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
Canagliflozin attenuates neurodegeneration and ameliorates dyskinesia through targeting the NLRP3/Nurr1/GSK-3β/SIRT3 pathway and autophagy modulation in rotenone-lesioned rats.
Abdelaziz AM, Rasheed NOA, Zaki HF, Salem HA, El-Sayed RM
Canagliflozin reduced brain inflammation and protected nerve cells in a rat model of Parkinson's disease, improving movement and reducing drug-induced dyskinesia by activating protective pathways involving Nurr1, SIRT3, and autophagy while suppressing harmful inflammation.
- Canagliflozin improved movement and reduced dyskinesia in Parkinson's rats
- It boosted Nurr1 and SIRT3, key proteins for brain cell protection
- It reduced brain inflammation by blocking NLRP3 and caspase-1
- It enhanced autophagy, helping clear damaged brain cells
- The drug also balanced GSK-3β and mTOR, which affect cell survival
Implications of prenatal exposure to hyperandrogen for hippocampal neurodevelopment and autism-like behavior in offspring.
Qiao D, Mu C, Chen H, Wen D, Wang Z, Zhang B, Guo F, Wang C, Zhang R, Wang C, Cui H, Li S
Prenatal exposure to high androgen levels in mice disrupts brain development and causes autism-like behaviors in offspring, and a gene called Nr4a2 plays a key role in this process. Boosting Nr4a2 or treating with amodiaquine reversed these effects, suggesting a potential pathway for future therapies.
- High androgen exposure in pregnancy harms brain development in mice
- Nr4a2 gene is central to the brain changes seen
- Boosting Nr4a2 or using amodiaquine improved outcomes
- Findings may help understand and treat NR4A2-related conditions
NR4A1 and NR4A2 orphan nuclear receptors regulate endothelial-to-hematopoietic transition in mouse hematopoietic stem cell specification.
Sá da Bandeira D, Nevitt CD, Segato Dezem F, Marção M, Liu Y, Kelley Z, DuBose H, Chabot A, Hall T, Caprio C, Okhomina V, Kang G, Plummer J, McKinney-Freeman S, Clements WK, Ganuza M
NR4A1 and NR4A2 genes are essential for the development of blood-forming stem cells in mouse embryos, controlling the transition from blood vessel cells to blood stem cells. Without these genes, blood stem cells fail to mature properly and cannot sustain long-term blood production.
- NR4A1 and NR4A2 are critical for blood stem cell formation
- Loss of these genes blocks blood stem cell maturation
- Defects are linked to failure in turning off Notch signaling
- Growth factors can partially restore blood stem cell function
- Findings may inform future therapies for blood disorders
The endocannabinoid anandamide mediates anti-inflammatory effects through activation of NR4A nuclear receptors.
Teichmann T, Pflüger-Müller B, Giménez VMM, Sailer F, Dirks H, Zehr S, Warwick T, Brettner F, Munoz-Tello P, Zimmer A, Tegeder I, Thomas D, Gurke R, Günther S, Heering J, Proschak E, Geisslinger G, Bibli IS, Heringdorf DMZ, Manucha W, Windbergs M, Knapp S, Weigert A, Leisegang MS, Kojetin D, Brandes RP
Anandamide, a natural compound in the body, reduces inflammation in blood vessel cells by activating NR4A2 and NR4A1 proteins. This activation turns off inflammatory genes by recruiting a suppressor protein to their DNA, offering a potential new way to treat inflammation-related conditions.
- Anandamide reduces inflammation by activating NR4A2 and NR4A1
- NR4A2 activation turns off inflammatory genes like CCL2
- Anandamide binds directly to NR4A proteins to trigger this effect
- Blocking NR4A proteins stops anandamide’s anti-inflammatory action
- This pathway could inspire new treatments for inflammation
Gene Therapy for Parkinson's Disease Using Midbrain Developmental Genes to Regulate Dopaminergic Neuronal Maintenance.
Kim J, Chang MY
This paper explores gene therapies that protect dopamine-producing neurons in Parkinson's disease by targeting key developmental genes like Nurr1 and Foxa2, which help maintain neuron health and resist damage. These approaches aim to slow disease progression, not just replace dopamine, and show promise in preclinical and early clinical studies.
- Nurr1 and Foxa2 help protect dopamine neurons
- Gene therapies targeting these genes may slow Parkinson's progression
- Approaches focus on neuron survival, not just dopamine levels
- Combining neuron and glial cell targeting shows potential
- Neurotrophic factors and cellular repair pathways are also promising
OTUD7B inhibited hepatic injury from NAFLD by inhibiting K48-linked ubiquitination and degradation of β-catenin.
Sun J, Jin X, Li Y
OTUD7B protects the liver in fatty liver disease by stabilizing β-catenin, a key protein that reduces fat buildup and inflammation. NR4A2 boosts OTUD7B production, linking this gene to liver protection. This suggests that enhancing OTUD7B or NR4A2 could be a potential treatment strategy.
- OTUD7B reduces liver fat and inflammation in fatty liver disease
- OTUD7B stabilizes β-catenin by blocking its breakdown
- NR4A2 increases OTUD7B levels, linking the two genes
- Boosting OTUD7B may protect the liver in NR4A2-related conditions
- This pathway could be a target for future therapies
Loss of PHF6 causes spontaneous seizures, enlarged brain ventricles and altered transcription in the cortex of a mouse model of the Börjeson-Forssman-Lehmann intellectual disability syndrome.
McRae HM, Leong MPY, Bergamasco MI, Garnham AL, Hu Y, Corbett MA, Whitehead L, El-Saafin F, Sheikh BN, Wilcox S, Hannan AJ, Gécz J, Smyth GK, Thomas T, Voss AK
Loss of PHF6 in mice causes spontaneous seizures and enlarged brain ventricles, along with early neuronal activity and changes in genes linked to brain development, including NR4A2. These findings suggest PHF6 plays a critical role in regulating brain structure and function during development.
- PHF6 loss leads to seizures and enlarged brain ventricles in mice
- Neurons mature too early and show abnormal activity
- Genes like NR4A2 and RELN are overactive without PHF6
- PHF6 helps control neural stem cell growth and neuron formation
- These changes mirror features seen in Börjeson-Forssman-Lehmann syndrome
Differential roles of NR4A2 (NURR1) paralogs in the brain and behavior of zebrafish.
Kalyn M, Garvey R, Lee H, Mbesha HA, Curry J, Saxena V, Mennigen JA, Ekker M
Zebrafish with mutations in the nr4a2a gene show Parkinson's-like symptoms, including reduced dopamine neurons and impaired movement, while nr4a2b mutants have behavioral issues and signs of cellular stress. These findings reveal how different versions of the NR4A2 gene affect brain function and could help develop treatments for NR4A2-related disorders.
- nr4a2a loss causes Parkinson's-like symptoms in zebrafish
- nr4a2b mutants show behavioral changes and cellular stress
- Both genes affect dopamine neuron health and regeneration
- Metabolic changes suggest compensatory responses in neurons
- Findings may guide therapies for NR4A2-related conditions
Identification and validation of diagnostic markers related to immunogenic cell death and infiltration of immune cells in diabetic nephropathy.
Jin D, Tu X, Xu W, Zheng H, Zeng J, Bi P, Yang R, Li Y, Ni J, Zhu C, Chen H, Yu D, Wan F
The study identifies NR4A2 and other genes as potential markers in diabetic nephropathy, linking immune cell activity and chemokines to disease progression. These findings may help improve diagnosis and point to new treatment strategies targeting inflammation and cell death pathways.
- NR4A2 is linked to diabetic nephropathy development
- Immune cell markers and chemokines are involved in disease progression
- Hub genes like NR4A2 show strong diagnostic potential
- Findings may inform future therapies targeting inflammation
- Validation in mouse models supports relevance
Advanced paternal age exacerbates neuroinflammation in offspring via m6A modification-mediated intergenerational inheritance.
Mao Y, Meng Y, Zou K, Qin N, Wang Y, Yan J, Chen P, Cheng Y, Shi W, Zhou C, Chen H, Sheng J, Liu X, Pan J, Huang H
Advanced paternal age leads to cognitive and autism-like behaviors in offspring due to epigenetic changes in sperm that affect brain inflammation. Specifically, a gene called NR4A2 becomes abnormally modified and underactive, contributing to overactive immune cells in the brain. Targeting a protein called YTHDC1 can reduce brain inflammation and improve behavior in affected offspring.
- Older fathers pass on epigenetic changes that harm offspring brain function
- NR4A2 gene is underactive due to abnormal RNA methylation
- Microglia become overactive, driving brain inflammation
- YTHDC1 protein worsens symptoms by suppressing NR4A2
- Blocking YTHDC1 improves behavior and reduces brain inflammation
Author Correction: CB2 receptor activation inhibits the phagocytic function of microglia through activating ERK/AKT-Nurr1 signal pathways.
Han QW, Shao QH, Wang XT, Ma KL, Chen NH, Yuan YH
Activating CB2 receptors in microglia reduces their ability to clear debris, which may worsen brain inflammation and neurodegeneration. This effect occurs through a specific signaling pathway involving Nurr1, a protein linked to NR4A2-related syndrome.
- CB2 activation reduces microglia's cleanup function
- This happens via ERK/AKT-Nurr1 signaling
- Nurr1 is the same protein affected in NR4A2 syndrome
- May impact brain health in neurodevelopmental disorders
- Suggests cannabinoids could worsen symptoms
Fam3a-mediated prohormone convertase switch in α-cells regulates pancreatic GLP-1 production in an Nr4a2-Foxa2-dependent manner.
Wang D, Wei T, Cui X, Xia L, Jiang Y, Yin D, Liao X, Li F, Li J, Wu Q, Lin X, Lang S, Le Y, Yang J, Yang J, Wei R, Hong T
Blocking Fam3a in pancreatic alpha cells increases GLP-1 production by switching prohormone processing, which boosts insulin release and improves blood sugar control through a pathway involving Nr4a2 and Foxa2. This suggests a potential way to enhance natural GLP-1 in people with NR4A2-related syndromes.
- Fam3a loss in alpha cells raises GLP-1 levels
- Nr4a2 and Foxa2 control GLP-1 production
- Increased GLP-1 improves insulin and blood sugar
- This pathway could be targeted to boost GLP-1
- Findings may help treat metabolic issues in NR4A2 patients
Transcriptomic Profiling of Primary Microglia: Effects of miR-19a-3p and miR-19b-3p on Microglia Activation.
Sahebdel F, Zia A, Quinta HR, Morse LR, Olson JK, Battaglino RA
MicroRNAs miR-19a and miR-19b drive inflammation in brain immune cells called microglia through different pathways, with miR-19b specifically targeting NR4A2, a gene linked to neurodevelopmental disorders like NR4A2-related syndrome. This suggests that miR-19b may influence brain function beyond pain and inflammation, potentially affecting neurological development and behavior.
- miR-19b targets NR4A2, a gene tied to NR4A2-related syndrome
- NR4A2 is involved in regulating microglial inflammation
- miR-19b may disrupt normal NR4A2 function in the brain
- This links a microRNA to a known neurodevelopmental gene
- Potential for miR-19b to influence neurological symptoms
Prostaglandin E2 signaling through prostaglandin E receptor subtype 2 and Nurr1 induces fibroblast growth factor 23 production.
Feger M, Hammerschmidt K, Liesche I, Rausch S, Alber J, Föller M
Prostaglandin E2 signaling through the EP2 receptor and the Nurr1 protein increases production of FGF23, a hormone that regulates phosphate and vitamin D levels. This pathway may contribute to elevated FGF23 in conditions like chronic kidney disease and could be a target for treatment.
- PGE2 boosts FGF23 via EP2 and Nurr1 in bone cells
- EP2 activation raises FGF23 levels in mice
- Nurr1 is a key transcription factor in this process
- This pathway may affect mineral balance and disease progression
- Could offer new treatment targets for FGF23-related disorders
Role of Elavl-like RNA-binding protein in retinal development and signal transduction.
Wutikeli H, Yu Y, Zhang T, Cao J, Nawy S, Shen Y
Elavl2 and Elavl4 RNA-binding proteins regulate the development of retinal amacrine cells through distinct pathways, affecting vision, particularly low-light (scotopic) vision. Elavl2 also interacts with GABAB receptors, suggesting a role in signal transmission.
- Elavl2 and Elavl4 control amacrine cell development in the retina
- Elavl4 regulates Neurod1 via Satb1 to promote cell differentiation
- Elavl2 binds to GABAB receptors, impacting signal transmission
- Disruption leads to reduced scotopic (night) vision
- These proteins act through different molecular pathways
Claustrum and dorsal endopiriform cortex complex cell-identity is determined by Nurr1 and regulates hallucinogenic-like states in mice.
Mantas I, Flais I, Masarapu Y, Ionescu T, Frapard S, Jung F, Le Merre P, Saarinen M, Tiklova K, Salmani BY, Gillberg L, Zhang X, Chergui K, Carlén M, Giacomello S, Hengerer B, Perlmann T, Svenningsson P
Nurr1 is essential for defining the identity of neurons in the claustrum and dorsal endopiriform cortex, a brain region linked to hallucinations. Without Nurr1, these neurons lose their unique gene patterns and fail to respond to hallucinogenic drugs, altering brain circuit activity.
- Nurr1 controls neuron identity in the claustrum
- Loss of Nurr1 disrupts hallucinogen response
- Brain circuit changes affect hallucinogenic states
- Nurr1 may be a target for studying related brain functions
Astragaloside IV Treats Parkinson's Disease by Regulating the Proliferation and Differentiation of NSCs through the SHH-Nurr1 Pathway.
Wu Z, Zhang J, Gao H, Li W
Astragaloside IV helps treat Parkinson's disease by boosting the growth and specialization of neural stem cells through the SHH-Nurr1 pathway, which is critical for making dopamine-producing neurons. This suggests a potential therapy to replace lost brain cells in Parkinson's.
- Astragaloside IV promotes neural stem cell growth and specialization
- It works through the SHH-Nurr1 signaling pathway
- Nurr1 is essential for making dopamine neurons
- This could lead to new treatments for Parkinson's disease
- Findings are based on cell and animal studies