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
Expanding the Clinical Spectrum of NR4A2-Related Disorder: A Systematic Literature Review and Case Series.
Borden C, Nasir MB, Roberts MB, Palange L, Wang X
NR4A2-related disorder causes a wide range of neurodevelopmental issues, including intellectual disability, seizures, and movement problems, and may also affect other body systems like the kidneys, gut, and endocrine system. New cases show unexpected metabolic and hormonal issues, suggesting the condition is more varied than previously thought.
- NR4A2 variants cause intellectual disability and developmental delay in most patients
- Seizures and movement disorders are common, but not universal
- Extra-neurological issues like kidney and gut problems occur in nearly half
- New cases reveal endocrine and metabolic problems not seen before
- The condition is likely underdiagnosed due to its broad and varied symptoms
Molecular Screening Reveals De Novo Loss-of-Function NR4A2 Variants in Saudi Children with Autism Spectrum Disorders: A Single-Center Study.
Alharbi NM, Baaboud WF, Shawky H, Alrofaidi AA, Farsi RM, Algothmi KM, Hassoubah SA, Basingab FS, Azhari SA, Alharbi MG, Yahya R, Alhazmi S
De novo loss-of-function variants in the NR4A2 gene are found in a significant number of Saudi children with autism spectrum disorder, suggesting NR4A2 plays a key role in causing autism in this population. These variants are linked to neurodevelopmental delays and speech impairments, with some recurring across affected individuals.
- NR4A2 loss-of-function variants are linked to autism in Saudi children
- Variants are de novo and often recurrent in this population
- Some variants are classified as pathogenic, affecting gene function
- NR4A2 variants correlate with speech and developmental delays
- Findings suggest a major role in autism etiology for this group
Exploring the genetic characteristics of overweight-related osteoarthritis using machine learning.
Jiang Z, Xu C, Shi W, Lin Z, Li H, Zhang H, Li Z
This study identifies six genes, including NR4A2, linked to overweight-related osteoarthritis, and develops a diagnostic model that may help guide future immune-based treatments for this condition.
- NR4A2 is among six genes tied to overweight-related osteoarthritis
- The model predicts disease using gene expression and immune cell patterns
- Findings suggest potential for immune-targeted therapies
- The model was tested and validated in independent patient data sets
Structural and mechanistic profiling of Nurr1 modulation by vidofludimus enables structure-guided ligand design.
López-García Ú, Vietor J, Marschner JA, Heering J, Morozov V, Wein T, Merk D
Vidofludimus activates the Nurr1 protein, a key regulator in brain health, by binding to a specific site that changes the protein's shape and function. Researchers used this discovery to design a more effective version of the drug that binds stronger and works better, paving the way for improved treatments for NR4A2-related conditions.
- Vidofludimus activates Nurr1 by binding to a specific pocket on the protein
- This binding changes how Nurr1 works, helping it protect brain cells
- A new, more potent version of the drug was created using this structural insight
- The findings enable better design of future drugs targeting NR4A2
- This advances the potential for treating NR4A2-related disorders
Retinoid X Receptor as a Therapeutic Target to Treat Neurological Disorders Associated with α-Synucleinopathy.
Zhylkibayev A, Starr CR, Hossain MI, Kumar S, Andrabi SA, Grant MB, Atigadda VR, Gorbatyuk MS, Gorbatyuk OS
Activating the RXR protein protects brain cells and reduces toxic alpha-synuclein buildup in a mouse model of Parkinson’s disease, while also calming harmful brain inflammation and boosting levels of two key protective proteins, NURR1 and PPARα.
- RXR activation reduces toxic alpha-synuclein clumps
- RXR preserves dopamine-producing neurons
- RXR lowers brain inflammation and glial activation
- RXR boosts levels of NURR1 and PPARα
- Targeting RXR may slow Parkinson’s progression
Transcriptional evidence of reduced BDNF trophic capacity in the post-mortem human midbrain of schizophrenia cases with high inflammation.
Chandra JJ, Zhu Y, Petty A, Kostoglou Y, Haynes WX, Webster MJ, Weickert CS
People with schizophrenia, especially those with high brain inflammation, show reduced levels of BDNF and its key receptor TrkBTK+, which support dopamine neurons, along with increased levels of receptors that may harm these neurons. These changes suggest weakened trophic support for dopamine neurons, potentially worsening symptoms, and are not caused by antipsychotic medication. The findings point to inflammation as a key factor in damaging neuron health in schizophrenia.
- BDNF and TrkBTK+ are reduced in schizophrenia midbrain
- TrkBTK- and p75 receptors are increased, opposing neuron support
- Changes are worse in cases with high brain inflammation
- Antipsychotics do not cause these gene changes
- p75 is found in oligodendrocytes, not neurons
Alpha-Synuclein drives NURR1 and NLRP3 Inflammasome dysregulation in Parkinson's disease: From pathogenesis to potential therapeutic strategies.
Abdelaziz AM
Alpha-synuclein triggers harmful inflammation and weakens a key protective protein in brain cells, worsening Parkinson's disease. This process creates a cycle of damage that could be targeted by new treatments. The findings highlight a potential pathway for therapies aimed at stopping disease progression.
- Alpha-synuclein harms brain cells and activates inflammation
- NURR1, a protective brain protein, becomes less active
- Inflammation worsens neuron damage and disease
- Targeting this cycle may slow Parkinson's progression
- New treatments could focus on restoring NURR1 and blocking inflammasome
Expression of Prooncogenic Nuclear Receptor 4A (NR4A)-Regulated Genes β1-Integrin and G9a Inhibited by Dual NR4A1/2 Ligands.
Zhang L, Gatlin V, Gupta S, Salinas ML, Romero S, Cai JJ, Chapkin RS, Safe S
NR4A1 and NR4A2 regulate genes linked to cancer growth, including β1-integrin and G9a, and drugs that block both receptors reduce activity of these genes. This suggests a potential treatment strategy targeting these pathways, though the research is in cancer cells, not in people with NR4A2-related syndrome.
- NR4A1 and NR4A2 control cancer-related genes like β1-integrin and G9a
- Drugs blocking both receptors reduce activity of these genes
- The same genes are affected in both receptors, suggesting shared pathways
- Findings come from colon cancer cells, not human NR4A2 syndrome patients
- Potential for repurposing drugs, but not yet tested in NR4A2-related conditions
Correction: Molecular basis of ligand-dependent Nurr1-RXRα activation.
Yu X, Shang J, Kojetin DJ
Nurr1, a protein linked to NR4A2-related syndrome, works with another protein called RXRα to control gene activity in response to specific molecules. The study reveals how these molecules turn on Nurr1, which could help develop treatments that target this pathway.
- Nurr1 needs RXRα to activate genes
- Specific molecules turn on Nurr1 activity
- Understanding this switch may lead to new therapies
- This mechanism is relevant to NR4A2-related disorders
The selenocysteine-containing protein SELENOT maintains dopamine signaling in the midbrain to protect mice from hyperactivity disorder.
Guo Q, Li ZF, Hu DY, Li PJ, Wu KN, Fan HH, Deng J, Wu HM, Zhang X, Zhu JH
Mice without SELENOT in dopamine-producing brain cells show ADHD-like behaviors, including hyperactivity and attention problems, due to disrupted dopamine signaling. SELENOT helps control dopamine levels by regulating a protein called DAT through a pathway involving calcium and the NURR1 transcription factor. Medications used for ADHD, like methylphenidate, can reverse these symptoms in the mice.
- SELENOT loss causes ADHD-like behaviors in mice
- SELENOT controls dopamine levels via DAT regulation
- NURR1 activity is affected by SELENOT through calcium signaling
- ADHD drugs reverse hyperactivity in affected mice
- SELENOT protects midbrain dopamine function
Genetic variants associated with idiopathic Parkinson's disease in Latin America: A systematic review.
Duarte-Zambrano F, Alfonso-Cedeño DF, Barrero JA, Rodríguez-Vanegas LA, Moreno-Cárdenas V, Olarte-Díaz A, Arboleda G, Arboleda H
This review identifies genetic variants linked to Parkinson's disease in Latin American populations, including a risk-increasing INDEL in the NR4A2 gene and other known PD-related genes. The findings overlap with European studies but also suggest unique genetic factors, highlighting the need for more research in diverse, admixed populations.
- NR4A2 INDEL is linked to increased Parkinson's risk in Latin Americans
- Other key genes include SNCA, GBA, LRRK2, and APOE
- Some variants show protective effects, including in APOE and PICALM
- Findings support the need for ancestry-specific genetic research
- Results may inform personalized treatments for diverse populations
Development of In Vitro Parkinson's Disease Model Mediated by MPP+ and α-Synuclein Using Wharton's Jelly Mesenchymal Stem Cells.
Gamit N, Patil M, Soumya BS, Dharmarajan A, Warrier S
This study created a lab model of Parkinson's disease using stem cells from umbilical cords to mimic key features of the disease, including dopamine neuron loss and toxic protein buildup. The model shows changes in genes and proteins linked to Parkinson's and can be used to test potential treatments.
- Used umbilical cord stem cells to model Parkinson's disease
- Created dopamine-producing neurons that show Parkinson's-like damage
- Model shows key Parkinson's features: protein buildup and cell death
- Can test new Parkinson's drugs quickly and cheaply
- Results match known Parkinson's disease mechanisms
Satb2 and Nr4a2 are required for the differentiation of cortical layer 6b.
Zhao L, Tao YC, Hu L, Liu XY, Zhang Q, Zhang L, Ding YQ, Song NN
Satb2 and Nr4a2 are essential for the development of a specific layer of brain cells (layer 6b) that form early in the cortex. When either gene is disrupted, the proper formation of these neurons fails, suggesting they play critical but distinct roles in brain development.
- Satb2 and Nr4a2 are needed for layer 6b neuron development
- Loss of Satb2 reduces key layer 6b genes
- Nr4a2 levels rise when Satb2 is lost
- Both genes act through different pathways
- Disruption leads to faulty cortical layer formation
Increased NaV1.2 expression and its interaction with CaM contribute to the hyperexcitability induced by prolonged inhibition of CaMKII.
Liang H, Qin L, Feng R, Shim J, Huang X, Xu X, Zhao D, Yu Z, Boczek T, Li M, Tong Y, Huang J, Gao Q, Wang L, Cao X, Liu D, Du K, Xu J, Zhao Y, Wang W, Seehus CR, Zhao W, Guo F
Prolonged inhibition of CaMKII increases the expression of the NaV1.2 sodium channel and strengthens its interaction with calmodulin, leading to neuronal hyperexcitability. This mechanism may contribute to seizure-like activity and could be targeted with a peptide that blocks calmodulin binding to NaV1.2.
- CaMKII inhibition raises NaV1.2 levels and activity
- Increased NaV1.2-calmodulin binding boosts neuronal excitability
- NR4A2 normally suppresses Scn2a; its drop after CaMKII inhibition lifts this brake
- A peptide blocking NaV1.2-calmodulin interaction reverses hyperexcitability
- This pathway may be a therapeutic target for NR4A2-related hyperexcitability
Towards a unified molecular mechanism for liganddependent activation of NR4A-RXR heterodimers.
Yu X, He Y, Kamenecka TM, Kojetin DJ
NR4A2 (Nurr1) and related NR4A proteins form complexes with RXR that can be activated by certain drugs in a non-classical way, where the two proteins separate when a drug binds. This mechanism may be relevant for treating brain and immune disorders, but it requires specific drug types to trigger. More diverse drugs are needed to fully understand and target this process.
- NR4A2-RXR activation can happen through protein separation, not just standard drug binding
- Specific drugs are needed to trigger the non-classical activation mechanism
- This mechanism may apply to brain and immune diseases
- Better drug tools are needed to study and treat NR4A-RXR disorders
- The findings suggest new ways to develop therapies for NR4A2-related conditions
Neurotoxic Effects of Atrazine on Dopaminergic System via miRNAs and Energy-Sensing Pathways.
Chen X, Hu X, Liu H, He J, Li Y, Zhang X
Atrazine exposure harms the dopaminergic system in rats by reducing levels of key proteins like NURR1 and tyrosine hydroxylase, while increasing alpha-synuclein. This effect is linked to changes in miRNAs and energy-sensing pathways like AMPK and SIRT1, which may disrupt brain cell function and survival.
- Atrazine reduces NURR1, a protein critical for dopamine neuron health.
- It increases alpha-synuclein, linked to Parkinson’s-like damage.
- Changes in miR-322-5p and AMPK activity disrupt brain cell energy balance.
- These pathways may worsen neurodegeneration in vulnerable individuals.
- Findings suggest environmental toxins could worsen NR4A2-related conditions.
The Organogermanium Compound 3-(trihydroxygermyl)propanoic Acid Exerts Anti-Inflammatory Effects via Adenosine-NR4A2 Signaling.
Azumi J, Takeda T, Shibata S, Shimada Y, Aso H, Nakamura T
THGP reduces inflammation by boosting adenosine signaling, which activates the NR4A2 pathway, offering a new way to control inflammatory responses in cells.
- THGP activates NR4A2 through adenosine signaling
- This reduces inflammation without needing ATP
- THGP works on two different inflammatory pathways
- May help treat various inflammatory conditions
- NR4A2 is a key player in this anti-inflammatory effect
NURR1 Deficiency Is Associated to Altered Microglial Phenotype in Male Mice.
Montarolo F, Thielens S, Bove M, Bertolotto A, Tempia F, Hoxha E
NURR1 deficiency in male mice leads to fewer microglia and abnormal inflammation-related gene activity in the brain region controlling movement, which may explain behavioral issues even when dopamine neurons appear normal. These changes in microglia could contribute to neurological symptoms seen in NR4A2-related conditions.
- NURR1 deficiency reduces microglia in the brain's movement center
- Microglia show abnormal inflammation markers in NURR1-deficient mice
- Behavior problems occur without loss of dopamine neurons
- Altered stress and damage signals in microglia suggest ongoing brain disruption
- Findings point to immune cells as key players in NR4A2-related symptoms
Retinoid X Receptor as a Therapeutic Target to Treat Neurological Disorders Associated with α -Synucleinopathy.
Zhylkibayev A, Starr CR, Hossain MI, Barodia SK, Andrabi SA, Grant MB, Atigadda VR, Gorbatyuk MS, Gorbatyuk OS
Activating the RXR protein protects brain cells and reduces toxic alpha-synuclein buildup in a mouse model of Parkinson’s disease, while also calming harmful brain inflammation and boosting levels of key protective proteins like NURR1.
- RXR activation reduces toxic alpha-synuclein clumps
- Preserves dopamine-producing neurons
- Lowers brain inflammation and glial activation
- Boosts levels of NURR1 and PPARα
- Suggests RXR as a promising target for Parkinson’s therapy