséndiz-Albor AA, Rojas P
NR4A2 is a critical gene for brain health, and low levels of its activity are linked to Parkinson's, Alzheimer's, schizophrenia, and other brain disorders. The gene is controlled by epigenetic mechanisms like DNA methylation and microRNAs, which may serve as targets for future treatments.
- NR4A2 supports brain development and function
- Low NR4A2 levels are tied to Parkinson's and schizophrenia
- Epigenetic changes regulate NR4A2 expression
- These mechanisms could become treatment targets
- NR4A2 may help detect or treat brain disorders
Combined molecular characterization and dopa-responsive treatment in two patients with NR4A2-associated intellectual developmental disorder.
Liang N, Li T, Deng Y
Two children with NR4A2 gene mutations showed significant improvement in speech and movement after starting levodopa treatment, confirming that dopa-responsive therapy can help some children with this rare genetic condition. The study shows that genetic testing combined with functional analysis can identify treatable cases.
- Levodopa improves speech and motor skills in some NR4A2 children
- Genetic testing with RNA analysis helps confirm treatable mutations
- NR4A2-related disorders can respond to dopaminergic therapy
- Early diagnosis enables targeted treatment
- Clinical improvement seen in both patients after treatment
Nr4a2, A Key Factor Controlling the Development and Functional Maintenance of Forebrain Car3 Neurons.
Tao YC, Zhao L, Zhang Q, Liu XY, Liu WT, Li ZX, Hu L, Zhang L, Chen JY, Ding YQ, Song NN
NR4A2 is essential for the development and ongoing function of a specific group of neurons in the forebrain called Car3 neurons, which are involved in regulating behavior. Without NR4A2, these neurons do not form properly and mice show hyperactivity and reduced anxiety, suggesting NR4A2 plays a critical role in brain circuits linked to movement and emotion.
- NR4A2 controls development and function of forebrain Car3 neurons
- Loss of NR4A2 causes hyperactivity and less anxiety in mice
- Car3 neurons share a common gene profile when NR4A2 is missing
- NR4A2 misexpression turns on Car3-specific genes
- NR4A2 is vital for proper brain circuit formation
Comprehensive Analysis of N6-Methyladenosine Methylation in Transverse Aortic Constriction-Induced Cardiac Fibrosis Based on MeRIP-Seq Analysis.
Liu S, Zhao P, He Y, Wang J, Song B, Yu C
This study found that m6A methylation increases in mouse hearts after pressure overload, driving cardiac fibrosis by altering key genes. The gene NR4A2 was identified as a hub gene in a network linked to fibrosis, suggesting it may play a role in heart disease. These findings point to m6A regulation as a potential target for treating heart fibrosis.
- m6A methylation increases in heart fibrosis
- NR4A2 is a key hub gene in fibrosis-related networks
- m6A changes affect genes involved in heart disease
- Potential drug targets identified through gene networks
- Findings may lead to new treatments for heart fibrosis
A spatial single-cell atlas of the claustro-insular region uncovers key regulators of neuronal identity and excitability.
Fodoulian L, Boillat M, Moulinier M, Carleton A, Rodriguez I
NR4A2 helps control the identity and electrical activity of neurons in a brain region linked to attention, emotion, and self-awareness. In mice, reducing NR4A2 levels only changed claustrum neurons, causing them to switch their molecular profile and firing patterns, which may explain some neurological symptoms in NR4A2-related disorders.
- NR4A2 maintains neuron identity in the claustrum
- Low NR4A2 causes neurons to change their molecular makeup
- These changes affect how neurons fire and communicate
- The claustrum is especially sensitive to NR4A2 levels
- Findings may explain neurological symptoms in NR4A2 syndrome
Identification and Validation of Inverse Agonists for Nuclear Receptor Subfamily 4 Group A Member 2.
Tian L, Lin Y, Cheng C, Yang H, Qiu X, Li S, Jia C, Le W
This study identified a new compound, K-strophanthoside, that acts as an inverse agonist of NR4A2 (Nurr1), reducing its abnormal activity. The compound binds directly to the NR4A2 protein and mimics the effect of turning down its function, offering a potential tool for treating conditions linked to overactive NR4A2.
- A new inverse agonist for NR4A2 was discovered
- The compound reduces NR4A2's overactive transcription
- It binds directly to the NR4A2 protein's ligand site
- This offers a potential treatment strategy for NR4A2-related disorders
- The finding provides a valuable research tool for NR4A2 biology
Saikosaponin A, a bioactive compound from Bupleuri radix, protects dopaminergic neurons and correlates with NURR1 expression in 6-hydroxydopamine-injected hemi-Parkinsonian mouse model.
Huh E, Choi Y, Kim JH, Lee S, Oh MS
Saikosaponin A protects dopamine-producing brain cells in a mouse model of Parkinson's disease and increases levels of the NURR1 protein, which is linked to NR4A2-related syndrome in humans.
- Saikosaponin A protects dopamine neurons in Parkinson's mice
- It boosts NURR1 protein levels, relevant to NR4A2 function
- Findings suggest potential for treating NR4A2-related neurological conditions
- Mouse model mimics key features of human dopamine neuron loss
Evaluating SH-SY5Y cells as a dopaminergic neuronal model: morphological, transcriptomic, and proteomic insights.
Işlek Camadan EE, Sarihan M, Kasap M, Akpinar G, Koçyiğit E
Differentiated SH-SY5Y cells show some dopaminergic features but remain unstable and require constant external signals to maintain neuron-like traits, limiting their usefulness as a reliable model for Parkinson’s disease or NR4A2-related conditions.
- SH-SY5Y cells develop neuron-like shapes after treatment
- Dopaminergic markers like Nurr1 increase but inconsistently
- Cells need ongoing signals to stay differentiated
- Proteins linked to neurodevelopment change during differentiation
- Model may not reflect mature, stable neurons
Distinct endothelial gene responses to acute exercise in skeletal muscle.
Addington AK, Wall RM, Wei X, Frate SD, Olsen ML, Drake JC, Craige SM
This study identifies how blood vessel cells in muscle respond to a single exercise session by changing their gene activity, revealing specific genes and pathways involved in vascular adaptation and communication. These changes include activation of stress-response genes like NR4A2 and pathways linked to blood vessel growth and metabolic signaling.
- Endothelial cells in muscle change gene activity after exercise
- NR4A2 is among key genes activated in response to exercise
- Exercise triggers pathways for blood vessel growth and stress response
- These responses help coordinate muscle adaptation and systemic benefits
- Findings highlight endothelial cells as central to exercise's health effects
Computational association in parkinson's disease SNPs with brain structural and functional alterations.
Subramaniyan S, Kuriakose BB, Nattan V, Alhazmi AH, Wong LS, Muthusamy K
This study used computational methods to identify harmful genetic variants in key Parkinson's disease genes, including NURR1, and found a drug already approved for Parkinson's that may bind strongly to multiple disease-related proteins. The results suggest a potential repurposing opportunity for existing treatments.
- Identified harmful genetic variants in Parkinson's-related genes including NURR1
- Found an FDA-approved drug with strong binding to multiple Parkinson's proteins
- Results suggest possible drug repurposing for Parkinson's disease
- Computational models support further investigation of this drug candidate
Single-nucleus chromatin accessibility profiling identifies cell types and functional variants contributing to major depression.
Chawla A, Cakmakci D, Fiori LM, Zang W, Maitra M, Yang J, Żurawek D, Frosi G, Rahimian R, Mitsuhashi H, Davoli MA, Denniston R, Chen GG, Yerko V, Mash D, Girdhar K, Akbarian S, Mechawar N, Suderman M, Li Y, Nagy C, Turecki G
Major depression is linked to changes in gene regulation in specific brain cells, especially deep-layer excitatory neurons where the NR4A2 protein plays a key role in responding to stress. Genetic variants associated with depression disrupt how NR4A2 binds to DNA, affecting genes involved in brain cell communication.
- NR4A2 is active in brain cells linked to depression
- Depression risk genes disrupt NR4A2 binding sites
- Changes in gene regulation affect brain cell communication
- Microglia also show immune-related gene changes in depression
Carboxylic Acid Bioisosteres Boost Nurr1 Agonist Selectivity.
Stiller T, Gege C, Saeb W, Vietor J, López-García Ú, Busch R, Kohlhof H, Vitt D, Merk D
A modified version of the drug vidofludimus, designed to activate the Nurr1 protein without affecting DHODH, shows strong selectivity for Nurr1 and activates genes linked to brain cell protection. This suggests a promising path for developing safer treatments for neurodegenerative conditions like Parkinson’s.
- New Nurr1 activator avoids DHODH side effects
- Boosts genes linked to brain cell health
- May lead to better Parkinson’s treatments
- Tetrazole replacement improved selectivity
Nurr1 deficiency impairs autophagy-lysosomal function through GBA-dependent transcriptional regulation in Parkinson's disease pathogenesis.
Cheng C, Yang H, Tian L, Ni Y, Jia C, Le W, Wang Q
Nurr1 deficiency disrupts the autophagy-lysosomal system by reducing the activity of a key enzyme called GBA, leading to impaired clearance of cellular waste. This dysfunction contributes to Parkinson's disease pathology and may be reversible by restoring GBA levels.
- Nurr1 regulates lysosomal function through GBA expression
- Nurr1 loss causes lysosomes to become less acidic and less effective
- Restoring GBA improves lysosomal function in Nurr1-deficient cells
- This pathway links Nurr1 to Parkinson's disease mechanisms
- Targeting GBA could be a potential therapy for Nurr1-related disorders
NR4A2 attenuates early brain injury after intracerebral hemorrhage by promoting M2 microglial polarization via TLR4/TRAF6/NF-κB pathway inhibition.
Hu D, Huang C, Tang L, Lei J, Wang J, Hu W, Chen M, Song S, Lu L, Xu P
NR4A2 helps protect the brain after a stroke caused by bleeding, by reducing inflammation and supporting repair. It works by shifting immune cells in the brain toward a healing state and preserving the blood-brain barrier.
- NR4A2 levels drop after brain bleeding
- Boosting NR4A2 reduces brain damage and improves recovery
- NR4A2 promotes healing immune cells in the brain
- NR4A2 blocks a key inflammation pathway
- Targeting NR4A2 could lead to new treatments
Berberine mitigates colitis-associated neuroinflammation and anxiety through modulation of the AMPK/NURR1 pathway.
Habiba ES, Fathelbab MH, AbdElaziz MM, El-Sayed NS, Mady MM, Khamis GM
Berberine reduces gut inflammation and anxiety-like behavior in rats with colitis by activating the AMPK/NURR1 pathway, suggesting it may help treat both physical and mental health symptoms in inflammatory bowel disease.
- Berberine reduces colitis and anxiety in rats
- It works by boosting AMPK and NURR1 activity
- This pathway links gut inflammation to brain changes
- Results suggest a potential treatment for IBD-related symptoms
- Effects were dose-dependent and observed in both gut and brain
Nurr1 modulators - a patent review (2019-present).
Egner M, Merk D
New drugs that target the Nurr1 protein are being developed and patented, with potential use in treating neurodegenerative diseases like Parkinson’s and some cancers. These drugs aim to activate Nurr1 to protect brain cells and reduce inflammation, though some claims lack strong evidence.
- Nurr1-targeting drugs are in development for brain diseases and cancer
- Several promising compounds are now protected by patents
- Some patent claims lack solid proof or specific examples
- Nurr1 activation may protect brain cells and reduce inflammation
- Progress is being made, but not all claims are well validated
Adult human subventricular zone microglia promote a pro-neurogenic niche for neuronal progenitors in Parkinson's disease.
Pecoraro S, Verkerke M, Sluijs JA, van Het Hof B, van der Pol SMA, van Strien ME, van der Kant R, de Vries C, de Vries HE, van de Berg WDJ, Hol EM, Donega V
Microglia in the brain's subventricular zone of people with Parkinson's disease help create an environment that supports the growth of new neurons, and a gene called NR4A2 plays a key role in making these microglia supportive. This suggests boosting NR4A2 could help repair brain damage in Parkinson's and possibly other neurodegenerative conditions.
- PD microglia promote new neuron growth in the brain
- NR4A2 helps switch microglia to a repair-friendly state
- Targeting NR4A2 may support brain repair in neurodegenerative diseases
- This effect was seen in human brain tissue from Parkinson's patients