Structural insights into ligand-binding pocket formation in Nurr1 by molecular dynamics simulations.
Windshügel B
Computer simulations reveal that the Nurr1 protein forms a temporary pocket to bind docosahexaenoic acid (DHA), explaining how this fatty acid activates the receptor. This structural insight helps researchers design specific drugs that target Nurr1 for Parkinson's disease treatment.
- Simulations show Nurr1 creates a transient pocket to bind DHA.
- The binding site matches previous experimental observations.
- Only minor protein shape changes are needed for drug binding.
- Findings support the design of new Parkinson's medications.
Development of a novel NURR1/NOT agonist from hit to lead and candidate for the potential treatment of Parkinson's disease.
Lesuisse D, Malanda A, Peyronel JF, Evanno Y, Lardenois P, De-Peretti D, Abécassis PY, Barnéoud P, Brunel P, Burgevin MC, Cegarra C, Auger F, Dommergue A, Lafon C, Even L, Tsi J, Luc TPH, Almario A, Olivier A, Castel MN, Taupin V, Rooney T, Vigé X
Researchers developed a new drug candidate that activates the NURR1 protein and shows neuroprotective effects in laboratory and animal models. This work focuses on Parkinson's disease treatment rather than NR4A2-related developmental syndromes.
- The drug candidate activates NURR1/NOT receptors with high potency.
- It demonstrates neuroprotective and anti-inflammatory activity in preclinical models.
- The study targets Parkinson's disease, not NR4A2 developmental disorders.
- No human clinical data or NR4A2-specific genetic findings are reported.
The orphan nuclear receptor Nor1/Nr4a3 is a negative regulator of β-cell mass.
Close AF, Dadheech N, Villela BS, Rouillard C, Buteau J
This study identifies Nor1 (Nr4a3), a different gene from the child's NR4A2, as a negative regulator of pancreatic beta-cell mass that promotes cell death in response to inflammation. The research demonstrates that reducing Nor1 levels protects beta-cells and improves glucose tolerance in mice, suggesting potential therapeutic avenues for type 2 diabetes. This work does not address NR4A2 biology or the specific syndrome affecting the child.
- Nor1 is a different gene from NR4A2 and regulates pancreatic beta-cell mass.
- High Nor1 levels cause beta-cell death, especially during inflammation.
- Reducing Nor1 protects cells and improves glucose tolerance in mice.
- Findings target type 2 diabetes treatment, not NR4A2-related syndromes.
Molecular Insights into NR4A2(Nurr1): an Emerging Target for Neuroprotective Therapy Against Neuroinflammation and Neuronal Cell Death.
Jakaria M, Haque ME, Cho DY, Azam S, Kim IS, Choi DK
This review identifies NR4A2 as a key regulator that protects dopaminergic neurons from inflammation and cell death, highlighting its potential as a therapeutic target for neurodegenerative diseases. It summarizes current knowledge on how NR4A2 functions in the brain and discusses various molecules that could activate it to treat conditions like Parkinson's disease.
- NR4A2 protects dopaminergic neurons by inhibiting inflammation in glial cells.
- NR4A2 levels decrease in aging brains and in Parkinson's patients.
- Activators of NR4A2 show promise in animal models of neurodegeneration.
- MicroRNAs like miR-145-5p regulate NR4A2 expression in stroke models.
- The paper reviews NR4A2's role across multiple neurodegenerative diseases.
Global Gene Knockout of Kcnip3 Enhances Pain Sensitivity and Exacerbates Negative Emotions in Rats.
Guo YP, Zhi YR, Liu TT, Wang Y, Zhang Y
Knocking out the Kcnip3 gene in rats increases pain sensitivity and worsens anxiety and depression-like behaviors. This study also finds that the absence of Kcnip3 alters the expression of several genes involved in dopamine signaling, including NR4A2.
- Kcnip3 knockout rats show heightened acute and chronic pain responses.
- These rats exhibit increased anxiety and depression-like behaviors.
- Nr4a2 expression changes alongside other dopamine-related genes in the forebrain.
- The study links KChIP3 to emotional processing and nociception.
Dysregulation of Dopaminergic Regulatory Factors TH, Nurr1, and Pitx3 in the Ventral Tegmental Area Associated with Neuronal Injury Induced by Chronic Morphine Dependence.
Shi W, Zhang Y, Zhao G, Wang S, Zhang G, Ma C, Cong B, Li Y
Chronic morphine exposure damages dopamine-producing neurons in the brain by reducing key regulatory proteins. This study shows that prolonged drug dependence leads to physical injury in these specific nerve cells.
- Morphine dependence causes visible damage to dopamine neurons in rat brains.
- Levels of TH, Nurr1, and Pitx3 proteins drop significantly during chronic exposure.
- Nerve cell injury correlates with the loss of these regulatory factors.
[The mechanism underlying Gingko biloba extract alleviating acrylamide-induced inflammatory response of mouse microglia].
Wang C, Yang Z, He X
Ginkgo biloba extract reduces inflammation in mouse brain cells by altering how specific proteins bind to DNA. This study uses mouse microglia and does not involve human patients or NR4A2-related syndrome treatments.
- Study uses mouse brain cells, not human tissue or patients.
- Ginkgo biloba extract lowers inflammatory markers in these cells.
- Mechanism involves protein binding changes on DNA promoters.
- No clinical data or relevance to NR4A2 syndrome treatments.
Subcellular Localization of NR4A2 Orphan Nuclear Receptor Expression in Human and Mouse Synovial Joint Tissue.
Smyth A, Gogarty M, Crean D, Murphy EP
This study maps where NR4A2 proteins are located within joint tissues from patients with rheumatoid arthritis and mouse models. It provides a technical method for visualizing these receptors in inflamed synovium but does not investigate neurological function or treatment options for NR4A2-related syndromes.
- NR4A2 helps regulate inflammation in diseases like rheumatoid arthritis.
- Researchers used immunohistochemistry to locate NR4A2 in human and mouse joint tissue.
- The paper focuses on inflammatory resolution rather than neurological development.
- No findings relate to dopaminergic neurons or pediatric neurodevelopmental disorders.
Potential effects and molecular mechanisms of melatonin on the dopaminergic neuronal differentiation of human amniotic fluid mesenchymal stem cells.
Phonchai R, Phermthai T, Kitiyanant N, Suwanjang W, Kotchabhakdi N, Chetsawang B
Melatonin promotes the differentiation of human amniotic fluid stem cells into dopaminergic neurons in a laboratory dish. This effect occurs through specific cellular signaling pathways involving melatonin receptors and protein kinases.
- Melatonin increases markers for dopaminergic neurons in stem cell cultures.
- The process relies on ERK and CaMKII signaling pathways.
- Cell viability remains unaffected by melatonin treatment.
- This is an in vitro study using human stem cells, not a clinical trial.
Study of the NR4A family gene expression in patients with multiple sclerosis treated with Fingolimod.
Montarolo F, Perga S, Martire S, Brescia F, Caldano M, Lo Re M, Panzica G, Bertolotto A
This study measures NR4A2 gene expression in the blood of multiple sclerosis patients rather than investigating the genetic cause or treatment of NR4A2-related syndromes. It finds that Fingolimod, a drug for MS, increases NR4A2 levels in patients compared to untreated individuals. The research focuses on how an existing drug affects this gene's expression in a different disease context.
- Study involves multiple sclerosis patients, not children with NR4A2 syndrome.
- Fingolimod treatment increases NR4A2 blood levels in MS patients over two years.
- Untreated MS patients show lower NR4A2 levels than healthy controls.
- NR4A1 and NR4A3 expression remains unchanged by the drug.
- Findings suggest Fingolimod may help recover NR4A2 deficits in MS.
Different duration of parathyroid hormone exposure distinctively regulates primary response genes Nurr1 and RANKL in osteoblasts.
Choi H, Magyar CE, Nervina JM, Tetradis S
This study shows that short and long exposure to parathyroid hormone (PTH) triggers different genes in bone-building cells, with Nurr1 responding quickly and RANKL needing prolonged exposure. These gene responses help explain how PTH can either build or break down bone, depending on how it's given. Understanding these triggers may lead to better treatments for bone diseases.
- Short PTH boosts Nurr1, linked to bone building
- Long PTH boosts RANKL, linked to bone breakdown
- Different gene responses explain PTH’s dual effects
- Nurr1 and RANKL are regulated by distinct pathways
- Timing of PTH exposure controls which genes turn on
Diabetes and smoking are more important for prognosis of patients with peripheral arterial disease than some genetic polymorphisms.
Boc V, Božic Mijovski M, Pohar Perme M, Blinc A
Genetic variations in the NR4A2 gene do not affect the risk or outcomes of peripheral arterial disease (PAD), but diabetes and smoking significantly worsen survival and event-free survival in people with PAD.
- NR4A2 gene variants are not linked to PAD or worse outcomes
- Diabetes doubles the risk of cardiovascular death in PAD patients
- Smoking doubles the risk of death or major events in PAD
- Diabetics with PAD have lower 5-year survival than non-diabetics
- Never-smokers with PAD have the best survival rates
NR4A nuclear receptors in cardiac remodeling and neurohormonal regulation.
Medzikovic L, de Vries CJM, de Waard V
NR4A nuclear receptors, including Nurr1, play important roles in regulating heart stress responses and neurohormonal systems like the sympathetic nervous system and renin-angiotensin-aldosterone system, which are involved in heart failure progression.
- NR4A receptors help control heart stress and neurohormonal activity
- They influence systems that drive heart failure when overactive
- Nurr1 is a key regulator in cardiac and neurohormonal responses
- These receptors may offer new targets for treating heart disease
Nurr1 (NR4A2) regulates Alzheimer's disease-related pathogenesis and cognitive function in the 5XFAD mouse model.
Moon M, Jung ES, Jeon SG, Cha MY, Jang Y, Kim W, Lopes C, Mook-Jung I, Kim KS
This study shows that activating the Nurr1 protein reduces Alzheimer's-like symptoms in mice, but it does not provide evidence for treating NR4A2-related syndrome in children. The research focuses on a different disease (Alzheimer's) using animal models, with no direct application to human genetic variants of NR4A2. Parents should view this as basic biology research rather than a potential treatment pathway for their child.
- Study uses Alzheimer's mouse models, not humans or NR4A2 syndrome patients.
- Nurr1 activation reduced plaques and improved cognition in mice with Alzheimer's pathology.
- No data exists on how this affects dopaminergic neurons in NR4A2-related conditions.
- Findings are preclinical and do not translate to current clinical options for NR4A2 families.
Differential expression of a stress-regulated gene Nr4a2 characterizes early- and late-born hippocampal granule cells.
Imura T, Kobayashi Y, Suzutani K, Ichikawa-Tomikawa N, Chiba H
This study identifies Nr4a2 as a stress-regulated gene in mouse hippocampal neurons, showing that acute stress suppresses its expression while chronic stress increases it. It further demonstrates that long-term stress impairs the survival of new neurons and alters their distribution in aged mice.
- Nr4a2 is preferentially expressed by early-born hippocampal granule cells in mice.
- Acute stress suppresses Nr4a2 expression, while chronic stress induces it.
- Chronic restraint stress impairs the survival of newly generated neurons.
- Long-term stress reduces late-born neuron proportions in aged mice.
Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1.
de Vera IMS, Munoz-Tello P, Zheng J, Dharmarajan V, Marciano DP, Matta-Camacho E, Giri PK, Shang J, Hughes TS, Rance M, Griffin PR, Kojetin DJ
The protein structure of Nurr1 contains a hidden, dynamic pocket that can open to bind unsaturated fatty acids. This finding suggests the protein is 'druggable' and could potentially be targeted by new medications in the future.
- Nurr1 has a hidden binding pocket that opens to accept fatty acids.
- The pocket changes shape rapidly, unlike other nuclear receptors.
- This proves Nurr1 can bind molecules, making it a potential drug target.
- Future research may develop therapies for Nurr1-related diseases like Parkinson's.
Dbx1-Derived Pyramidal Neurons Are Generated Locally in the Developing Murine Neocortex.
Rueda-Alaña E, Martínez-Garay I, Encinas JM, Molnár Z, García-Moreno F
This study maps the developmental origin of specific neurons in the mouse neocortex, finding that Dbx1-derived pyramidal neurons are generated locally rather than migrating from the ventral pallium. The research provides a new framework for understanding cortical neuron migration patterns during embryonic development.
- The study uses an in vivo mouse model to track neuronal migration during embryonic development.
- Dbx1-expressing progenitors are found throughout pallial areas, not just the ventral pallium.
- No evidence supports tangential migration of these neurons from the ventral pallium to the neocortex.
- Dbx1-derived pyramidal neurons originate locally within the dorsal pallial neuroepithelium.
Image-guided phenotyping of ovariectomized mice: altered functional connectivity, cognition, myelination, and dopaminergic functionality.
Anckaerts C, van Gastel J, Leysen V, Hinz R, Azmi A, Simoens P, Shah D, Kara F, Langbeen A, Bols P, Laloux C, Prevot V, Verhoye M, Maudsley S, Van der Linden A
This study uses MRI and proteomics to show that hormonal disruption in mice causes cognitive deficits, altered brain connectivity, and changes in dopaminergic signaling. NR4A2 appears only as a predicted upstream regulator of dopamine function in this context, with no direct analysis of the gene or its variants.
- Ovariectomy in mice disrupts hypothalamus-pituitary-gonadal signaling and causes cognitive deficits.
- MRI reveals selective dysconnectivity in specific brain regions following hormonal disruption.
- Proteomics identifies altered dopaminergic functionality, including predicted NR4A2 involvement.
- The study focuses on general aging and endocrine effects, not NR4A2 genetics.
Illuminated night alters hippocampal gene expressions and induces depressive-like responses in diurnal corvids.
Taufique SKT, Prabhat A, Kumar V
This study examines how artificial light at night affects gene expression and behavior in crows, finding that dim light suppresses genes associated with mood regulation including NR4A2. The research uses a bird model to explore environmental impacts on circadian rhythms and neurogenesis, with no direct application to human genetic syndromes.
- Dim light at night reduces sleep and induces depressive-like behaviors in crows.
- NR4A2 gene expression decreases alongside other mood-related genes under artificial light.
- The study focuses on environmental epigenetics, not human genetic mutations.
- No clinical relevance to NR4A2-related syndromes or potential treatments exists.
Nurr1 exacerbates cerebral ischemia-reperfusion injury via modulating YAP-INF2-mitochondrial fission pathways.
Zhang Z, Yu J
This study shows that Nurr1 worsens brain damage after stroke by triggering excessive mitochondrial fission and neuron death in mice. Removing or blocking Nurr1 protects neurons and reduces injury in this animal model of cerebral ischemia-reperfusion.
- Nurr1 levels rise significantly during cerebral ischemia-reperfusion injury in mice.
- Genetic removal of Nurr1 reduces brain infarction size and neuron apoptosis.
- Nurr1 drives neuron death by activating mitochondrial fission via the YAP-INF2 pathway.
- Blocking this pathway sustains mitochondrial health and improves neuronal survival.
Epinephrine Released During Traumatic Events May Strengthen Contextual Fear Memory Through Increased Hippocampus mRNA Expression of Nr4a Transcription Factors.
Oliveira A, Martinho R, Serrão P, Moreira-Rodrigues M
This study shows that stress hormones strengthen fear memories in mice by increasing the expression of Nr4a genes in the hippocampus. It does not provide information on human NR4A2 syndrome, treatment options, or clinical outcomes for children.
- The research uses only mouse models and cell-level measurements.
- It focuses on fear memory consolidation, not neurodevelopmental disorders.
- No human data or clinical trials are included in this paper.
- Findings do not translate to current management of NR4A2 syndrome.
Progression of myocardial ischemia leads to unique changes in immediate-early gene expression in the spinal cord dorsal horn.
Saddic LA, Howard-Quijano K, Kipke J, Kubo Y, Dale EA, Hoover D, Shivkumar K, Eghbali M, Mahajan A
This study examines how heart damage alters gene expression in the spinal cord of pigs, finding that NR4A2 is one of several genes activated during chronic ischemia. The research focuses on cardiovascular autonomic pathways and does not investigate neurodevelopmental outcomes or treatments relevant to NR4A2-related syndromes.
- Study uses a pig model of heart disease, not human patients or NR4A2-specific models.
- NR4A2 appears as one of many genes upregulated in the spinal cord during chronic heart injury.
- Findings relate to autonomic nervous system responses to cardiac stress, not brain development.
- No clinical data, patient phenotypes, or therapeutic implications for NR4A2 syndromes are presented.
Sevoflurane anesthesia represses neurogenesis of hippocampus neural stem cells via regulating microRNA-183-mediated NR4A2 in newborn rats.
Shao CZ, Xia KP
Sevoflurane anesthesia suppresses the growth and maturation of newborn rat brain stem cells by increasing miR-183, which in turn reduces NR4A2 levels. This mechanism suggests that early exposure to this anesthetic may interfere with normal brain development in neonates.
- Sevoflurane increases miR-183 and decreases NR4A2 in newborn rat hippocampal stem cells.
- High miR-183 levels inhibit the proliferation and differentiation of these neural stem cells.
- NR4A2 is a direct target of miR-183, linking the anesthetic effect to this specific gene.
- The study uses newborn rats, not humans, to model potential developmental risks.
Lethal Factor Domain-Mediated Delivery of Nurr1 Transcription Factor Enhances Tyrosine Hydroxylase Activity and Protects from Neurotoxin-Induced Degeneration of Dopaminergic Cells.
Paliga D, Raudzus F, Leppla SH, Heumann R, Neumann S
A lab study shows that a modified Nurr1 protein protects dopamine-producing cells from damage in cell cultures. This approach has not been tested in humans or animals, so it does not currently offer a treatment option for children with NR4A2-related syndrome.
- Researchers created a fusion protein to deliver Nurr1 into human dopaminergic cells.
- The modified protein increased tyrosine hydroxylase activity in cultured cells.
- The treatment protected cells from neurotoxin-induced degeneration in vitro.
- This is early-stage molecular biology with no clinical or animal data.
Compensatory Expression of Nur77 and Nurr1 Regulates NF-κB-Dependent Inflammatory Signaling in Astrocytes.
Popichak KA, Hammond SL, Moreno JA, Afzali MF, Backos DS, Slayden RD, Safe S, Tjalkens RB
A specific compound called C-DIM5 reduces inflammatory signaling in astrocytes by activating the NR4A family of receptors, including Nurr1. This mechanism suggests that targeting these receptors could potentially protect neurons from inflammation-driven damage.
- C-DIM5 suppresses inflammatory genes in astrocytes via NR4A receptor activation.
- The drug requires both Nur77 and Nurr1 to inhibit NF-kB signaling.
- This is preclinical cell culture research, not human clinical data.
- No approved drugs currently target these specific receptors for therapy.
Medial habenula maturational deficits associate with low motivation for voluntary physical activity.
Grigsby KB, Kelty TJ, Booth FW
This study identifies structural and genetic differences in the medial habenula of rats that correlate with their natural tendency to exercise, highlighting Nurr1 as a marker of neuronal maturity in this context. The findings suggest that the development of specific brain circuits drives motivation for physical activity rather than directly addressing NR4A2-related syndromes.
- Rats bred to run more show higher Nurr1 and neuronal maturity markers in the medial habenula.
- Low-activity rats exhibit immature dendritic structures in the same brain region.
- Nurr1 expression correlates with running distance only in high-activity animals.
- The study links habenula maturation to voluntary physical activity motivation.
- This is a rat model of exercise behavior, not an NR4A2 clinical or therapeutic study.
The involvement of NR4A1 and NR4A2 in the regulation of the luteal function in rats.
Qi L, Guo N, Wei Q, Jin P, Wang W, Mao D
NR4A2 and NR4A1 are involved in regulating luteal function in rats, with NR4A2 primarily found in steroid-producing cells of the corpus luteum and showing expression changes during luteal development and regression. These findings suggest NR4A2 plays a role in maintaining and breaking down the corpus luteum, a process critical for reproductive cycles.
- NR4A2 is present in luteal steroidogenic cells in rats
- NR4A2 expression changes during luteal development and regression
- NR4A2 levels rise quickly in response to luteolytic signals
- NR4A2 may regulate key functions in the corpus luteum
- Findings are relevant to understanding hormonal regulation in reproduction
Abrogation of the Circadian Nuclear Receptor REV-ERBα Exacerbates 6-Hydroxydopamine-Induced Dopaminergic Neurodegeneration.
Kim J, Jang S, Choi M, Chung S, Choe Y, Choe HK, Son GH, Rhee K, Kim K
Removing the circadian protein REV-ERBα worsens dopamine neuron loss and motor deficits in a mouse model of Parkinson's disease. This damage occurs because the absence of REV-ERBα triggers harmful neuroinflammation, suggesting that normal REV-ERBα function helps protect these neurons.
- REV-ERBα competes with NURR1 to regulate dopamine neuron genes.
- Lacking REV-ERBα increases vulnerability of dopamine neurons to toxins in mice.
- The worsening damage is driven by neuroinflammation and microglial activation.
- Normal REV-ERBα activity appears protective for dopamine neuron survival.
Maternal Vitamin D Prevents Abnormal Dopaminergic Development and Function in a Mouse Model of Prenatal Immune Activation.
Luan W, Hammond LA, Vuillermot S, Meyer U, Eyles DW
Maternal vitamin D supplementation prevents abnormal dopamine neuron development and function in a mouse model of prenatal immune stress. Vitamin D increases the number of mature dopamine neurons and restores their normal positioning in fetal brains.
- Vitamin D prevents hypersensitivity to dopamine stimulation in offspring exposed to prenatal immune stress.
- Maternal vitamin D increases mature Nurr1-positive dopamine neuron counts in fetal mice.
- Vitamin D restores normal positioning of mesencephalic dopamine neurons in the developing brain.
- The study uses a mouse model, not human patients or NR4A2-specific genetics.
Generation of dopamine neuronal-like cells from induced neural precursors derived from adult human cells by non-viral expression of lineage factors.
Playne R, Jones K, Connor B
Researchers successfully converted adult human skin cells into dopamine neuronal-like cells using non-viral genetic factors, demonstrating a new method for modeling Parkinson's disease in the lab. The study confirms that these reprogrammed cells express key dopamine markers but fail to fully mature into authentic midbrain neurons despite various experimental adjustments. This work establishes a platform for drug screening rather than offering immediate clinical insights or treatments for NR4A2-related conditions.
- Adult human skin cells convert to dopamine neuronal-like cells via non-viral reprogramming.
- Cells express dopamine markers but lack critical early midbrain developmental signals.
- Adding patterning factors does not produce authentic A9 dopamine neuron phenotypes.
- Method provides an in vitro model for Parkinson's disease drug screening.
- No clinical data, patient outcomes, or direct NR4A2 treatment implications are presented.
Endogenous Purification of NR4A2 (Nurr1) Identified Poly(ADP-Ribose) Polymerase 1 as a Prime Coregulator in Human Adrenocortical H295R Cells.
Noro E, Yokoyama A, Kobayashi M, Shimada H, Suzuki S, Hosokawa M, Takehara T, Parvin R, Shima H, Igarashi K, Sugawara A
This study identifies PARP1 as a key partner for the NR4A2 protein in adrenal cells, showing that blocking PARP1 reduces aldosterone production. This finding is specific to adrenal hormone regulation and does not provide information about NR4A2's role in brain development or potential treatments for NR4A2-related syndromes.
- PARP1 interacts directly with NR4A2 in human adrenal cells.
- Inhibiting PARP1 reduces aldosterone secretion in these cells.
- The research focuses on steroid hormone synthesis, not neurological function.
- No connection to dopaminergic neurons or motor symptoms is established.
Epigenetic Regulation of Aldosterone Synthase Gene by Sodium and Angiotensin II.
Takeda Y, Demura M, Wang F, Karashima S, Yoneda T, Kometani M, Hashimoto A, Aono D, Horike SI, Meguro-Horike M, Yamagishi M, Takeda Y
DNA methylation controls the activity of transcription factors, including NR4A2 (NURR1), by physically blocking their ability to bind to DNA. When specific DNA regions are methylated, NR4A2 cannot interact with its target sites, which prevents it from regulating gene expression.
- Methylation of NR4A2 binding sites directly reduces the protein's ability to bind DNA.
- This study focuses on adrenal hormone regulation, not brain development or dopamine.
- NR4A2 appears as one of several transcription factors affected by methylation.
- The research uses rat models and cell lines, with no human clinical data.