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
NR4A ablation improves mitochondrial fitness for long persistence in human CAR-T cells against solid tumors.
Nakagawara K, Ando M, Srirat T, Mise-Omata S, Hayakawa T, Ito M, Fukunaga K, Yoshimura A
Deleting all three NR4A genes in human CAR-T cells makes them more resistant to exhaustion, improves their ability to kill solid tumors, and helps them survive longer in the body by boosting mitochondrial function. This approach works across different donors, including older individuals, and shows strong promise for treating solid tumors.
- NR4A gene deletion boosts CAR-T cell survival and tumor-killing ability
- Triple knockout enhances mitochondrial energy production
- Improved performance seen in cells from diverse donors, including older adults
- Results show stronger anti-tumor effects in both lab and animal models
- Targeting NR4A may lead to better CAR-T therapies for solid tumors
Author Correction: The Nurr1 ligand indole acetic acid hydrazide loaded onto ZnFe2O4 nanoparticles suppresses proinflammatory gene expressions in SimA9 microglial cells.
Qasim R, Thiab TA, Alhindi T, Al-Hunaiti A, Imraish A
A compound called indole acetic acid hydrazide, delivered via zinc ferrite nanoparticles, reduces inflammation in mouse brain cells that model microglial activity. This suggests a potential way to calm harmful brain inflammation in NR4A2-related disorders.
- A drug candidate reduces brain cell inflammation
- Nanoparticles deliver the drug effectively
- Targets microglial overactivity linked to NR4A2 issues
- May help with neuroinflammation in NR4A2 syndrome
Whole-genome sequencing identifies novel genes for autism in Chinese trios.
Chang S, Liu JJ, Zhao Y, Pang T, Zheng X, Song Z, Zhang A, Gao X, Luo L, Guo Y, Liu J, Yang L, Lu L
This study used whole-genome sequencing in Chinese autism families and identified NR4A2 as a high-confidence risk gene for autism, along with several other genes linked to brain development and gene regulation. The findings suggest that NR4A2 variants may disrupt gene expression and contribute to autism symptoms, with supporting evidence from gene networks and brain activity patterns.
- NR4A2 is a strong autism risk gene identified in Chinese families
- NR4A2 variants affect gene expression and brain-related processes
- Other genes like SHANK3 and CHD8 were also confirmed
- De novo variants increase with parental age
- Findings support NR4A2's role in neurodevelopment
ASCL1-mediated direct reprogramming: converting ventral midbrain astrocytes into dopaminergic neurons for Parkinson's disease therapy.
Yong SH, Kim SM, Kong GW, Ko SH, Lee EH, Oh Y, Park CH
This study shows that astrocytes from the ventral midbrain can be directly converted into dopamine-producing neurons using a single gene, ASCL1, which may lead to new treatments for Parkinson's disease. The reprogrammed neurons matured over two weeks and showed key markers of healthy dopamine neurons.
- ASCL1 alone reprograms ventral midbrain astrocytes into dopamine neurons
- Reprogrammed neurons express key markers of mature dopaminergic neurons
- Only ventral midbrain astrocytes, not others, can be converted this way
- This approach could lead to regenerative therapies for Parkinson's disease
- No need for additional transcription factors like NURR1 or LMX1A
CCL22 Induces the Polarization of Immature Dendritic Cells into Tolerogenic Dendritic Cells in Radiation-Induced Lung Injury through the CCR4-Dectin2-PLC-γ2-NFATC2-Nr4a2-PD-L1 Signaling Pathway.
Liu B, Wang Y, Ma L, Chen G, Yang Z, Zhu M
Ionizing radiation triggers lung cells to release CCL22, which recruits immune cells and reprograms them into tolerant cells that reduce inflammation. This process involves a specific signaling pathway that activates Nr4a2, a gene linked to immune regulation, and may offer new treatment targets for radiation lung injury.
- Radiation increases CCL22 in lung cells
- CCL22 recruits immune cells to injury sites
- CCL22 reprograms immune cells into tolerant types
- Nr4a2 is a key gene in this immune regulation pathway
- This pathway could be targeted to treat radiation lung injury
Structural Optimization of Oxaprozin for Selective Inverse Nurr1 Agonism.
Willems S, Busch R, Nawa F, Ballarotto M, Lillich FF, Kasch T, López-García Ú, Marschner JA, Rüger LA, Renelt B, Ohrndorf J, Arifi S, Zaienne D, Proschak E, Pabel J, Merk D
Researchers modified oxaprozin, a drug originally used for arthritis, to create new compounds that specifically target Nurr1, a protein linked to brain health and neurodegenerative diseases. These new compounds block Nurr1's constant activity and show improved strength and selectivity, offering a potential path for treating conditions like Parkinson’s and Alzheimer’s.
- Oxaprozin was redesigned to target Nurr1 more precisely
- New compounds block Nurr1’s constant activity
- Improved potency and selectivity for Nurr1 over other receptors
- Potential for treating Parkinson’s and Alzheimer’s disease
- A step toward developing therapies for NR4A2-related disorders
The roles of orphan nuclear receptor 4 group A1 and A2 in fibrosis.
Gao L, Wang H, Fang F, Liu J, Zhao C, Niu J, Wang Z, Zhong Y, Wang X
NR4A2 helps prevent fibrosis by blocking the TGF-β signaling pathway, which drives scar tissue buildup. Lower NR4A2 activity may contribute to excessive fibrosis in organs like the lungs, liver, and kidneys.
- NR4A2 reduces fibrosis by inhibiting TGF-β signaling
- Low NR4A2 levels may worsen tissue scarring
- NR4A2 protects against collagen and fibronectin buildup
- NR4A2 is a potential target for anti-fibrotic treatments
Genoarchitectural Definition of the Adult Mouse Mesocortical Ring: A Contribution to Cortical Ring Theory.
Puelles L, Alonso A, García-Calero E
This study defines the molecular boundaries of a specific brain region in mice called the mesocortex, which may help clarify the structure and function of brain areas involved in higher thinking and behavior. It shows that a region previously thought to be part of the mesocortex, the retrosplenial area, does not share its molecular signature and likely belongs elsewhere, refining how we understand brain organization.
- The mesocortex has a unique molecular profile in mice.
- The retrosplenial area is not part of the mesocortex, despite prior belief.
- NR4A2 is expressed in the retrosplenial area, not in the mesocortex.
- This study redefines brain region boundaries using gene expression data.
- Findings may help interpret human brain disorders involving NR4A2.
Development of Nurr1 agonists from amodiaquine by scaffold hopping and fragment growing.
Sai M, Hank EC, Tai HM, Kasch T, Lewandowski M, Vincendeau M, Marschner JA, Merk D
Researchers developed new Nurr1 agonists from the drug amodiaquine, creating potent compounds that activate Nurr1, a key protein involved in brain health. In lab-grown human brain tissue with a Parkinson’s-related mutation, the new compounds restored a critical protein, suggesting potential for treating NR4A2-related disorders.
- New Nurr1 activators were designed from amodiaquine
- Compounds show strong activity at nanomolar levels
- Restored a key brain protein in Parkinson’s-like human tissue
- These are promising tools for studying NR4A2-related conditions
- Potential for future therapies targeting Nurr1
Analysis of machine learning based integration to identify the crosslink between inflammation and immune response in non-alcoholic fatty liver disease through bioinformatic analysis.
Yu R, Huang Y, Hu X, Chen J
This study identifies NR4A2 as one of five key genes linked to nonalcoholic fatty liver disease (NAFLD), suggesting it may serve as a diagnostic marker and potential treatment target. The findings highlight NR4A2's role in immune responses and liver inflammation, offering insights into how metabolic and immune processes interact in NAFLD.
- NR4A2 is a top candidate biomarker in NAFLD
- NR4A2 is linked to immune cell activity and liver inflammation
- The gene may help diagnose or treat NAFLD
- Findings connect metabolism, immunity, and liver damage
- Results support new diagnostic and therapeutic strategies
iPSC-Derived Astrocytes and Neurons Replicate Brain Gene Expression, Epigenetic, Cell Morphology and Connectivity Alterations Found in Autism.
Mostafavi Abdolmaleky H, Alam R, Nohesara S, Deth RC, Zhou JR
Cells derived from autism patients show gene expression and epigenetic changes similar to those seen in autistic brains, including altered levels of NURR1 and inflammation-related genes, which may help develop personalized treatments.
- NURR1 is reduced in autism-derived astrocytes
- Inflammation genes like IL6 and TGFB2 are overactive
- Epigenetic changes match those in real autistic brain tissue
- Neurons show poor growth and connectivity
- These lab-grown cells mirror real brain changes
The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis.
Woo MS, Bal LC, Winschel I, Manca E, Walkenhorst M, Sevgili B, Sonner JK, Di Liberto G, Mayer C, Binkle-Ladisch L, Rothammer N, Unger L, Raich L, Hadjilaou A, Noli B, Manai AL, Vieira V, Meurs N, Wagner I, Pless O, Cocco C, Stephens SB, Glatzel M, Merkler D, Friese MA
NR4A2 and its target VGF drive brain cell death during inflammation by forcing neurons to rely on glycolysis, a metabolic shift that worsens neurodegeneration. Blocking VGF protects neurons in mouse models of MS, suggesting a potential treatment path.
- NR4A2 triggers harmful metabolic changes in neurons
- VGF secretion increases cell death during inflammation
- High VGF levels found in MS patients' brains and blood
- Deleting VGF protects neurons in MS mouse models
- Targeting this pathway may slow neurodegeneration