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
Clinical and genetic findings in autism spectrum disorders analyzed using exome sequencing.
Blázquez A, Rodriguez-Revenga L, Alvarez-Mora MI, Calvo R
Exome sequencing identified pathogenic variants in 10 out of 20 children with autism spectrum disorder who had no significant copy number variants on chromosomal microarray. One of the genes found, NR4A2, is linked to neurodevelopmental issues and may explain some cases of autism with intellectual disability and physical features.
- NR4A2 variant found in a child with autism and intellectual disability
- Exome sequencing helps find genetic causes when microarray is negative
- Children with NR4A2 variants often have hypotonia and dysmorphic features
- Finding a genetic cause can guide care and family counseling
- NR4A2 is a known neurodevelopmental gene with potential treatment implications
Modeling amyotrophic lateral sclerosis with amniotic membrane-derived mesenchymal stem cells: A novel approach for disease modeling.
Soumya BS, Gamit N, Patil M, Shreenidhi VP, Dharmarajan A, Warrier S
This study created a lab model of ALS using stem cells from amniotic membranes, turning them into motor neurons and introducing a mutated gene linked to ALS. The model shows key features of the disease, including neuron damage and changes in important genes like NURR1, making it useful for testing potential treatments.
- Used amniotic stem cells to model ALS in a dish
- Introduced ALS-linked SOD1 mutation to trigger disease features
- Showed loss of motor neuron markers and increased oxidative stress
- Found increased NURR1 expression, a gene linked to NR4A2
- Provides a fast, low-cost way to test ALS drugs
BRF110, an Orally Active Nurr1-RXRα-Selective Rexinoid, Enhances BDNF Expression without Elevating Triglycerides.
Asvos X, El Mubarak MA, Karampelas T, Rampias T, Tamvakopoulos C, Sivolapenko GB, Papakyriakou A, Topouzis S, Vassilatis DK, Fokas D
BRF110 is a new drug candidate that selectively activates the Nurr1-RXRα protein pair, boosts brain-derived neurotrophic factor (BDNF) levels, protects dopamine-producing brain cells, and crosses the blood-brain barrier—without raising triglycerides, a common side effect of similar drugs. This makes it a promising potential treatment for conditions involving Nurr1 dysfunction, such as NR4A2-related syndromes.
- BRF110 activates Nurr1-RXRα, a key protein pair linked to NR4A2-related disorders
- It increases BDNF, a brain-protective protein important for neuron health
- It penetrates the brain and protects dopamine neurons
- It does not raise triglycerides, avoiding a major side effect of older drugs
- It represents a safer, more targeted approach to rexinoid therapy
A Nurr1 Agonist Derived from the Natural Ligand DHI Induces Neuroprotective Gene Expression.
Egner M, Busch R, López-García Ú, Lewandowski M, Höfner G, Wein T, Marschner JA, Merk D
A new compound designed to activate the Nurr1 protein—linked to NR4A2-related syndrome—boosts production of brain-protective genes in neurons, suggesting potential for treating neurodegeneration and supporting Nurr1 as a therapeutic target.
- A new Nurr1 activator mimics a natural brain molecule
- It boosts brain-protective genes like BDNF
- The compound is stable, selective, and safe in cells
- Activating Nurr1 may help protect neurons in NR4A2-related conditions
Embryonic exposure to valproic acid and neonicotinoid deteriorates the hyperpolarizing GABA shift and impairs long-term potentiation of excitatory transmission in the local circuit of intermediate medial mesopallium of chick telencephalon.
Matsushima T, Toji N, Wada K, Shikanai H, Izumi T
Exposure to valproic acid or the pesticide imidacloprid during embryonic development disrupts key brain processes in chicks that are essential for learning and memory, including the normal shift of GABA signaling from excitatory to inhibitory and the strengthening of neural connections. These disruptions are linked to reduced activity of genes NR4A1 and NR4A2, which are also involved in human neurodevelopmental disorders.
- Valproic acid and imidacloprid impair brain circuit function critical for learning
- GABA signaling fails to become inhibitory, disrupting neural communication
- NR4A1 and NR4A2 gene activity is reduced by both chemicals
- Bumetanide can rescue some of the damage, suggesting a potential treatment path
- These findings may inform therapies for NR4A2-related neurodevelopmental conditions
Celecoxib Enhances Oxidative Muscle Fibre Formation and Improves Muscle Functions Through Prokr1 Activation in Mice.
Park JH, Mok J, Park S, Kim D, Kang MS, Park TS, Park J
Celecoxib activates PROKR1 signaling, increases oxidative muscle fibers, and improves muscle strength, metabolism, and insulin sensitivity in mice, even under conditions that promote muscle wasting. These benefits occur when celecoxib is given during early development and persist into adulthood.
- Celecoxib boosts PROKR1 signaling and oxidative muscle fibers
- Improves muscle strength and metabolism in mice
- Effects last into adulthood despite high-fat diet
- Increases NR4A2, a gene linked to NR4A2-related syndrome
- Suggests potential for treating muscle issues in NR4A2 patients
Discovery of Endothelial-Monocyte Crosstalk in Ischemic-Reperfusion Injury Following Liver Transplantation Based on Integration of Single-Cell RNA and Transcriptome RNA Sequencing.
Sun C, Li L, Li D, Wang Z
This study identifies a key interaction between liver blood vessel cells and immune cells after liver transplant injury, highlighting the ANXA1-FPR2 signaling pathway as a major driver of inflammation. The findings suggest that blocking this pathway could reduce tissue damage and improve transplant outcomes.
- Liver blood vessel and immune cell interaction worsens transplant injury
- ANXA1-FPR2 pathway drives inflammation after liver transplant
- NR4A2 is upregulated in monocytes during injury
- Targeting ANXA1-FPR2 may reduce transplant damage
- Findings are supported by mouse models and human data
Contribution of the dopaminergic system in toxoplasmic encephalitis neuroimmunopathogenesis.
Anteplıoğlu T, Dincel GC, Alçiğir ME, Bışkın Türkmen M, Yapici TS, Kul O, Al-Olayan E, Alshahrani MY, El-Ashram S
Infection with Toxoplasma gondii disrupts dopamine system proteins in the brain, increasing tyrosine hydroxylase but decreasing dopamine receptors, transporter, and Nurr1, which may contribute to neurological and behavioral symptoms. These changes occur over time and suggest potential targets for treating brain complications in chronic infection.
- Infection increases tyrosine hydroxylase, boosting dopamine production
- Dopamine receptors and transporter levels drop, impairing dopamine signaling
- Nurr1, a key regulator of dopamine neurons, is significantly reduced
- These changes correlate with behavioral and neurological symptoms
- Findings may inform treatments targeting dopamine system dysfunction
Luteolin ameliorates rat model of metabolic syndrome-induced cardiac injury by apoptosis suppression and autophagy promotion via NR4A2/p53 regulation.
Dai X, Liang B, Sun Y
Luteolin reduces heart damage in rats with metabolic syndrome by blocking cell death, reducing inflammation, and boosting the body's natural cleanup process, partly through regulating the NR4A2 and p53 genes.
- Luteolin protects the heart in metabolic syndrome
- It reduces cell death and inflammation
- It boosts autophagy via NR4A2/p53
- NR4A2 is a key regulator in heart protection
- Findings suggest a potential treatment path
Overexpression of FTO alleviates traumatic brain injury induced posttraumatic epilepsy by upregulating NR4A2 expression via m6A demethylation.
Xiao M, Wang X, Xiao E, Ming Q
Overexpressing FTO reduces epilepsy and brain damage after traumatic brain injury by increasing NR4A2 levels through a specific epigenetic mechanism. This suggests FTO could be a potential treatment target for post-traumatic epilepsy in humans.
- FTO reduces epilepsy after brain injury by boosting NR4A2
- NR4A2 is protected from degradation by FTO's m6A demethylation
- Lower NR4A2 levels are linked to worse brain injury and seizures
- Targeting FTO may help treat post-traumatic epilepsy
- This mechanism is confirmed in mouse models of brain injury
Bioinformatics-driven identification and validation of hub genes regulating endometriosis-related infertility within human granulosa cells.
Luo J, Wang H, Zhou L, Wang J, Song M, Cheng Y, Rao M, Zhao S, Tang L
The study identifies BTG2 as a key gene in granulosa cells that may predict fertility outcomes in women with endometriosis-related infertility. Lower BTG2 levels are linked to poorer IVF results, suggesting it could help assess egg quality without invasive testing.
- BTG2 is a top hub gene in endometriosis-related infertility
- Low BTG2 levels predict poor IVF outcomes
- BTG2 levels correlate with egg retrieval and embryo quality
- BTG2 may serve as a non-invasive fertility biomarker
- NR4A2 was among the hub genes identified
JMJD3 deficiency disturbs dopamine biosynthesis in midbrain and aggravates chronic inflammatory pain.
He XB, Guo F, Zhang W, Fan J, Le W, Chen Q, Ma Y, Zheng Y, Lee SH, Wang HJ, Wu Y, Zhou Q, Yang R
JMJD3 helps control dopamine production in brain cells, and when it's missing, dopamine levels drop and chronic pain worsens. This effect happens because JMJD3 normally removes a chemical block on genes needed for dopamine creation, including the NURR1 gene, which is also linked to NR4A2-related syndrome.
- JMJD3 boosts dopamine production by removing gene-blocking marks
- Loss of JMJD3 reduces NURR1 and dopamine in brain cells
- Low dopamine from JMJD3 deficiency increases pain sensitivity
- NURR1 gene activity depends on JMJD3 in dopamine neurons
- This mechanism may explain pain issues in NR4A2/NURR1 disorders