Development of a Potent Nurr1 Agonist Tool for In Vivo Applications.
Vietor J, Gege C, Stiller T, Busch R, Schallmayer E, Kohlhof H, Höfner G, Pabel J, Marschner JA, Merk D
A new drug that activates the Nurr1 protein shows strong potential for treating neurological conditions. It works well in cells and animals, with good stability and brain penetration, making it a powerful tool for studying Nurr1-related diseases.
- New drug activates Nurr1, a key protein in brain health
- Works effectively in brain cells and animal models
- Better than previous compounds in potency and safety
- May help develop treatments for Parkinson’s and similar disorders
- Favorable properties for use in future human studies
Want of Wnt in Parkinson's disease: Could sFRP disrupt interplay between Nurr1 and Wnt signaling?
Gamit N, Dharmarajan A, Sethi G, Warrier S
Nurr1, a key protein for brain cells that produce dopamine, is disrupted in Parkinson's disease. This review suggests that a protein called sFRP may interfere with Nurr1's function by blocking Wnt signaling, a pathway that supports healthy brain cells. Targeting sFRP could be a new way to treat Parkinson's by restoring Nurr1 activity.
- Nurr1 is essential for dopamine-producing brain cells
- Wnt signaling helps activate Nurr1 and protect brain cells
- sFRP blocks Wnt signaling and may worsen Parkinson's
- Reducing sFRP could help restore Nurr1 function
- This offers a potential new treatment strategy for Parkinson's
Genome-wide DNA methylation analysis in families with multiple individuals diagnosed with schizophrenia and intellectual disability.
Zhang S, Shi K, Lyu N, Zhang Y, Liang G, Zhang W, Wang X, Wen H, Wen L, Ma H, Wang J, Yu X, Guan L
DNA methylation changes in genes linked to brain development and immune function, including NR4A2, are associated with schizophrenia and intellectual disability in families with multiple affected individuals. These epigenetic alterations may contribute to neurodevelopmental disorders by disrupting key biological pathways.
- NR4A2 methylation changes are linked to schizophrenia and intellectual disability
- Altered methylation affects neurodevelopment and immune system pathways
- Findings come from families with multiple affected members, increasing reliability
- DNA methylation may play a key role in the development of neurodevelopmental disorders
Aberrant somatic calcium channel function in cNurr1 and LRRK2-G2019S mice.
Skiteva O, Yao N, Mantas I, Zhang X, Perlmann T, Svenningsson P, Chergui K
In two mouse models of Parkinson's disease linked to NR4A2 (Nurr1) and LRRK2, the way calcium channels work in dopamine neuron cell bodies is disrupted, with opposite changes in T-type and L-type channels that may be driven by oxidative stress. These changes happen in the cell body but not in the nerve endings, suggesting a specific vulnerability in the neuron's core that could contribute to degeneration.
- NR4A2 loss disrupts T-type calcium channels in dopamine neurons
- LRRK2 mutation alters L-type calcium channel function
- Calcium channel changes occur in cell bodies, not nerve endings
- Oxidative stress may drive these calcium channel abnormalities
- Antioxidants and LRRK2 inhibitors reverse the changes
Protective effect of Nr4a2 (Nurr1) against LPS-induced depressive-like behaviors via regulating activity of microglia and CamkII neurons in anterior cingulate cortex.
He Y, Wang Y, Yu H, Tian Y, Chen X, Chen C, Ren Y, Chen Z, Ren Y, Gong X, Cheng K, Liu X, Zhong L, Guo Y, Xie P
Nr4a2 helps protect against depression-like behaviors in mice by reducing brain inflammation and improving the health of key brain cells in the anterior cingulate cortex. Boosting Nr4a2 activity, either with a drug or by directly increasing its levels, reverses brain changes and behavior problems caused by inflammation.
- Nr4a2 reduces brain inflammation linked to depression
- Boosting Nr4a2 improves neuron and microglia health
- Activating Nr4a2 reverses depression-like behaviors
- Drugs that increase Nr4a2 may help treat depression
- The anterior cingulate cortex is a key brain area involved
A potential protective role of the nuclear receptor-related factor 1 (Nurr1) in multiple sclerosis motor cortex: a neuropathological study.
Pansieri J, Pisa M, Yates RL, Esiri MM, DeLuca GC
Nurr1, a protein linked to brain protection, is increased in the motor cortex of people with multiple sclerosis and is associated with more surviving neurons and fewer harmful immune cells. This suggests Nurr1 may help protect the brain from damage in multiple sclerosis by reducing inflammation and preventing nerve cell loss.
- Nurr1 levels are higher in multiple sclerosis brain tissue
- High Nurr1 links to more surviving neurons
- Nurr1 correlates with fewer harmful immune cells
- Nurr1 may protect the brain in multiple sclerosis
- Could lead to new treatments targeting Nurr1
Activity-Dependent Nr4a2 Induction Modulates Synaptic Expression of AMPA Receptors and Plasticity via a Ca2+/CRTC1/CREB Pathway.
Català-Solsona J, Lituma PJ, Lutzu S, Siedlecki-Wullich D, Fábregas-Ordoñez C, Miñano-Molina AJ, Saura CA, Castillo PE, Rodriguez-Álvarez J
Neuronal activity boosts Nr4a2, a gene linked to NR4A2-related syndrome, which in turn increases brain-derived neurotrophic factor (BDNF) and AMPA receptors at synapses, enhancing learning-related plasticity in the hippocampus. This process depends on calcium and a specific signaling pathway involving CREB and CRTC1.
- Activity increases Nr4a2, boosting synaptic plasticity
- Nr4a2 enhances BDNF and AMPA receptors
- The pathway involves calcium, CREB, and CRTC1
- Nr4a2 may be a target for treating synaptic disorders
- Findings are relevant to NR4A2-related neurodevelopmental conditions
Correction for Zhao et al., Integrative analysis reveals structural basis for transcription activation of Nurr1 and Nurr1-RXRα heterodimer.
This study reveals how the Nurr1 protein and its partner RXRα work together to turn on genes important for brain development and function, providing a detailed structural view of their interaction.
- Nurr1 and RXRα form a complex that activates key brain genes
- The structure of this complex explains how it binds DNA and functions
- Findings may help design drugs to boost Nurr1 activity in NR4A2-related disorders
- Offers a foundation for treating neurological conditions linked to Nurr1 dysfunction
The Influence of Prenatal Exposure to Methamphetamine on the Development of Dopaminergic Neurons in the Ventral Midbrain.
Alsanie WF, Abdelrahman S, Felimban RI, Alkhatabi HA, Gaber A, Alosimi EA, Alhomrani M, Habeeballah H, Hauser CAE, S Alamri A, Althobaiti A, Alsharif A, Alzahrani AS, Al-Ghamdi MS, Raafat BM, Alswat KA, Althobaiti YS, Asiri YA
Prenatal methamphetamine exposure disrupts the development of dopamine-producing brain cells in mouse embryos by altering key genes needed for their formation, even at doses considered therapeutic. This suggests methamphetamine use during pregnancy may harm fetal brain development, particularly the dopamine system.
- Methamphetamine alters genes critical for dopamine neuron development
- No effect on cell survival, but gene changes impair neuron maturation
- Even therapeutic doses may affect fetal brain development
- Dopamine-related genes like Th and Dat are significantly reduced
- Findings highlight risks of methamphetamine use in pregnancy
Transcriptomic Analysis Reveals mRNA and Alternative Splicing Events in Ovine Skeletal Muscle Satellite Cells during Proliferation and Differentiation.
Chen Q, Huang C, Su Y, Zhao Q, Pu Y, He X, Jiang L, Ma Y, Zhao Q, Ye S
This study found that NR4A2, a gene involved in muscle development, changes how it is spliced during the growth and specialization of sheep muscle stem cells. The results suggest NR4A2 works with another key gene, MEF2C, to control muscle formation, which may help explain how muscle develops and regenerates.
- NR4A2 splicing changes during muscle stem cell development
- NR4A2 likely works with MEF2C to control muscle formation
- Splicing changes may affect muscle growth and repair
- Findings could inform future therapies for muscle disorders
Suppression of neuroinflammation and α-synuclein oligomerization by rotarod walking exercise in subacute MPTP model of Parkinson's disease.
Leem YH, Park JS, Park JE, Kim DY, Kim HS
Rotarod exercise reduces brain inflammation and harmful clumps of alpha-synuclein in a mouse model of Parkinson’s disease, which may protect dopamine neurons and improve movement. These benefits are linked to increased protective proteins and reduced oxidative stress.
- Exercise reduced brain inflammation and alpha-synuclein clumps
- Improved movement and protected dopamine neurons
- Boosted brain-protective proteins like Nurr1 and BDNF
- Lowered oxidative stress and blocked key aggregation pathways
- Suggests physical training may slow Parkinson’s progression
Machine learning-based predictive models and drug prediction for schizophrenia in multiple programmed cell death patterns.
Feng Y, Shen J
This study identified NR4A2 as one of 10 key genes linked to schizophrenia, using machine learning to build a highly accurate diagnostic model. The model showed strong performance in predicting schizophrenia, and potential treatments like valproic acid and green tea extract (EGCG) were suggested based on these genes.
- NR4A2 is a top candidate gene in a schizophrenia prediction model
- The model accurately distinguishes schizophrenia patients with AUC up to 0.94
- Valproic acid and EGCG are potential treatment candidates
- Immune cell changes, especially in NK cells, are linked to schizophrenia
- Findings may help identify new therapies for NR4A2-related conditions
Nicotine-Mediated Recruitment of GABAergic Neurons to a Dopaminergic Phenotype Attenuates Motor Deficits in an Alpha-Synuclein Parkinson's Model.
Lai JI, Porcu A, Romoli B, Keisler M, Manfredsson FP, Powell SB, Dulcis D
Nicotine can reprogram certain GABA neurons in the brain's movement control center to produce dopamine, which helps improve motor function in a mouse model of Parkinson's disease. This effect involves the activation of the Nurr1 gene and may offer a path for new treatments that mimic nicotine's protective effects without its risks.
- Nicotine reprograms GABA neurons to produce dopamine
- Nurr1 gene activation is key to this change
- Motor symptoms improved in Parkinson's mice
- GABA neurons projecting to movement areas are involved
- Combining Nurr1 and neuron activation mimics nicotine effect
[Directed differentiation of human induced pluripotent stem cells into midbrain].
Xu J, Li Y, Zhong G, Fang Z, Liu C, Ma C, Wang C, Guo Y, Liu C
This study developed a method to turn human stem cells into midbrain dopamine cells that can survive and improve movement in Parkinson's disease rats. The cells expressed key markers like NURR1 and successfully turned into functional neurons in the brain.
- Human stem cells became midbrain dopamine cells with high NURR1 expression
- Cells survived and improved movement in Parkinson's rats
- NURR1 is a critical marker for these therapeutic cells
- The process creates cells that work in both lab and living brains
- This approach could help treat brain disorders like NR4A2-related syndrome
CREB Is Activated by the SCF/KIT Axis in a Partially ERK-Dependent Manner and Orchestrates Survival and the Induction of Immediate Early Genes in Human Skin Mast Cells.
Franke K, Bal G, Li Z, Zuberbier T, Babina M
CREB is a key protein that helps skin mast cells survive and activate immediate early genes, including NR4A2, in response to SCF/KIT signaling. This process depends partly on ERK but happens even when ERK doesn’t move into the nucleus.
- CREB is activated by SCF/KIT signaling in skin mast cells
- CREB promotes cell survival and triggers NR4A2 and other immediate early genes
- Activation requires KIT kinase activity and partial ERK involvement
- CREB is active in the nucleus and drives gene expression without needing ERK to enter the nucleus
- Blocking CREB reduces cell survival, showing its critical role
FOXG1 drives transcriptomic networks to specify principal neuron subtypes during the development of the medial pallium.
Ba R, Yang L, Zhang B, Jiang P, Ding Z, Zhou X, Yang Z, Zhao C
FOXG1 is a key regulator of brain development that controls the formation of specific neuron types in the memory and emotion centers of the brain. It works by turning on and off specific genes, including Nr4a2, which is linked to a rare neurodevelopmental disorder in children.
- FOXG1 directs formation of critical brain neurons
- It activates Nr4a2, a gene tied to NR4A2-related syndrome
- Disruption of FOXG1 may lead to brain wiring issues
- Findings reveal how brain cell types are specified
- Provides insight into related neurodevelopmental disorders
Mechanistic insights into the role of vitamin D and computational identification of potential lead compounds for Parkinson's disease.
John Marshal J, Kuriakose BB, Alhazmi AH, Muthusamy K
This study identifies three promising compounds that activate NURR1, a protein linked to Parkinson's disease and potentially relevant to NR4A2-related syndrome. The compounds show strong binding to NURR1 in computer simulations and may support dopaminergic neuron function.
- Three compounds strongly bind to NURR1 in simulations
- NURR1 activation may help protect dopamine neurons
- Compounds need lab testing to confirm effectiveness
- Findings could inform future treatments for NR4A2-related conditions
Prolonged Differentiation of Neuron-Astrocyte Co-Cultures Results in Emergence of Dopaminergic Neurons.
de Leeuw VC, van Oostrom CTM, Zwart EP, Heusinkveld HJ, Hessel EVS
This study shows that human stem cells can develop into dopaminergic neurons in a lab model over 70 days, with key dopamine-related genes and proteins steadily increasing and forming a stable network. The model may help test how chemicals affect the dopamine system, which is relevant for both Parkinson’s and neurodevelopmental conditions.
- Dopaminergic neurons form in a 70-day human stem cell model
- Key dopamine genes and proteins increase over time
- Model may detect chemicals that disrupt dopamine function
- Could help assess neurotoxicity in development and disease
Genetic screening of Filipinos suspected with familial Parkinson's disease: A pilot study.
Caritativo ECA, Yu JRT, Bautista JMP, Nishioka K, Jamora RDG, Yalung PM, Ng AR, Hattori N
This study found that PINK1 gene mutations are a common cause of early-onset familial Parkinson's disease in Filipinos, with symptoms starting around age 40. One other family had a PRKN mutation, and both mutations follow recessive inheritance patterns.
- PINK1 mutations are a major cause of early-onset Parkinson's in this group
- Symptoms began at an average age of 40.4 years
- Mutations follow recessive inheritance patterns
- Findings support larger genetic studies in diverse populations
- Results align with global data on PINK1 and PRKN
Single-nucleus RNA and ATAC sequencing uncovers the molecular and cellular characteristics in the musk gland of Chinese forest musk deer (Moschus berezovskii).
Liu C, Hong T, Yu L, Chen Y, Wang S, Ren Z
This study used advanced sequencing to map the cell types and gene activity in the musk gland of Chinese forest musk deer, identifying two distinct acinar cell types involved in musk production. It found that specific transcription factors, including NR4A2, regulate genes linked to musk secretion, offering insights into the biological mechanisms behind this process.
- Two acinar cell types in the musk gland produce musk
- NR4A2 is a key regulator of musk-related genes
- Gene activity is controlled by specific transcription factors
- Findings reveal how cells communicate during musk secretion
- Data validated by lab techniques like immunohistochemistry
IGF2-NR4A2 Signaling Regulates Macrophage Subtypes to Attenuate Liver Cirrhosis.
Yao L, Hu X, Yuan M, Zhang Q, Liu P, Yang L, Dai K, Jiang Y
IGF2 boosts the ability of bone marrow-derived macrophages to reduce liver scarring and inflammation in mice by activating NR4A2, which shifts macrophages toward a healing type that breaks down scar tissue. This combination therapy works better than macrophages alone.
- IGF2 activates NR4A2 in macrophages
- NR4A2 promotes healing macrophage type
- IGF2 + macrophages reduce liver scarring
- Macrophages produce more scar-breaking enzymes
- Combination therapy outperforms macrophages alone
Systems level analysis of sex-dependent gene expression changes in Parkinson's disease.
Tranchevent LC, Halder R, Glaab E
NR4A2, a gene linked to Parkinson's disease, shows sex-specific changes in brain gene activity that may influence disease symptoms and progression. These differences involve mitochondrial function and gene regulation networks, suggesting NR4A2 could be a target for new treatments tailored to sex-related patterns in Parkinson's.
- NR4A2 activity differs between males and females in Parkinson's disease
- Sex-specific gene changes affect mitochondrial function and brain networks
- NR4A2 activation protects neurons in Parkinson's models
- These findings suggest sex-specific treatments targeting NR4A2 may be possible
Efficient Generation of Dopaminergic Neurons from Mouse Ventral Midbrain Astrocytes.
Han JY, Lee EH, Kim SM, Park CH
This study shows that mouse brain cells called astrocytes from the midbrain can be directly turned into dopamine-producing neurons and neural precursor cells using specific genes. These converted cells behave like real dopamine neurons and could potentially be used to treat Parkinson’s disease.
- Midbrain astrocytes can be turned into dopamine neurons
- Using Ascl1 and Nurr1 genes boosts conversion efficiency
- Converted cells show key traits of functional dopamine neurons
- Offers a potential cell therapy for Parkinson’s disease
- May inform future treatments for NR4A2-related disorders
Ganglioside Microdomains on Cellular and Intracellular Membranes Regulate Neuronal Cell Fate Determination.
Itokazu Y, Yu RK
Gangliosides GD3 and GM1 play key roles in regulating neural stem cell function and neuronal development. GD3 supports stem cell maintenance and mitochondrial health, while GM1 promotes neuron formation by altering gene activity through epigenetic mechanisms involving Nurr1 and other transcription factors.
- GD3 maintains neural stem cells and supports mitochondrial function
- GM1 drives neuron development by modifying gene expression
- GM1 recruits Nurr1 to activate genes for dopamine-producing neurons
- Gangliosides act in multiple cellular locations to control brain cell fate
- These findings suggest potential pathways for treating NR4A2-related disorders
The lncRNA LUCAT1 is elevated in inflammatory disease and restrains inflammation by regulating the splicing and stability of NR4A2.
Vierbuchen T, Agarwal S, Johnson JL, Galia L, Lei X, Stein K, Olagnier D, Gaede KI, Herzmann C, Holm CK, Heine H, Pai A, O'Hara Hall A, Hoebe K, Fitzgerald KA
LUCAT1 helps control inflammation by stabilizing and correctly splicing the NR4A2 protein, which is crucial for turning off immune responses. In people with inflammatory diseases like IBD and asthma, LUCAT1 levels are high and linked to worse symptoms.
- LUCAT1 boosts NR4A2 stability and splicing
- Low NR4A2 leads to stronger inflammation
- High LUCAT1 levels match worse disease in patients
- LUCAT1 acts as a brake on immune overactivity
- NR4A2 is a key player in immune regulation
Advances in NURR1-Regulated Neuroinflammation Associated with Parkinson's Disease.
Al-Nusaif M, Lin Y, Li T, Cheng C, Le W
NURR1 helps protect dopamine-producing brain cells by reducing harmful inflammation in glial cells. Boosting NURR1 activity may slow Parkinson's disease progression by calming this inflammation and preventing neuron loss.
- NURR1 reduces brain inflammation that damages dopamine neurons
- Activating NURR1 protects neurons in Parkinson's disease models
- Targeting NURR1 may slow disease progression by controlling inflammation
- Inflammation in glial cells is a key driver of Parkinson's neurodegeneration
Enhancing Neurological Competence of Nanoencapsulated Cordyceps/Turmeric Extracts in Human Neuroblastoma SH-SY5Y Cells.
Kaokaen P, Sorraksa N, Phonchai R, Chaicharoenaudomrung N, Kunhorm P, Noisa P
Nanoencapsulated cordyceps and turmeric extracts improved neuronal maturation and function in human brain cells, boosting dopamine-related genes like NURR1 and reducing markers of Alzheimer's disease. The treatments enhanced cellular uptake, promoted neuron development, and increased autophagy, suggesting potential for treating neurological conditions.
- Boosts NURR1 and dopamine production in brain cells
- Reduces Alzheimer's-related proteins and genes
- Improves neuron maturation and function
- Enhances delivery and uptake via nanoencapsulation
- Activates cellular cleanup process (autophagy)
Timing of MeCP2 Expression Determines Midbrain Dopamine Neuron Phenotype Specification.
He XB, Guo F, Li K, Yan J, Lee SH
MeCP2 must be expressed at the right time during development to allow midbrain dopamine neurons to form properly; if MeCP2 appears too early, it blocks the activation of genes needed for dopamine neuron identity. This timing is controlled by DNA methylation and demethylation processes involving TET1 and NURR1.
- MeCP2 timing is critical for dopamine neuron development
- Early MeCP2 blocks NURR1 from turning on dopamine genes
- TET1 removes DNA methylation to allow proper gene activation
- DNA methylation status can be manipulated to protect neuron identity
- This process may influence NR4A2/NURR1-related disorders
Integrative analysis reveals structural basis for transcription activation of Nurr1 and Nurr1-RXRα heterodimer.
Zhao M, Wang N, Guo Y, Li J, Yin Y, Dong Y, Zhu J, Peng C, Xu T, Liu J
This study reveals how Nurr1, a protein linked to NR4A2-related syndrome, activates gene transcription by changing shape and working with another protein, RXRα. The findings explain how DNA sequence and drug-like molecules can control Nurr1 activity, offering new paths for developing treatments.
- Nurr1 changes shape to turn on genes involved in brain health
- Nurr1 works with RXRα to boost gene activation
- DNA sequence can fine-tune Nurr1 activity without drugs
- Drugs binding to RXRα override DNA effects and boost activation
- These insights open doors for designing therapies targeting Nurr1