Impaired Neurodevelopmental Genes in Slovenian Autistic Children Elucidate the Comorbidity of Autism With Other Developmental Disorders.
Krgovic D, Gorenjak M, Rihar N, Opalic I, Stangler Herodez S, Gregoric Kumperscak H, Dovc P, Kokalj Vokac N
This study found that analyzing rare genetic variants in autism and related developmental disorder genes using reverse phenotyping improves diagnosis in children with autism, especially when clinical details are limited. Variants in genes like NR4A2 were identified as likely causes of autism and intellectual disability, highlighting shared genetic roots across developmental disorders.
- NR4A2 variants were found in autistic children, linking it to autism and intellectual disability
- Reverse phenotyping boosts diagnosis even with incomplete clinical data
- Genes linked to autism often also cause other developmental disorders
- Analyzing functionally similar genes increases detection of rare causes
- This approach identifies treatable or actionable genetic causes
Nurr1 Is Not an Essential Regulator of BDNF in Mouse Cortical Neurons.
Abdollahi M, Fahnestock M
Nurr1 does not control BDNF levels in mouse cortical neurons, even when neurons are active or treated with a drug that boosts Nurr1. This suggests Nurr1’s role in regulating BDNF is specific to certain brain areas like the midbrain and cerebellum, not the cortex.
- Nurr1 does not regulate BDNF in cortical neurons
- BDNF increase with Nurr1 activation is not due to direct control
- Nurr1’s effect on BDNF is brain-region specific
- Cortical neurons show no BDNF change when Nurr1 is reduced
- Findings challenge assumptions about Nurr1’s broad role in brain function
Transcriptome Profiling and Network Analysis Provide Insights Into the Pathogenesis of Vulvar Lichen Sclerosus.
Wang L, Lv Q, Guo J, Wang J, Pan J
In vulvar lichen sclerosus, genes that normally calm T cell activity, including NR4A2, are underactive, leading to excessive immune responses. This imbalance contributes to chronic inflammation and reduced skin cell growth, suggesting potential targets for treatment.
- NR4A2 is downregulated in VLS, boosting T cell activity
- Overactive T cells drive inflammation in VLS
- Skin cell growth is impaired due to reduced proliferation
- NR4A2 may be a key regulator in immune balance
- Findings point to possible new treatment strategies
Steroid nuclear receptor coactivator 2 controls immune tolerance by promoting induced Treg differentiation via up-regulating Nr4a2.
Zhang W, Cao X, Zhong X, Wu H, Feng M, Gwack Y, Isakov N, Sun Z
SRC2 helps make regulatory T cells that prevent autoimmune reactions by turning on the Nr4a2 gene, which is essential for immune tolerance; without SRC2, mice develop autoimmune symptoms and worse inflammation.
- SRC2 boosts Treg development by activating Nr4a2
- Nr4a2 is critical for making immune-tolerant T cells
- SRC2 deficiency leads to autoimmunity in mice
- Targeting SRC2 could help treat immune disorders
- NR4A2 is a key player in immune regulation
Cannabis alters DNA methylation at maternally imprinted and autism candidate genes in spermatogenic cells.
Schrott R, Greeson KW, King D, Symosko Crow KM, Easley CA, Murphy SK
Paternal cannabis use alters DNA methylation at key genes linked to autism and neurodevelopment, including NR4A2, in sperm precursor cells, which may increase the risk of autism spectrum disorder in offspring.
- Cannabis changes methylation at autism-linked genes in sperm cells
- NR4A2, a gene tied to NR4A2-related syndrome, is affected
- Changes occur in sperm stem and maturation cells
- These findings support a link between paternal cannabis use and autism risk
- The study uses a human cell model to mimic long-term cannabis exposure
CREB Inactivation by HDAC1/PP1γ Contributes to Dopaminergic Neurodegeneration in Parkinson's Disease.
Xu X, He X, Zhang Z, Chen Y, Li J, Ma S, Huang Q, Li M
In Parkinson's disease, a key survival signal in dopamine-producing brain cells is turned off because a protein complex involving HDAC1 and PP1γ removes an activating chemical mark from CREB. This inactivation reduces levels of NURR1, a critical protein for neuron health, leading to cell death. Blocking the interaction between CREB and HDAC1 restored protective gene activity and protected neurons in a mouse model of Parkinson's.
- CREB, a survival protein, is inactivated in Parkinson's brain cells
- HDAC1 and PP1γ work together to shut down CREB
- Reduced CREB activity lowers NURR1, harming dopamine neurons
- Blocking CREB-HDAC1 interaction protects neurons in mice
- This pathway could be a new target for Parkinson's treatments
NURR1-deficient mice have age- and sex-specific behavioral phenotypes.
Montarolo F, Martire S, Chiara F, Allegra S, De Francia S, Hoxha E, Tempia F, Capobianco MA, Bertolotto A
Old mice missing one copy of the NURR1 gene show motor problems, higher brain dopamine levels, and increased heart rate regardless of sex, but reduced movement is seen only in males. These findings suggest NURR1 deficiency causes sex-specific and age-related changes in behavior, dopamine, and heart function.
- NURR1 deficiency causes motor issues in old mice
- Brain dopamine levels are increased in NURR1-deficient mice
- Heart rate is higher in NURR1-deficient mice
- Reduced movement only seen in male mice
- Sex and age affect how symptoms appear
Prenatal Hypoxia Affects Nicotine Consumption and Withdrawal in Adult Rats via Impairment of the Glutamate System in the Brain.
Stratilov VA, Vetrovoy OV, Tyulkova EI
Prenatal hypoxia in rats increases the risk of nicotine addiction in adulthood by disrupting glutamate signaling in brain regions involved in reward and addiction. This disruption leads to heightened nicotine consumption and more severe withdrawal symptoms, likely due to overactive glutamate inputs to dopamine neurons.
- Prenatal hypoxia increases nicotine addiction risk in adult rats
- Glutamate system disruption is linked to addiction-like behaviors
- No change in dopamine levels, but altered signaling via DARPP-32
- Increased glutamate input to dopamine neurons in the reward pathway
- Findings suggest early brain stress may predispose to substance use
Nuclear receptor NOR-1 (Neuron-derived Orphan Receptor-1) in pathological vascular remodelling and vascular remodelling.
Ballester-Servera C, Cañes L, Alonso J, Puertas L, Taurón M, Rodríguez C, Martínez-González J
NR4A2 (Nurr1) and related proteins play a key role in controlling inflammation, cell survival, and vascular remodeling in diseases like atherosclerosis, aneurysms, and pulmonary hypertension. These receptors are activated by stress and injury and help regulate genes involved in vascular health and disease.
- NR4A2 is active in blood vessel damage and repair
- It controls inflammation and cell survival in vascular tissues
- Linked to major vascular diseases like atherosclerosis and aneurysms
- May influence how blood vessels respond to injury and stress
Wnt/β-catenin signaling pathway is involved in early dopaminergic differentiation of trabecular meshwork-derived mesenchymal stem cells.
Sahebdel F, Parvaneh Tafreshi A, Arefian E, Roussa E, Nadri S, Zeynali B
Trabecular meshwork-derived stem cells show a stronger ability to become dopamine-producing brain cells than other common stem cell types, and activating the Wnt/β-catenin pathway boosts this process. This suggests a potential path for developing new treatments for Parkinson’s disease using these specific stem cells.
- TM-MSCs become dopamine neurons more effectively than other stem cells
- Wnt/β-catenin signaling drives TM-MSCs toward a dopamine cell fate
- Nurr-1, a key dopamine gene, increases with Wnt activation
- CHIR (Wnt activator) boosts dopamine markers; IWP-2 (inhibitor) reduces them
- These stem cells may offer a better route for Parkinson’s cell therapy
Nurr1 Modulation Mediates Neuroprotective Effects of Statins.
Willems S, Marschner JA, Kilu W, Faudone G, Busch R, Duensing-Kropp S, Heering J, Merk D
Statins, commonly used cholesterol drugs, protect brain cells by activating Nurr1, a key protein involved in brain health. This activation reduces inflammation, improves energy use in brain cells, and helps control cell growth, suggesting a clear biological mechanism for statins' brain benefits.
- Statins activate Nurr1, a critical brain-protective protein
- Nurr1 activation reduces brain cell inflammation
- Statins improve energy metabolism in neurons via Nurr1
- Nurr1 is essential for statins' protective effects
- These findings explain how statins may help brain disorders
Prostaglandin A2 Interacts with Nurr1 and Ameliorates Behavioral Deficits in Parkinson's Disease Fly Model.
Rajan S, Toh HT, Ye H, Wang Z, Basil AH, Parnaik T, Yoo JY, Lim KL, Yoon HS
PGA2 binds to the Nurr1 protein and activates it, improving movement and protecting neurons in a fruit fly model of Parkinson's disease, suggesting a potential therapeutic approach for NR4A2-related conditions.
- PGA2 activates Nurr1 by binding to it
- This binding improves movement and neuron survival in flies
- The effect is similar to other prostaglandins that target Nurr1
- The mechanism involves a structural change in the Nurr1 protein
- Findings may inform treatments for NR4A2-related disorders
Orphan Nuclear Receptor NR4A2 Is Constitutively Expressed in Cartilage and Upregulated in Inflamed Synovium From hTNF-Alpha Transgenic Mice.
Lilley CM, Alarcon A, Ngo MH, Araujo JS, Marrero L, Mix KS
NR4A2 is highly active in joint tissues during arthritis development in a mouse model of rheumatoid arthritis, with its levels rising as inflammation worsens. The protein appears in inflamed synovium before symptoms start, suggesting it plays a key role in driving joint damage.
- NR4A2 increases in arthritic joints before symptoms appear
- NR4A2 and NF-κB are active in inflamed synovium
- NR4A2 levels rise late in disease progression
- NR4A2 may drive inflammation and joint destruction
- This model is useful for testing NR4A2-targeting treatments
Disrupted myelination network in the cingulate cortex of Parkinson's disease.
Xie S, Yang J, Huang S, Fan Y, Xu T, He J, Guo J, Ji X, Wang Z, Li P, Chen J, Zhang Y
The cingulate cortex in Parkinson's disease shows disrupted myelination due to reduced activity in genes that support oligodendrocytes and myelin production, with key transcription factors like NR4A2 playing a role in regulating these pathways. This suggests that promoting remyelination could be a promising new treatment strategy for Parkinson's disease.
- Myelin production is impaired in the cingulate cortex of Parkinson's patients
- Oligodendrocytes, the cells that make myelin, are damaged in this brain region
- NR4A2 is among several key genes linked to myelin formation and neurodegeneration
- Remyelination may be a viable treatment approach for Parkinson's disease
- Findings are supported by data from multiple Parkinson's and dementia with Lewy bodies cohorts
Essential Roles of the Transcription Factor NR4A1 in Regulatory T Cell Differentiation under the Influence of Immunosuppressants.
Sekiya T, Kasahara H, Takemura R, Fujita S, Kato J, Doki N, Katayama Y, Ozawa Y, Takada S, Eto T, Fukuda T, Ichinohe T, Takanashi M, Onizuka M, Atsuta Y, Okamoto S, Yoshimura A, Takaki S, Mori T
The transcription factor NR4A1 helps regulatory T cells develop even when patients are taking calcineurin inhibitor drugs, which usually block this process. Boosting NR4A1 activity can restore T cell regulation and improve outcomes in transplant models, suggesting a potential strategy to reduce side effects of immunosuppressive therapy.
- NR4A1 supports regulatory T cell development despite calcineurin inhibitors
- NR4A1 is not suppressed by immunosuppressants like cyclosporine A
- Activating NR4A1 can restore T cell regulation in treated patients
- A genetic variant linked to lower NR4A1 increases graft-versus-host disease risk
- NR4A1 may be a target to improve transplant outcomes and reduce side effects
Identification and Verification of Potential Hub Genes in Amphetamine-Type Stimulant (ATS) and Opioid Dependence by Bioinformatic Analysis.
Zhang W, Deng X, Liu H, Ke J, Xiang M, Ma Y, Zhang L, Yang M, Liu Y, Huang F
NR4A2 is one of the top hub genes linked to both amphetamine and opioid dependence, suggesting it plays a key role in brain changes related to addiction. The PI3K/Akt pathway, which NR4A2 influences, is strongly involved in neuron survival and function, potentially affecting brain development and behavior.
- NR4A2 is a top hub gene in addiction-related brain changes
- NR4A2 affects neuron development, survival, and response to stress
- The PI3K/Akt pathway is central to addiction-related brain processes
- NR4A2 levels change in brain cells after drug exposure
- These findings may help understand and treat NR4A2-related neurodevelopmental conditions
Transcriptional Regulation of the Synaptic Vesicle Protein Synaptogyrin-3 (SYNGR3) Gene: The Effects of NURR1 on Its Expression.
Li L, Ho PW, Liu H, Pang SY, Chang EE, Choi ZY, Malki Y, Kung MH, Ramsden DB, Ho SL
NURR1, a key protein for dopamine neuron health, directly boosts the expression of SYNGR3, a protein critical for dopamine recycling. This suggests that drugs activating NURR1 could help restore proper dopamine function in conditions like Parkinson’s disease.
- NURR1 increases SYNGR3 gene activity in brain-like cells
- SYNGR3 helps regulate dopamine levels in the brain
- Activating NURR1 raises SYNGR3 protein levels
- This pathway may be targeted to treat dopamine-related disorders
- Findings support NURR1 activators as potential therapy
Pharmacological Rescue with SR8278, a Circadian Nuclear Receptor REV-ERBα Antagonist as a Therapy for Mood Disorders in Parkinson's Disease.
Kim J, Park I, Jang S, Choi M, Kim D, Sun W, Choe Y, Choi JW, Moon C, Park SH, Choe HK, Kim K
This study shows that a drug called SR8278, which blocks a circadian protein called REV-ERBα, improves mood and anxiety symptoms in a mouse model of Parkinson's disease, especially at times equivalent to dusk—when sundowning occurs in people. The drug restores normal activity of key brain genes involved in dopamine production, suggesting it could help treat mood-related circadian issues in Parkinson's.
- SR8278 improves mood and anxiety in Parkinson's mice at dusk-like times
- The drug restores dopamine-related gene activity in the brain
- REV-ERBα blockade may treat circadian mood symptoms like sundowning
- Gene activity changes were seen in the ventral tegmental area
- Results suggest a potential therapy for Parkinson's mood disorders
ADRAM is an experience-dependent long noncoding RNA that drives fear extinction through a direct interaction with the chaperone protein 14-3-3.
Wei W, Zhao Q, Wang Z, Liau WS, Basic D, Ren H, Marshall PR, Zajaczkowski EL, Leighton LJ, Madugalle SU, Musgrove M, Periyakaruppiah A, Shi J, Zhang J, Mattick JS, Mercer TR, Spitale RC, Li X, Bredy TW
ADRAM is a brain lncRNA that helps form fear extinction memories by guiding a key protein to the NR4A2 gene, which is critical for learning and memory. This process depends on prior experience and directly links lncRNA activity to a gene known to be involved in neurodevelopmental disorders.
- ADRAM helps form fear extinction memories
- ADRAM recruits a protein to the NR4A2 gene
- NR4A2 is linked to neurodevelopmental conditions
- This mechanism depends on prior experience
- LncRNAs from enhancer regions regulate memory genes
Ferulic Acid Induces NURR1 Expression and Promotes Dopaminergic Differentiation in Neural Precursor Cells.
Sadeghi-Zadeh M, Homayouni Moghadam F, Nasr-Esfahani MH
Ferulic acid boosts the expression of NURR1, a key protein for developing dopamine-producing brain cells, and helps neural precursor cells turn into dopamine neurons. This suggests ferulic acid could support therapies aimed at replacing lost dopamine neurons.
- Ferulic acid increases NURR1, a critical factor for dopamine neuron development
- It promotes the growth of dopamine neurons from neural precursor cells
- Ferulic acid enhances neuron structure and function in lab studies
- It may help in developing treatments for conditions like NR4A2-related syndrome
Structural, molecular hybridization and network based identification of miR-373-3p and miR-520e-3p as regulators of NR4A2 human gene involved in neurodegeneration.
Singh J, Raina A, Sangwan N, Chauhan A, Avti PK
miR-373-3p and miR-520e-3p are the most likely microRNAs to regulate the NR4A2 gene, which is linked to neurodegeneration and brain development. These microRNAs bind strongly to both ends of the NR4A2 mRNA, potentially reducing its activity and affecting brain health.
- miR-373-3p and miR-520e-3p strongly target NR4A2 mRNA
- They bind at both 3' and 5' ends with perfect seed match
- This may reduce NR4A2 protein levels, affecting brain function
- These miRNAs are linked to key neurodegeneration pathways
- NR4A2 regulation may be a target for future therapies
Role of Nuclear-Receptor-Related 1 in the Synergistic Neuroprotective Effect of Umbilical Cord Blood and Erythropoietin Combination Therapy in Hypoxic Ischemic Encephalopathy.
Choi JW, Kang SJ, Choi JI, Kwack K, Kim M
Combining umbilical cord blood and erythropoietin therapy protects the brain in newborns with hypoxic-ischemic injury, and this effect depends on activating a gene called Nurr1 through the Wnt/β-catenin pathway.
- Nurr1 gene activation is key to the brain protection from combined therapy
- Wnt/β-catenin signaling is boosted by the treatment
- Combination therapy reduces brain damage more than either treatment alone
- Findings come from a mouse model of newborn brain injury
- Nurr1 is a potential target for future treatments in NR4A2-related conditions
The Selective Agonist for Sphingosine-1-Phosphate Receptors Siponimod Increases the Expression Level of NR4A Genes in Microglia Cell Line.
Montarolo F, Martire S, Marnetto F, Valentino P, Valverde S, Capobianco MA, Bertolotto A
Siponimod, a drug used to treat multiple sclerosis, increases the levels of NR4A2 and NR4A1 genes in microglia, brain cells involved in inflammation. This suggests a possible new way the drug reduces brain inflammation and protects nerves, which may be relevant for NR4A2-related conditions.
- Siponimod boosts NR4A2 and NR4A1 in brain microglia
- NR4A2 is anti-inflammatory and low in MS patients
- Effect seen only in microglia, not other brain or blood cells
- May explain siponimod’s protective effects in the brain
- Could inform future treatments for NR4A2-related disorders
Evidence That Substantia Nigra Pars Compacta Dopaminergic Neurons Are Selectively Vulnerable to Oxidative Stress Because They Are Highly Metabolically Active.
Ni A, Ernst C
SNpc dopaminergic neurons are highly vulnerable to oxidative stress because they have unusually high energy demands due to their unique structure and electrical activity, requiring constant ATP production. This metabolic burden makes them especially sensitive to disruptions in energy production, such as those caused by genetic defects or aging.
- SNpc neurons need more energy than other brain cells
- High energy use makes them prone to damage from stress
- Their development programs them for high metabolism
- This explains why they are lost in Parkinson’s disease
- Targeting energy metabolism may protect these neurons
The Effects of Prenatal Exposure to Pregabalin on the Development of Ventral Midbrain Dopaminergic Neurons.
Alsanie WF, Alhomrani M, Gaber A, Habeeballah H, Alkhatabi HA, Felimban RI, Abdelrahman S, Hauser CAE, Chaudhary AG, Alamri AS, Raafat BM, Alamri A, Anwar S, Alswat KA, Althobaiti YS, Asiri YA
Pregabalin exposure during early brain development disrupts the formation and function of dopamine-producing neurons in the midbrain, even at therapeutic doses, though it does not kill the neurons. This may affect movement, behavior, and cognition, raising concerns about using pregabalin during pregnancy.
- Pregabalin harms dopamine neuron development in early brain growth
- Therapeutic doses reduce ATP release, affecting neuron function
- Neuron survival remains intact, but wiring and maturation are impaired
- Findings suggest caution with pregabalin use in pregnancy
- Dopamine neurons are critical for movement, behavior, and thinking
[Protective effect of nuclear receptor related 1 (Nurr1) on nerves in rats with cerebral occlusion/reperfusion injury and its mechanism].
Hu D, Xie X, Zhang H
Overexpressing the Nurr1 protein protects brain cells in rats after a stroke-like injury by reducing brain damage, inflammation, and cell death. It does this by boosting antioxidant activity, lowering harmful oxidative stress, and blocking a key cell death pathway.
- Nurr1 reduces brain damage after stroke in rats
- Nurr1 lowers inflammation and oxidative stress
- Nurr1 protects nerve cells by blocking cell death
- Nurr1 boosts protective proteins and antioxidants
- Findings suggest Nurr1 could be a treatment target
Reprogramming by Cytosolic Extract of Human Embryonic Stem Cells to Improve Dopaminergic Differentiation Potential of Human Adipose Tissue-derived Stem Cells.
Mobasseri S, Javeri A, Fakhr Taha M
Treating human fat-derived stem cells with extracts from embryonic stem cells makes them more capable of turning into dopamine-producing brain cells, which could help in treating conditions like Parkinson's disease.
- Stem cell extract reprograms fat-derived cells to become more flexible
- Reprogrammed cells show stronger ability to become dopamine-producing neurons
- This method boosts key brain cell genes linked to Parkinson's disease
- The process is fast and could support future cell-based therapies
Integration of transcriptomics and metabolomics provides metabolic and functional insights into reduced insulin secretion in MIN6 β-cells exposed to deficient and excessive arginine.
Xu L, Lin X, Li X, Hu Z, Hou Q, Wang Y, Wang Z
Both too little and too much arginine impair insulin release from pancreatic cells, disrupting key metabolic pathways and increasing cellular stress. These findings suggest that arginine balance is critical for proper insulin function, with potential implications for metabolic health.
- Low and high arginine both reduce insulin secretion
- Arginine imbalance disrupts energy and amino acid metabolism
- Cellular stress and DNA damage increase under abnormal arginine levels
- Insulin release correlates with specific metabolites like glutamate and creatine
- NR4A2 and p53 may regulate responses to arginine changes
Striatal dopaminergic neurons as a potential target for GDNF based ischemic stroke therapy.
Beker MÇ, Beker M, Çağlayan AB, Bolat B, Kılıç Ü, Torun Köse G, Kılıç E
GDNF treatment did not increase dopamine-producing neurons after stroke in mice, but it reduced brain cell death and boosted protective proteins linked to dopamine neuron health. This suggests GDNF may help protect brain cells after stroke, even if it doesn’t directly grow new dopamine neurons.
- GDNF reduced brain cell death after stroke
- GDNF boosted protective proteins in dopamine neurons
- No increase in dopamine neurons found
- GDNF activated stress and repair pathways
- Results are from mouse stroke models, not humans
Scaffold Hopping from Amodiaquine to Novel Nurr1 Agonist Chemotypes via Microscale Analogue Libraries.
Willems S, Müller M, Ohrndorf J, Heering J, Proschak E, Merk D
Researchers developed new Nurr1-activating drugs by modifying the structure of amodiaquine, a known Nurr1 activator, leading to a completely different chemical structure with stronger activity. The study identified key features needed for effective Nurr1 activation, which could guide future drug development for NR4A2-related disorders.
- New Nurr1 drugs were created by redesigning amodiaquine
- The new compounds are more potent than the original lead
- A clear pattern of essential chemical features for Nurr1 activation was found
- These findings could speed up development of treatments for NR4A2-related conditions
Monocyte Gene and Molecular Expression Profiles Suggest Distinct Effector and Regulatory Functions in Beninese HIV Highly Exposed Seronegative Female Commercial Sex Workers.
Blondin-Ladrie L, Fourcade L, Modica A, Aranguren M, de Montigny N, Labbé AC, Alary M, Guédou F, Poudrier J, Roger M
Beninese women who remain uninfected with HIV despite frequent exposure show unique blood monocyte profiles linked to both immune defense and regulation, which may explain their natural resistance to HIV. These monocytes express genes involved in fighting HIV and controlling immune responses, including NR4A2, a gene associated with immune tolerance and inflammation control.
- HESN women have monocytes with enhanced HIV-fighting genes
- NR4A2 and other regulatory genes are upregulated in HESN monocytes
- Monocyte profiles match protective immune features seen in the genital tract
- These changes may underlie natural resistance to HIV infection
- Findings suggest immune regulation pathways could be therapeutic targets
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 the CB2 receptor in microglia boosts Nurr1 activity, which reduces the cells' ability to clear debris. This pathway involves ERK and AKT signaling and may influence neurodegeneration. The findings suggest that targeting CB2 or Nurr1 could affect brain inflammation and disease progression.
- CB2 activation increases Nurr1 in microglia
- Nurr1 reduces microglial phagocytosis
- ERK pathway is key in regulating Nurr1
- Blocking ERK reverses reduced phagocytosis
- This pathway may affect neurodegenerative diseases