Direct reprogramming of human fibroblasts into dopaminergic neuron-like cells.
Liu X, Li F, Stubblefield EA, Blanchard B, Richards TL, Larson GA, He Y, Huang Q, Tan AC, Zhang D, Benke TA, Sladek JR, Zahniser NR, Li CY
Scientists turned human skin cells into dopamine-producing brain cells using five key genes, creating cells that function like real dopamine neurons and improve symptoms in a Parkinson's disease rat model. This approach could lead to new cell therapies for Parkinson's and other dopamine-related disorders.
- Human skin cells were turned into dopamine neurons
- Reprogrammed cells act like real dopamine neurons
- They improved symptoms in a Parkinson's rat model
- Potential for future cell replacement therapy
- Uses genes linked to brain development and Parkinson's
FHL2 protein is a novel co-repressor of nuclear receptor Nur77.
Kurakula K, van der Wal E, Geerts D, van Tiel CM, de Vries CJ
FHL2 protein turns down the activity of Nur77, a nuclear receptor linked to NR4A2-related syndrome, by preventing it from binding to DNA and regulating genes. This interaction may influence vascular health and could affect how symptoms develop in people with NR4A2 mutations.
- FHL2 reduces Nur77's ability to control gene activity
- FHL2 blocks Nur77 from attaching to DNA
- FHL2 levels affect cell growth in blood vessels
- This interaction may influence NR4A2-related conditions
Prolonged membrane depolarization enhances midbrain dopamine neuron differentiation via epigenetic histone modifications.
He XB, Yi SH, Rhee YH, Kim H, Han YM, Lee SH, Lee H, Park CH, Lee YS, Richardson E, Kim BW, Lee SH
Prolonged electrical activity in developing brain cells boosts the formation of dopamine neurons by altering how genes are turned on, without needing calcium signals. This happens by relaxing tightly packed DNA around key genes and removing molecular brakes that block gene activation.
- Electric stimulation enhances dopamine neuron development
- Works without calcium or L-type channels
- Opens gene regions by modifying histone marks
- Removes repressor proteins from dopamine genes
- Helps Nurr1 activate genes needed for dopamine neurons
Dental pulp stem cells: osteogenic differentiation and gene expression.
Mori G, Brunetti G, Oranger A, Carbone C, Ballini A, Lo Muzio L, Colucci S, Mori C, Grassi FR, Grano M
Dental pulp stem cells can become bone-forming cells and show increased activity of the NURR1 gene during this process, which may help understand how these cells develop and function.
- DPSCs can turn into bone-forming cells in lab conditions
- NURR1 gene levels rise during DPSC bone development
- This suggests NURR1 plays a role in bone cell formation
- These cells may be useful for regenerative therapies
MicroRNA-mediated dysregulation of neural developmental genes in HPRT deficiency: clues for Lesch-Nyhan disease?
Guibinga GH, Hrustanovic G, Bouic K, Jinnah HA, Friedmann T
HPRT deficiency in human dopaminergic cells leads to increased levels of miR181a, which suppresses key genes needed for dopamine neuron development, potentially explaining the brain abnormalities in Lesch-Nyhan disease. This miR181a-driven gene disruption may contribute to the disease’s neurological symptoms.
- miR181a is overexpressed in HPRT-deficient dopamine cells
- miR181a suppresses genes critical for dopamine neuron development
- This gene suppression may drive brain defects in Lesch-Nyhan disease
- Targeting miR181a could be a potential therapeutic strategy
- Findings are in human cells, not just animal models
The impact of early life permethrin exposure on development of neurodegeneration in adulthood.
Carloni M, Nasuti C, Fedeli D, Montani M, Amici A, Vadhana MS, Gabbianelli R
Exposure to permethrin during early life reduces Nurr1 levels in the brain, which may impair dopamine neuron protection and increase inflammation, potentially raising the risk of neurodegenerative diseases later in life.
- Permethrin exposure lowers Nurr1 in the brain
- Nurr1 loss may harm dopamine neurons
- Early pesticide exposure alters brain chemistry
- Changes in blood markers mirror brain changes
- Findings may relate to neurodegeneration risk
Regulatory effects of costunolide on dopamine metabolism-associated genes inhibit dopamine-induced apoptosis in human dopaminergic SH-SY5Y cells.
Ham A, Lee SJ, Shin J, Kim KH, Mar W
Costunolide protects human dopamine-producing cells from death caused by excess dopamine, likely by boosting levels of key proteins that help manage dopamine and reduce toxic buildup. This suggests costunolide could be a potential treatment for Parkinson’s disease.
- Costunolide prevents dopamine-induced cell death
- Boosts Nurr1, DAT, and VMAT2 proteins
- Reduces harmful alpha-synuclein levels
- May help protect dopamine neurons
- Suggests a possible therapy for Parkinson’s
DJ-1 upregulates tyrosine hydroxylase gene expression by activating its transcriptional factor Nurr1 via the ERK1/2 pathway.
Lu L, Sun X, Liu Y, Zhao H, Zhao S, Yang H
DJ-1 boosts the production of a key dopamine-making enzyme by activating Nurr1, a critical brain protein, through a specific cellular signaling pathway. This process is disrupted by a common Parkinson’s-related DJ-1 mutation, which may contribute to disease.
- DJ-1 increases dopamine enzyme production via Nurr1
- Nurr1 must be activated and move into the nucleus to work
- The ERK1/2 pathway links DJ-1 to Nurr1 activation
- A common DJ-1 mutation blocks this protective pathway
- This mechanism may explain dopamine loss in some Parkinson’s cases
Delayed cortical impairment following lipopolysaccharide exposure in preterm fetal sheep.
Dean JM, van de Looij Y, Sizonenko SV, Lodygensky GA, Lazeyras F, Bolouri H, Kjellmer I, Huppi PS, Hagberg H, Mallard C
Fetal exposure to inflammation (mimicked by LPS) in preterm sheep causes lasting damage to both white matter and cortical brain regions, leading to reduced brain volume, impaired neuron development, and abnormal brain wave patterns. These findings suggest that infections during pregnancy may contribute to brain injury seen in preterm babies.
- Inflammation harms both white matter and cortex in preterm fetal brains
- Brain volume and neuron counts drop significantly after inflammation
- Abnormal brain wave patterns correlate with brain damage
- Damage occurs even before myelination begins
- Findings support infection as a cause of preterm brain injury
Dopamine D1 receptor modulation in nucleus accumbens lowers voluntary wheel running in rats bred to run high distances.
Roberts MD, Gilpin L, Parker KE, Childs TE, Will MJ, Booth FW
Rats bred to run long distances show reduced wheel running when dopamine D1 receptors in the brain's reward center are either activated or blocked, suggesting their high activity is driven by a finely tuned dopamine system. This effect does not occur in rats bred to run less, and differences in gene expression do not explain the behavior. The findings highlight how dopamine signaling in the brain influences natural reward-seeking behaviors like exercise.
- High-running rats reduce activity when D1 receptors are altered
- Low-running rats are unaffected by D1 receptor changes
- Gene expression levels do not differ between high- and low-running rats
- Dopamine signaling may drive natural reward for exercise
- Findings may inform treatments for inactivity or addiction
Pituitary adenylate cyclase-activating polypeptide controls stimulus-transcription coupling in the hypothalamic-pituitary-adrenal axis to mediate sustained hormone secretion during stress.
Stroth N, Liu Y, Aguilera G, Eiden LE
PACAP is a key regulator of the stress response system in the brain and adrenal glands, controlling hormone release by activating genes like CRH and Nr4a transcription factors in the hypothalamus and adrenal glands during stress. This process ensures sustained hormone secretion, and its disruption may affect how the body handles stress.
- PACAP drives stress hormone release via the hypothalamus
- PACAP activates CRH and Nr4a genes during stress
- Nr4a genes are critical for sustained adrenal hormone production
- PACAP deficiency impairs stress response gene activation
- PACAP links stress signals to long-term hormone output
Moracenin D from Mori Cortex radicis protects SH-SY5Y cells against dopamine-induced cell death by regulating nurr1 and α-synuclein expression.
Ham A, Lee HJ, Hong SS, Lee D, Mar W
Moracenin D, a compound from a traditional plant, protects human brain cells from dopamine damage by boosting NURR1 levels and reducing alpha-synuclein, a protein linked to Parkinson’s disease. This suggests it may help treat conditions involving NURR1 deficiency, including NR4A2-related syndrome.
- Moracenin D protects brain cells from dopamine damage
- It increases NURR1, a key protein missing in NR4A2 syndrome
- It reduces alpha-synuclein, which can build up in brain cells
- These effects suggest potential for treating NR4A2-related disorders
- Found in a plant used in traditional medicine
NR4A gene expression is dynamically regulated in the ventral tegmental area dopamine neurons and is related to expression of dopamine neurotransmission genes.
Eells JB, Wilcots J, Sisk S, Guo-Ross SX
NR4A genes, especially Nurr1, are tightly controlled by dopamine neuron activity in the brain's reward center. When dopamine signaling changes, these genes respond quickly, which may influence dopamine production and transport. This suggests that boosting Nurr1 could help restore normal dopamine function in NR4A2-related syndrome.
- Nurr1 levels drop without dopamine neuron activity
- Drugs that block dopamine receptors boost Nur77
- Nurr1 increases only when dopamine neurons fire normally
- NR4A genes control key dopamine genes like TH and DAT
- Targeting NR4A genes may improve dopamine function
Signaling of glial cell line-derived neurotrophic factor and its receptor GFRα1 induce Nurr1 and Pitx3 to promote survival of grafted midbrain-derived neural stem cells in a rat model of Parkinson disease.
Lei Z, Jiang Y, Li T, Zhu J, Zeng S
GDNF signaling helps grafted midbrain stem cells survive and develop into dopamine-producing neurons by boosting levels of Nurr1 and Pitx3, key proteins for dopamine neuron health. This process improves motor function in a rat model of Parkinson's disease and depends on the GFRα1 receptor.
- GDNF boosts Nurr1 and Pitx3 in stem cells
- GDNF improves survival and function of grafted neurons
- GFRα1 is essential for GDNF's effect
- This enhances motor recovery in Parkinson's rats
- Findings may guide future Parkinson's therapies
Altered layer-specific gene expression in cortical samples from patients with temporal lobe epilepsy.
Rossini L, Moroni RF, Tassi L, Watakabe A, Yamamori T, Spreafico R, Garbelli R
This study found that in children with temporal lobe epilepsy, the deeper layers of the brain cortex—especially layers V and VI—show abnormal gene activity, including changes in NURR1 and ER81, which are linked to NR4A2. These disruptions may explain why brain circuits are miswired in epilepsy and could help improve diagnosis. Abnormal brain cell clusters in white matter also showed unusual gene patterns, suggesting developmental issues beyond the cortex.
- NURR1 and ER81 genes are disrupted in deep brain layers
- Abnormal gene patterns may underlie epilepsy-related brain wiring issues
- White matter cell clusters show mixed gene activity
- Layer-specific genes help identify brain malformations
- Findings may improve epilepsy diagnosis and understanding
Relationship between sensorimotor gating deficits and dopaminergic neuroanatomy in Nurr1-deficient mice.
Vuillermot S, Feldon J, Meyer U
Mice with reduced Nurr1, a gene linked to Parkinson's and schizophrenia, show impaired sensorimotor gating, which correlates with lower dopamine-related markers in brain regions critical for movement and behavior. These findings suggest that Nurr1 deficiency disrupts dopamine system structure, contributing to behavioral symptoms seen in related human disorders.
- Nurr1 deficiency causes sensorimotor gating problems in mice
- Dopamine neuron loss and reduced markers in striatum correlate with behavior
- Dopamine system changes in brain areas linked to movement and reward
- Findings mirror brain and behavior issues in Parkinson's and schizophrenia
- Suggests potential for targeting dopamine pathways in NR4A2-related conditions
Direct generation of functional dopaminergic neurons from mouse and human fibroblasts.
Caiazzo M, Dell'Anno MT, Dvoretskova E, Lazarevic D, Taverna S, Leo D, Sotnikova TD, Menegon A, Roncaglia P, Colciago G, Russo G, Carninci P, Pezzoli G, Gainetdinov RR, Gustincich S, Dityatev A, Broccoli V
Scientists turned skin cells from mice and humans directly into functional dopamine-producing brain cells using just three genes, including NR4A2 (NURR1). These lab-made neurons behave like real brain dopamine cells and could help treat Parkinson's disease and study brain disorders.
- NR4A2 (NURR1) is key to making dopamine neurons from skin cells
- Generated neurons release dopamine and fire like real brain cells
- Work done on both healthy and Parkinson's patient cells
- Avoids stem cell stage, reducing tumor risk
- Potential for disease modeling and cell therapy
Nurr1 is not essential for the development of prepulse inhibition deficits induced by prenatal immune activation.
Vuillermot S, Feldon J, Meyer U
Prenatal immune activation causes prepulse inhibition deficits in mice, even when the Nurr1 gene is partially missing, suggesting Nurr1 is not required for these behavioral changes. This finding implies other pathways may drive the neurological effects seen in conditions like schizophrenia.
- Nurr1 is not needed for immune-induced prepulse inhibition deficits
- Prenatal inflammation still disrupts behavior without full Nurr1 function
- Other molecular pathways likely contribute to these deficits
- Findings may help identify new treatment targets
Neuronal plasticity of human Wharton's jelly mesenchymal stromal cells to the dopaminergic cell type compared with human bone marrow mesenchymal stromal cells.
Datta I, Mishra S, Mohanty L, Pulikkot S, Joshi PG
Human Wharton's jelly mesenchymal stromal cells can transform into dopamine-producing neurons just as effectively as bone marrow-derived cells, with similar levels of key dopamine markers and function, suggesting both sources are equally promising for potential therapies targeting dopamine-related disorders.
- WJ MSCs differentiate into dopamine neurons as well as BM MSCs
- Both cell types produce similar levels of dopamine and key markers
- Induced WJ MSCs release dopamine in response to stimulation
- No major differences in plasticity or function between the two sources
- Findings support WJ MSCs as a viable alternative for cell-based therapies
Nuclear receptors Nur77 and Nurr1 modulate mesenchymal stromal cell migration.
Maijenburg MW, Gilissen C, Melief SM, Kleijer M, Weijer K, Ten Brinke A, Roelofs H, Van Tiel CM, Veltman JA, de Vries CJ, van der Schoot CE, Voermans C
Nur77 and Nurr1 are nuclear receptors that boost the movement of mesenchymal stromal cells, which could help improve how these cells travel to injury sites in therapies. These receptors are activated by signals that guide cell migration and also influence immune-related molecules without losing the cells' ability to suppress immune responses.
- Nur77 and Nurr1 boost MSC migration
- They are activated by key migration signals
- They reduce S-phase cells, affecting cell cycle
- They increase immune-modulating factors
- MSCs keep immune-suppressing ability
Multiple noncoding exons 1 of nuclear receptors NR4A family (nerve growth factor-induced clone B, Nur-related factor 1 and neuron-derived orphan receptor 1) and NR5A1 (steroidogenic factor 1) in human cardiovascular and adrenal tissues.
Demura M, Wang F, Yoneda T, Karashima S, Mori S, Oe M, Kometani M, Sawamura T, Cheng Y, Maeda Y, Namiki M, Ino H, Fujino N, Uchiyama K, Tsubokawa T, Yamagishi M, Nakamura Y, Ono K, Sasano H, Demura Y, Takeda Y
The study found that NR4A2 (NURR1) and related genes use different noncoding exons in heart and adrenal tissues, with patterns linked to disease states like adrenal tumors and heart muscle disease. These differences suggest a role for gene regulation in organ-specific function and disease.
- NR4A2 uses different exons in heart vs. adrenal tissue
- Exon usage differs in adrenal tumors and heart disease
- NR4A2 and NR5A1 levels vary by tissue type
- Gene regulation may affect heart and adrenal function
- Findings suggest tissue-specific control of gene activity
Schizophrenia-relevant behaviors in a genetic mouse model of constitutive Nurr1 deficiency.
Vuillermot S, Joodmardi E, Perlmann T, Ove Ögren S, Feldon J, Meyer U
Mice with reduced Nurr1, a gene linked to dopamine brain development, show specific behaviors similar to schizophrenia, including increased movement, abnormal responses to a drug that mimics psychosis, and impaired sensorimotor filtering. These changes suggest that Nurr1 deficiency may contribute to core features of psychotic disorders, especially those involving dopamine and brain circuitry. The mice did not show broader cognitive or social deficits seen in schizophrenia.
- Nurr1 deficiency causes psychosis-like behaviors in mice
- Key issues include hyperactivity and poor sensorimotor gating
- Mice react more strongly to MK-801, a schizophrenia-mimicking drug
- No major problems with social or memory functions were found
- Nurr1 is critical for proper dopamine system development
Convergent functional genomics of anxiety disorders: translational identification of genes, biomarkers, pathways and mechanisms.
Le-Niculescu H, Balaraman Y, Patel SD, Ayalew M, Gupta J, Kuczenski R, Shekhar A, Schork N, Geyer MA, Niculescu AB
This study identifies NR4A2 and other genes, brain-blood biomarkers, and biological pathways linked to anxiety disorders using a combined approach in mice and humans. It finds strong genetic connections between anxiety and schizophrenia, suggesting shared biological roots and potential new treatment targets.
- NR4A2 is a top candidate gene for anxiety disorders
- Anxiety shares genetic links with schizophrenia
- Blood biomarkers like FOS and HSPA1B may reflect brain changes
- Hippocampus plays a key role in anxiety-related gene activity
- Findings support 'schizo-anxiety' as a possible new disorder category
ES cell-derived renewable and functional midbrain dopaminergic progenitors.
Chung S, Moon JI, Leung A, Aldrich D, Lukianov S, Kitayama Y, Park S, Li Y, Bolshakov VY, Lamonerie T, Kim KS
Scientists have developed a method to grow large numbers of midbrain dopaminergic progenitor cells from stem cells that can turn into dopamine-producing neurons, which may help treat Parkinson's disease. These cells grow well in the lab, stay stable, and when transplanted, they integrate into brain tissue, improve movement, and do not cause tumors.
- Stem cell-derived dopamine progenitors can be grown in large quantities
- Cells maintain identity and turn into functional dopamine neurons
- Transplanted cells improve motor function in animal models
- No tumor formation observed after transplantation
- Cells show strong migration and integration in brain tissue
Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson's disease models.
Domanskyi A, Geissler C, Vinnikov IA, Alter H, Schober A, Vogt MA, Gass P, Parlato R, Schütz G
Deleting the Pten gene in adult dopamine-producing brain cells protects them from degeneration in mouse models of Parkinson's disease, improves dopamine levels, and restores movement function. This suggests that blocking Pten could be a potential therapy for Parkinson's.
- Pten deletion protects dopamine neurons in Parkinson's models
- Boosts dopamine production and key neuron survival genes
- Improves movement problems caused by neuron loss
- Activates mTOR pathway, which supports neuron health
- Suggests Pten inhibition as a possible Parkinson's treatment
Age-related changes in dopamine signaling in Nurr1 deficient mice as a model of Parkinson's disease.
Zhang L, Le W, Xie W, Dani JA
Mice with one defective copy of the NR4A2 gene (Nurr1) show early problems with dopamine release, even before significant neuron loss, suggesting that NR4A2 dysfunction disrupts dopamine signaling long before Parkinson’s symptoms appear. This mirrors what may happen in people with NR4A2-related syndrome, highlighting early brain changes that could be targeted therapeutically.
- NR4A2 deficiency impairs dopamine release before neuron loss
- Dopamine signaling declines with age in NR4A2-deficient mice
- Reduced dopamine reuptake initially compensates but fails over time
- Early dopamine dysfunction may be a key feature in NR4A2-related syndrome
- Findings suggest a window for early intervention
Effect of SOM230 (pasireotide) on corticotropic cells: action in dogs with Cushing's disease.
Castillo V, Theodoropoulou M, Stalla J, Gallelli MF, Cabrera-Blatter MF, Haedo MR, Labeur M, Schmid HA, Stalla GK, Arzt E
Pasireotide (SOM230) effectively reduces ACTH production and tumor size in dogs with Cushing's disease, improving clinical signs without side effects. It works by blocking POMC gene activity through SSTR2 receptors, which also affects the NR4A2/Nurr1 transcription factor.
- Pasireotide reduces ACTH and cortisol in dogs with Cushing's disease
- It shrinks pituitary tumors and improves symptoms
- It blocks ACTH production at the gene level via SSTR2
- NR4A2/Nurr1 activity is reduced by pasireotide in cell models
- No serious side effects were observed in treated dogs
Chronic methamphetamine administration causes differential regulation of transcription factors in the rat midbrain.
Krasnova IN, Ladenheim B, Hodges AB, Volkow ND, Cadet JL
This study found that prior exposure to methamphetamine protects rat brains from dopamine damage, possibly by changing the levels of key brain development proteins called transcription factors. The protection may come from increased levels of two proteins, Otx2 and Pitx3, which help maintain dopamine neurons.
- Methamphetamine pre-exposure protects dopamine neurons
- Protective effect linked to increased Otx2 and Pitx3
- Nurr1 levels drop after methamphetamine damage
- Dopamine transporter changes depend on prior exposure
- These changes may explain neuron survival after injury
Inflammation: a role for NR4A orphan nuclear receptors?
McMorrow JP, Murphy EP
NR4A2 and related proteins help control inflammation in the body, and their abnormal activity may contribute to chronic inflammatory diseases like arthritis and psoriasis. These proteins act as switches that regulate immune responses, potentially offering targets for new treatments.
- NR4A2 regulates immune responses and inflammation
- Abnormal NR4A2 activity links to chronic diseases
- NR4A proteins may be targets for anti-inflammatory therapies
- They act as rapid responders to inflammatory signals
Loss of braking signals during inflammation: a factor affecting the development and disease course of multiple sclerosis.
Gilli F, Navone ND, Perga S, Marnetto F, Caldano M, Capobianco M, Pulizzi A, Malucchi S, Bertolotto A
In people with multiple sclerosis, key genes that normally help turn off inflammation—like NR4A2—are underactive, which may drive disease progression. Lower levels of these genes are linked to more relapses and worsening disability, and some treatments can boost their activity.
- NR4A2 helps control inflammation and is underactive in MS
- Low NR4A2 levels predict more relapses and disability
- Interferon beta and glatiramer acetate increase NR4A2 activity
- Natalizumab does not affect NR4A2 levels
- Restoring these 'braking' genes may help treat MS
Network-like impact of MicroRNAs on neuronal lineage differentiation of unrestricted somatic stem cells from human cord blood.
Iwaniuk KM, Schira J, Weinhold S, Jung M, Adjaye J, Müller HW, Wernet P, Trompeter HI
A group of 18 microRNAs decreases during the development of dopamine-producing neurons from cord blood stem cells, allowing key proteins to promote neuronal growth and function. These microRNAs act together in a network to regulate pathways critical for brain cell development.
- 18 microRNAs drop during neuron formation from stem cells
- This boosts proteins that guide neuron development and function
- Targets include genes linked to dopamine neurons and brain wiring
- The microRNAs work as a coordinated network, not individually
- Findings may help develop therapies for NR4A2-related disorders
Comparative aspects of subplate zone studied with gene expression in sauropsids and mammals.
Wang WZ, Oeschger FM, Montiel JF, García-Moreno F, Hoerder-Suabedissen A, Krubitzer L, Ek CJ, Saunders NR, Reim K, Villalón A, Molnár Z
This study compares brain development across species and finds that certain genes linked to early cortical neurons are active in similar brain regions in both mammals and birds/reptiles, suggesting a shared evolutionary origin for these cells. The findings help clarify how the brain's foundational layers formed in ancient vertebrates.
- Key genes in early brain development are shared across mammals, birds, and reptiles
- Subplate-like cells may have existed in the common ancestor of all these species
- Gene expression patterns suggest a conserved origin for early cortical neurons
- Findings support evolutionary continuity in brain development
Molecular annotation of integrative feeding neural circuits.
Pérez CA, Stanley SA, Wysocki RW, Havranova J, Ahrens-Nicklas R, Onyimba F, Friedman JM
This study identifies specific brain neurons involved in controlling feeding behavior, including those expressing Nurr1 and Cnr1 in areas linked to appetite and reward. These neurons connect across brain regions and become more active during fasting, suggesting they help regulate eating. The findings provide molecular markers to study these circuits in detail.
- Nurr1 and Cnr1 neurons are active during fasting
- These neurons connect brain regions involved in feeding
- Markers help identify and study feeding circuits
- Findings may guide future treatments for eating disorders