Structurally Distinct Nurr1 Ligands Exhibit Different Pharmacological Characteristics in Regulating Inflammatory Responses of Microglial BV-2 Cells.
Nakanishi R, Kurauchi Y, Kotani S, Hitora-Imamura N, Seki T, Katsuki H
Different Nurr1-targeting drugs reduce brain inflammation in lab tests in unique ways, with one drug blocking a key inflammatory pathway and another boosting Nurr1 protein levels, suggesting some drugs may work better than others for NR4A2-related conditions.
- Three Nurr1 ligands reduce inflammation in brain immune cells
- 5-CNA strongly blocks iNOS and IL-6, unlike others
- Amodiaquine stops NF-κB from entering the nucleus
- C-DIM12 increases Nurr1 protein levels in cells
- Drugs can cancel each other’s effects when combined
Unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neuropathology and behavioral deficits in parkinsonian rats with α-synucleinopathy.
Gatica-Garcia B, Bannon MJ, Martínez-Dávila IA, Soto-Rojas LO, Reyes-Corona D, Escobedo L, Maldonado-Berny M, Gutierrez-Castillo ME, Espadas-Alvarez AJ, Fernandez-Parrilla MA, Mascotte-Cruz JU, Rodríguez-Oviedo CP, Valenzuela-Arzeta IE, Luna-Herrera C, Lopez-Salas FE, Santoyo-Salazar J, Martinez-Fong D
Giving a single dose of the Nurr1 gene to dopamine neurons in one side of the brain reduces damage and movement problems on both sides of the brain in a rat model of Parkinson's disease. This treatment lowers harmful protein buildup, protects brain cells, reduces brain inflammation, and improves motor function.
- Unilateral Nurr1 gene delivery protects both sides of the brain
- Reduces toxic alpha-synuclein clumps and neuron loss
- Decreases brain inflammation and boosts protective factors
- Improves movement and motor behavior
- Supports Nurr1 as a potential therapy for Parkinson’s
Transcriptional profiling of Kiss1 neurons from arcuate and rostral periventricular hypothalamic regions in female mice.
Manchishi S, Prater M, Colledge WH
This study compared the gene activity in two groups of kisspeptin-producing neurons in female mice, revealing distinct molecular profiles that help explain their different roles in fertility and hormone regulation.
- Kisspeptin neurons in two brain regions have unique gene signatures
- NR4A2 is expressed in arcuate neurons, not rostral ones
- These neurons use different neurotransmitters and signaling pathways
- Findings may help understand reproductive disorders and hormone control
- Data could inform future treatments targeting these neurons
Natural products and synthetic analogs as selective orphan nuclear receptor 4A (NR4A) modulators.
Safe S
Certain natural and synthetic compounds can selectively target NR4A2 (Nurr1), a protein linked to neurological development and function, and may influence its activity in ways that could be useful for treating conditions like NR4A2-related syndrome. These compounds show varied effects on NR4A receptors, suggesting potential for developing targeted therapies with specific benefits.
- Natural and synthetic compounds bind NR4A2 and other NR4A receptors
- Some compounds selectively activate or modulate NR4A2 activity
- Cytosporone B analogs show distinct effects on NR4A2 and related receptors
- These findings support development of targeted NR4A modulators
- Potential for new treatments in NR4A2-related disorders
Application of OpenArray Technology to Assess Changes in the Expression of Functionally Significant Genes in the Substantia Nigra of Mice in a Model of Parkinson's Disease.
Troshev D, Kolacheva A, Pavlova E, Blokhin V, Ugrumov M
This study found that in a mouse model of Parkinson's disease, key genes involved in dopamine production, transport, and neuronal health are significantly reduced in the brain's substantia nigra. These changes mirror those seen in human Parkinson's and highlight pathways that could be targeted to protect or restore dopaminergic neurons.
- NR4A2 expression is reduced in Parkinson's model mice
- Dopamine-related genes are downregulated
- Neuronal transport and antioxidant systems are impaired
- Changes suggest potential therapeutic targets
- Findings align with human Parkinson's pathology
Correction to: Adeno-associated virus (AAV) 9-mediated gene delivery of Nurr1 and Foxa2 ameliorates symptoms and pathologies of Alzheimer disease model mice by suppressing neuro-inflammation and glial pathology.
Yang Y, Seok MJ, Kim YE, Choi Y, Song JJ, Sulistio YA, Kim SH, Chang MY, Oh SJ, Nam MH, Kim YK, Kim TG, Im HI, Koh SH, Lee SH
This study shows that delivering the Nurr1 gene using AAV9 virus reduces brain inflammation and improves symptoms in mice with Alzheimer's-like disease, suggesting a potential treatment approach for NR4A2-related disorders.
- AAV9 delivers Nurr1 gene to the brain
- Reduces brain inflammation and glial cell problems
- Improves symptoms in Alzheimer's model mice
- Nurr1 is the human gene affected in NR4A2 syndrome
- Suggests gene therapy could help NR4A2-related conditions
Correction: Adeno-associated virus (AAV) 9-mediated gene delivery of Nurr1 and Foxa2 ameliorates symptoms and pathologies of Alzheimer disease model mice by suppressing neuro-inflammation and glial pathology.
Yang Y, Seok MJ, Kim YE, Choi Y, Song JJ, Sulistio YA, Kim SH, Chang MY, Oh SJ, Nam MH, Kim YK, Kim TG, Im HI, Koh SH, Lee SH
Gene therapy using AAV9 to deliver Nurr1 and Foxa2 genes reduces brain inflammation and improves symptoms in mice with Alzheimer's-like disease, suggesting a potential treatment approach for neurodegenerative conditions involving Nurr1 dysfunction.
- AAV9 delivers Nurr1 and Foxa2 genes to the brain
- Reduces brain inflammation and glial cell overactivity
- Improves symptoms in Alzheimer's model mice
- Nurr1 is the human gene mutated in NR4A2-related syndrome
- Supports gene therapy as a possible future treatment
(-)-Epigallocatechin-3-gallate promotes intestinal epithelial proliferation and barrier function after ischemia/reperfusion injury via activation of Nurr1.
Gao J, Wang Y, Jia Z, Xue J, Zhou T, Zu G
EGCG, a compound in green tea, helps repair intestinal cells and strengthen the gut barrier after injury by activating the Nurr1 protein, which is relevant to NR4A2-related syndrome.
- EGCG boosts gut cell growth and barrier strength after injury
- It works by turning on the Nurr1 protein
- Blocking Nurr1 stops EGCG’s benefits
- Effects seen in both rats and gut cells
- Nurr1 is the same protein affected in NR4A2 syndrome
The role of Nurr1-miR-30e-5p-NLRP3 axis in inflammation-mediated neurodegeneration: insights from mouse models and patients' studies in Parkinson's disease.
Li T, Tan X, Tian L, Jia C, Cheng C, Chen X, Wei M, Wang Y, Hu Y, Jia Q, Ni Y, Al-Nusaif M, Li S, Le W
This study identifies a molecular pathway involving Nurr1, miR-30e-5p, and NLRP3 that drives inflammation and brain cell damage in Parkinson’s disease. The findings show that low Nurr1 levels lead to reduced miR-30e-5p, which fails to suppress NLRP3, causing harmful inflammation and dopamine neuron loss.
- Nurr1 deficiency increases brain inflammation and neuron damage
- miR-30e-5p normally blocks NLRP3; low levels worsen inflammation
- This pathway is active in both Parkinson’s patients and mouse models
- Targeting this axis may lead to new treatments for Parkinson’s
- Blood tests could one day track this pathway as a biomarker
The Promotion of Humoral Immune Responses in Humans via SOCS1-Mediated Th2-Bias Following SARS-CoV-2 Vaccination.
Liu X, Han J, Cui R, Peng M, Song H, Li R, Chen G
After SARS-CoV-2 vaccination, people who produced more antibodies had a shift toward Th2 immune responses driven by increased SOCS1 and NR4A2 in regulatory T cells. These genes help boost antibody production, suggesting they could be targets for improving vaccine responses.
- NR4A2 and SOCS1 are linked to stronger antibody responses after vaccination
- Th2 immune bias improves humoral immunity in humans
- Treg cells with high NR4A2/SOCS1 produce more antibodies
- MALAT1 and NEAT1 lncRNAs are also involved in antibody production
- These genes may guide better vaccine strategies or treatments
Compensatory Processes in Striatal Neurons Expressing the Tyrosine Hydroxylase Gene in Transgenic Mice in a Model of Parkinson's Disease.
Troshev D, Bannikova A, Blokhin V, Pavlova E, Kolacheva A, Ugrumov M
In a mouse model of Parkinson's disease, neurons in the striatum increase production of dopamine by turning on genes that make dopamine-synthesizing enzymes, especially in response to dopamine neuron loss. This compensatory activity happens in both nerve fibers and cell bodies, suggesting the brain can naturally boost dopamine in the striatum when needed.
- Striatal neurons increase dopamine production after dopamine neuron loss
- The brain activates TH and Nurr1 genes to boost dopamine synthesis
- Dopamine-making enzymes appear in neuron cell bodies, not just fibers
- This natural compensation may help maintain movement control
- Targeting this process could improve Parkinson's treatments
Epigenetic regulation of beta-endorphin synthesis in hypothalamic arcuate nucleus neurons modulates neuropathic pain in a rodent pain model.
Tao Y, Zhang Y, Jin X, Hua N, Liu H, Qi R, Huang Z, Sun Y, Jiang D, Snutch TP, Jiang X, Tao J
This study identifies a specific epigenetic pathway in brain neurons that controls pain by regulating the production of beta-endorphin, a natural pain-relieving substance. It shows that nerve injury triggers changes in gene regulation involving NR4A2, leading to increased levels of a microRNA that blocks the creation of beta-endorphin, worsening pain.
- NR4A2 activation increases a microRNA that blocks pain relief
- This microRNA stops the production of beta-endorphin
- The pathway is linked to neuropathic pain in rats and humans
- Targeting this pathway could lead to new pain treatments
- Changes occur in brain neurons involved in pain control
Exploring Fatty Acid Mimetics as NR4A Ligands.
Stiller T, Merk D
Fatty acid mimetics (FAMs) can activate or inhibit NR4A receptors, including NURR1, which is linked to NR4A2-related syndrome. Researchers discovered new FAM compounds that strongly bind and modulate NR4A receptors, showing promise as potential treatments.
- FAMs bind and activate NURR1, the protein affected in NR4A2 syndrome
- New FAM compounds show strong activity at submicromolar levels
- These compounds could become future therapies for NR4A2-related conditions
- The findings support developing FAM-based drugs for neurological disorders
Structure-Guided Design of Nurr1 Agonists Derived from the Natural Ligand Dihydroxyindole.
Sai M, Vietor J, Kornmayer M, Egner M, López-García Ú, Höfner G, Pabel J, Marschner JA, Wein T, Merk D
Researchers developed new compounds that activate Nurr1, a key protein involved in brain development and function, using a natural molecule as a starting point. These compounds show strong binding and activity in cells, suggesting potential for treating NR4A2-related disorders by boosting Nurr1 function.
- New Nurr1-activating compounds were designed from a natural molecule
- Compounds show strong binding and cellular activity
- Multiple binding sites may allow flexible drug design
- Findings support Nurr1 as a treatable target for NR4A2 syndrome
Single-nuclei RNA sequencing uncovers heterogenous transcriptional signatures in Parkinson's disease associated with nuclear receptor-related factor 1 defect.
Kambey PA, Liu WY, Wu J, Bosco B, Nadeem I, Kanwore K, Gao DS
Nurr1 deficiency in dopaminergic neurons leads to increased expression of Cd74 and other immune-related genes, triggering neuron damage and Parkinson's-like symptoms. This suggests that targeting Cd74 or related immune pathways could be a new treatment strategy for Parkinson's disease.
- Nurr1 deficiency increases Cd74 expression in dopamine neurons
- Cd74 rise is linked to immune activation and neuron loss
- This immune response may drive Parkinson's symptoms
- Cd74 could be a new target for Parkinson's treatments
- Findings come from mouse models with Nurr1 knockdown
Bioinformatics led discovery of biomarkers related to immune infiltration in diabetes nephropathy.
Wang S, Chen S, Gao Y, Zhou H
This study identified NR4A2 as one of seven key genes linked to immune activity in diabetic kidney disease, suggesting it may play a role in inflammation and immune cell recruitment in the kidneys. The findings highlight potential biomarkers for diagnosing and treating diabetic nephropathy.
- NR4A2 is a hub gene linked to immune infiltration in diabetic kidney disease
- Seven genes, including NR4A2, are potential biomarkers for disease progression
- Immune cell patterns differ between patient subgroups based on these genes
- Findings may guide future diagnosis and treatment strategies
- Results are based on human gene expression data and in vitro validation
A role of NR4A2 in Graves' disease: regulation of Th17/Treg.
Zhao S, Wang X, Huang F, Zhou Y, Meng D, Zhao D, Wang J, Zhang H, Wu L, Zhang Y, Zhao L, Zhang L, Song Y, Wang Q
NR4A2 levels are low in immune cells of people with Graves' disease, which reduces the production of regulatory T cells and disrupts immune balance, contributing to the disease. This suggests NR4A2 could be a target for new treatments.
- NR4A2 is underactive in Graves' disease patients
- Low NR4A2 reduces regulatory T cells and IL-10
- NR4A2 does not affect Th17 cells
- NR4A2 imbalance disrupts immune balance
- Restoring NR4A2 may help treat Graves' disease
Ferulic Acid reduces amyloid beta mediated neuroinflammation through modulation of Nurr1 expression in microglial cells.
Moghimi-Khorasgani A, Homayouni Moghadam F, Nasr-Esfahani MH
Ferulic acid helps calm overactive brain immune cells (microglia) by boosting Nurr1, a protein that reduces brain inflammation, especially in the presence of toxic amyloid beta. This suggests ferulic acid could help protect the brain in conditions involving neuroinflammation, including those linked to NR4A2/NURR1 dysfunction.
- Ferulic acid boosts Nurr1, reducing brain inflammation
- It helps microglia return to a healthy, non-inflammatory state
- May protect against amyloid beta damage in the brain
- Could be used preventatively or therapeutically
- Supports NR4A2/NURR1 pathway function
Neuroprotective effects of osmotin in Parkinson's disease-associated pathology via the AdipoR1/MAPK/AMPK/mTOR signaling pathways.
Park JS, Choe K, Lee HJ, Park TJ, Kim MO
Osmotin protects brain cells in models of Parkinson's disease by boosting the Nurr1 protein, reducing brain inflammation, clearing toxic alpha-synuclein buildup, and improving movement and memory. It works through key cellular pathways linked to energy regulation and cell survival.
- Osmotin boosts Nurr1, a critical brain protein
- Reduces alpha-synuclein buildup via autophagy
- Protects dopamine-producing neurons
- Improves motor and cognitive symptoms
- Acts through AdipoR1/MAPK/AMPK/mTOR pathways
Mechanisms of NURR1 Regulation: Consequences for Its Biological Activity and Involvement in Pathology.
García-Yagüe ÁJ, Cuadrado A
NURR1 is a critical protein for brain development and function, especially in dopamine-producing neurons, and its malfunction is linked to neurological diseases. The protein's activity is controlled by several mechanisms, including chemical modifications and interactions with other proteins, which affect its stability and function.
- NURR1 is essential for dopamine neuron development and function
- Its activity is regulated by phosphorylation and SUMOylation
- Changes in location or protein partners also affect NURR1 function
- Dysregulation of NURR1 is linked to neurodegenerative diseases
- Understanding these controls may lead to new treatments
The spatiotemporal dynamics of spatially variable genes in developing mouse brain revealed by a novel computational scheme.
Hong Y, Song K, Zhang Z, Deng Y, Zhang X, Zhao J, Jiang J, Zhang Q, Guo C, Peng C
This study developed a new computational tool, SVGbit, to identify key genes active in specific brain regions during mouse brain development. It found that Nr4a2 expression helps separate the neocortex and hippocampus as the brain matures, highlighting its role in brain organization.
- Nr4a2 expression changes during brain development
- SVGbit identifies important brain region genes
- Gene combinations help define brain sub-regions
- Tool works with mouse brain data
- Findings may inform NR4A2-related syndrome
An optimized Nurr1 agonist provides disease-modifying effects in Parkinson's disease models.
Kim W, Tripathi M, Kim C, Vardhineni S, Cha Y, Kandi SK, Feitosa M, Kholiya R, Sah E, Thakur A, Kim Y, Ko S, Bhatia K, Manohar S, Kong YB, Sindhu G, Kim YS, Cohen B, Rawat DS, Kim KS
A newly developed Nurr1 activator, 4A7C-301, protects dopamine neurons and improves motor and smell-related symptoms in mouse models of Parkinson's disease, suggesting it may slow or stop disease progression.
- 4A7C-301 is a brain-penetrant Nurr1 activator
- It protects dopamine neurons in Parkinson's models
- It improves motor and non-motor symptoms without side effects
- It reduces key brain abnormalities linked to Parkinson's
- This compound may be a disease-modifying therapy for Parkinson's
Downregulation of microRNA-145a-5p promotes steatosis-to-NASH progression through upregulation of Nr4a2.
Li B, Yang Z, Mao F, Gong W, Su Q, Yang J, Liu B, Song Y, Jin J, Lu Y
Lower levels of a small RNA called miR-145a-5p lead to higher levels of the NR4A2 protein, which worsens liver damage in fatty liver disease. In people with NASH, miR-145a-5p is low and NR4A2 is high, suggesting that boosting miR-145a-5p or blocking NR4A2 could be a treatment strategy.
- miR-145a-5p reduces NR4A2 levels in the liver
- Low miR-145a-5p worsens fatty liver disease
- High NR4A2 drives liver inflammation and scarring
- Human NASH livers show low miR-145a-5p and high NR4A2
- Boosting miR-145a-5p may treat NASH
Origin and development of the claustrum in rhesus macaque.
Li H, Duque A, Rakic P
The claustrum in rhesus macaques develops from a unique region of the brain that forms neurons between embryonic days 48 and 55, expressing key genes like NR4A2. This region is distinct from surrounding brain areas and forms a layered structure that may support higher cognitive functions. The claustrum also develops its own specialized inhibitory neurons independently of the nearby cortex.
- Claustrum neurons form between E48 and E55 in macaques
- NR4A2 is expressed in early claustrum development
- Claustrum is a separate brain region, not part of the insular cortex
- Unique layering may support complex brain functions
- Inhibitory neurons mature independently of the cortex
Sodium Butyrate Ameliorates Deoxynivalenol-Induced Oxidative Stress and Inflammation in the Porcine Liver via NR4A2-Mediated Histone Acetylation.
Zong Q, Li K, Qu H, Hu P, Xu C, Wang H, Wu S, Wang S, Liu HY, Cai D, Bao W
Sodium butyrate reduces liver damage caused by a common mycotoxin in pigs by activating the NR4A2 protein, which helps control harmful inflammation and oxidative stress through changes in gene regulation. This suggests NR4A2 may be a key target for protecting organs from toxin-induced injury.
- NR4A2 activation reduces inflammation and oxidative stress
- Sodium butyrate boosts NR4A2 function in liver cells
- NR4A2 controls gene activity via histone modifications
- This mechanism may protect against toxin damage
- Findings could inform treatments for NR4A2-related disorders
Insulin enhances contextual fear memory independently of its effect in increasing plasma adrenaline.
Oliveira A, Seixas R, Pereira F, Azevedo M, Martinho R, Serrão P, Moreira-Rodrigues M
Insulin boosts fear memory in mice even without adrenaline, suggesting insulin directly affects brain processes involved in memory formation. This effect may involve changes in brain gene activity, particularly BDNF, independent of stress hormones.
- Insulin improves fear memory in mice without adrenaline
- Insulin increases BDNF gene expression in the brain
- Memory boost happens even when adrenaline is absent
- Insulin acts directly in the brain, not just through stress hormones
- Suggests insulin plays a key role in memory formation
Alternative activation.
Young K, Fanning S
Nurr1, a key protein linked to brain development and neurodegenerative diseases, can be activated by certain molecules in a new way that may help control its activity, offering potential for future treatments.
- Nurr1 regulates brain health and is linked to Parkinson’s and other disorders.
- A new mechanism allows molecules to turn on Nurr1’s activity.
- This discovery could lead to drugs that boost Nurr1 function in NR4A2-related conditions.
- The findings may help develop therapies targeting Nurr1 in neurodevelopmental and neurodegenerative diseases.
DNA methylation clocks for clawed frogs reveal evolutionary conservation of epigenetic aging.
Zoller JA, Parasyraki E, Lu AT, Haghani A, Niehrs C, Horvath S
Epigenetic aging processes are evolutionarily conserved between frogs and humans, with key genes like NR4A2 involved in neural development and aging-related diseases. This suggests Xenopus frogs could be useful models for studying aging and neurodegenerative conditions linked to NR4A2.
- Epigenetic aging is conserved from frogs to humans
- NR4A2 is linked to age-related changes in neural genes
- Frogs may model human aging and NR4A2-related disorders
- Conserved CpGs are in genes tied to brain development
De Novo Design of Nurr1 Agonists via Fragment-Augmented Generative Deep Learning in Low-Data Regime.
Ballarotto M, Willems S, Stiller T, Nawa F, Marschner JA, Grisoni F, Merk D
Researchers used artificial intelligence to design new molecules that activate the Nurr1 protein, which is linked to a rare genetic disorder in children. The method worked well even with very little existing data, producing highly potent and structurally unique compounds that could become future treatments.
- AI designed new Nurr1-activating drugs with high potency
- Method works with minimal prior data on the target
- Results offer promising leads for NR4A2-related syndrome therapies
- Structurally novel compounds may avoid resistance or side effects
- Early-stage discovery tool with therapeutic potential
Latroeggtoxin-VI protects nerve cells and prevents depression by inhibiting NF-κB signaling pathway activation and excessive inflammation.
Wang H, Zhai Y, Lei Z, Chen S, Sun M, Yin P, Duan Z, Wang X
Latroeggtoxin-VI reduces brain inflammation and protects nerve cells in mouse models of depression by blocking the NF-κB pathway and preserving Nurr1 levels, suggesting potential for treating conditions involving neuroinflammation and Nurr1 deficiency.
- LETX-VI blocks brain inflammation by inhibiting NF-κB signaling
- It protects nerve cells and reduces depression-like behaviors in mice
- It prevents the loss of Nurr1, a key protein linked to NR4A2-related disorders
- The compound reduces activation of microglia and astrocytes in the brain
- Findings suggest a possible therapeutic path for neuroinflammatory conditions
Lithium's effects on therapeutic targets and MRI biomarkers in Parkinson's disease: A pilot clinical trial.
Guttuso T, Shepherd R, Frick L, Feltri ML, Frerichs V, Ramanathan M, Zivadinov R, Bergsland N
Medium-dose lithium aspartate increased levels of Nurr1 and SOD1 in blood cells and reduced brain fluid buildup in areas linked to Parkinson's symptoms, suggesting potential disease-modifying effects, though it caused side effects in some patients.
- Medium-dose lithium boosted Nurr1 and SOD1 in blood cells
- It reduced brain fluid buildup linked to cognitive and motor decline
- Side effects led to dropout in 33% of patients
- Findings suggest lithium may slow Parkinson's progression
- Further study needed on safety and long-term benefits
Molecular basis of ligand-dependent Nurr1-RXRα activation.
Yu X, Shang J, Kojetin DJ
RXRα ligands activate the Nurr1-RXRα complex by weakening the interaction between them, releasing Nurr1 to turn on genes involved in brain health. This mechanism is different from how most drugs work and could lead to better treatments for NR4A2-related disorders.
- RXRα ligands release active Nurr1 by breaking its bond with RXRα
- This activation does not require RXRα to be turned on like usual
- The process acts like a molecular switch to turn on protective brain genes
- New drugs could be designed to target this specific interaction
- This explains how some compounds help in neurodegenerative diseases