Identification of a novel co-regulator interaction surface on the ligand binding domain of Nurr1 using NMR footprinting.
Codina A, Benoit G, Gooch JT, Neuhaus D, Perlmann T, Schwabe JW
Nurr1, a key protein for brain development, uses a previously unknown surface on its structure to interact with other proteins that control gene activity. This discovery reveals how Nurr1 works without needing a traditional binding site for signals, which may help develop treatments for NR4A2-related disorders.
- Nurr1 uses a new protein interaction site to control genes
- This site is on the protein's ligand-binding domain
- The site binds co-repressor proteins via a hydrophobic groove
- Mutations in this site stop Nurr1 from working
- This mechanism is unique to Nurr1 and similar proteins
Differentiation and transcription factor gene therapy in experimental parkinson's disease: sonic hedgehog and Gli-1, but not Nurr-1, protect nigrostriatal cell bodies from 6-OHDA-induced neurodegeneration.
Hurtado-Lorenzo A, Millan E, Gonzalez-Nicolini V, Suwelack D, Castro MG, Lowenstein PR
In a rat model of Parkinson's-like brain damage, gene therapy using Sonic Hedgehog (ShhN) and its target Gli-1 protected dopamine-producing brain cells from dying, but the Nurr-1 gene did not. This suggests ShhN and Gli-1 may help preserve these critical neurons in neurodegenerative conditions.
- ShhN and Gli-1 protected brain cell bodies in Parkinson's-like damage
- Nurr-1 gene therapy did not protect neurons in this model
- Protection occurred even when over 70% of neurons were lost
- ShhN and Gli-1 may be useful for treating neuron loss in NR4A2-related syndromes
- This supports exploring differentiation factors in gene therapy
Nurr1, an orphan nuclear receptor with essential functions in developing dopamine cells.
Perlmann T, Wallén-Mackenzie A
Nurr1 is a critical protein for the development and survival of dopamine neurons, and it may also help maintain these neurons in adults. It works with another protein, RXR, and drugs that activate RXR can protect dopamine neurons, suggesting a potential treatment path for related disorders.
- Nurr1 is essential for dopamine neuron development
- It partners with RXR to support neuron survival
- RXR-activating drugs may protect dopamine neurons
- Nurr1 likely helps maintain dopamine neurons in adults
- Nurr1 has roles beyond the brain in the body
Genetic contributions to Parkinson's disease.
Huang Y, Cheung L, Rowe D, Halliday G
Mutations in the NR4A2 gene, also known as Nurr1, are linked to Parkinson's disease and disrupt key processes needed for dopamine neuron survival. This research highlights how genetic changes affect brain cells in Parkinson's, offering insights that could lead to new treatments.
- NR4A2/Nurr1 mutations cause Parkinson's-like brain cell loss
- These genes are vital for dopamine neuron health
- Understanding these genes may reveal new treatment targets
- Genetic and environmental factors together influence Parkinson's risk
NR4A2 and schizophrenia: lack of association in a Portuguese/Brazilian study.
Ruano D, Macedo A, Dourado A, Soares MJ, Valente J, Coelho I, Santos V, Azevedo MH, Goodman A, Hutz MH, Gama C, Lobato MI, Belmonte-de-Abreu P, Palha JA
This study found no evidence of previously reported NR4A2 gene mutations in Portuguese or Brazilian people with schizophrenia, but it does not rule out other genetic changes or altered gene activity in the disorder.
- No known NR4A2 mutations were found in 258 schizophrenia patients
- NR4A2 is linked to brain development and dopamine systems
- Other mutations or gene expression changes may still play a role
- Findings do not support a major role for these specific mutations in schizophrenia
Efficient induction of dopaminergic neurons from embryonic stem cells for application to Parkinson's disease.
Kim DW
Genetically modifying embryonic stem cells to produce more Nurr1 protein, combined with specific lab culture conditions, creates dopamine-producing neurons very efficiently—up to 90% in some cases—offering a promising approach for cell-based therapies in Parkinson's disease.
- Adding extra Nurr1 boosts dopamine neuron production from stem cells
- Combining Nurr1 with special culture methods yields up to 90% dopamine neurons
- These neurons make more dopamine and show strong Parkinson’s-relevant traits
- The method works well in lab and in animal models after transplantation
- This could lead to better cell therapies for Parkinson’s disease
Pleiotrophin mRNA is highly expressed in neural stem (progenitor) cells of mouse ventral mesencephalon and the product promotes production of dopaminergic neurons from embryonic stem cell-derived nestin-positive cells.
Jung CG, Hida H, Nakahira K, Ikenaka K, Kim HJ, Nishino H
Pleiotrophin is highly active in neural stem cells from the mouse brain and boosts the creation of dopamine-producing neurons from stem cells, suggesting it may help in treating conditions like NR4A2-related syndrome where dopamine neurons are affected.
- Pleiotrophin is highly expressed in brain stem cells
- It increases dopamine neuron production from stem cells
- It boosts Nurr1, a key gene for dopamine neurons
- Its effect rivals that of sonic hedgehog, a known growth factor
- This suggests pleiotrophin could support neuron repair
Novel splicing variant of the human orphan nuclear receptor Nurr1 gene.
Xu PY, Le WD
A new version of the Nurr1 gene, called a splicing variant, was found in non-brain tissues like liver, muscle, and blood cells, but not in the brain. This variant produces a protein that is less active in turning on genes, which may affect how cells function.
- A new Nurr1 variant was found in non-neuronal tissues
- The variant has a 75 bp deletion in exon 5
- It shows 39% lower gene activity in lab tests
- Not found in brain or spinal cord tissue
- May act as a weaker or alternative regulator of gene expression
Forskolin cooperating with growth factor on generation of dopaminergic neurons from human fetal mesencephalic neural progenitor cells.
Wang X, Li X, Wang K, Zhou H, Xue B, Li L, Wang X
Combining forskolin with FGF8 significantly boosts the creation of dopamine-producing neurons from human fetal brain cells, which could help develop treatments for Parkinson's and similar disorders.
- Forskolin enhances FGF8's ability to make dopamine neurons
- Treated cells produced dopamine and key dopamine-related genes
- This combination may improve neuron generation for therapy
- Results support potential use in treating neurodegenerative diseases
GDNF promotes neuronal differentiation and dopaminergic development of mouse mesencephalic neurospheres.
Roussa E, Krieglstein K
GDNF helps mouse brain stem cells develop into dopamine-producing neurons, which is relevant for understanding and potentially treating NR4A2-related disorders.
- GDNF boosts development of dopamine neurons in mouse brain cells
- It increases cells with early dopamine markers like Nurr1
- GDNF promotes neuron formation from stem cells
- This supports potential therapies targeting dopamine pathways
Over-expression of bHLH genes facilitate neural formation of mouse embryonic stem (ES) cells in vitro.
Kanda S, Tamada Y, Yoshidome A, Hayashi I, Nishiyama T
Overexpressing certain bHLH genes, especially Mash1, helps mouse stem cells turn into neurons quickly and efficiently in the lab, with strong signs of early neural development and dopaminergic neurons.
- Mash1 overexpression speeds up neuron formation in stem cells
- Neural markers like Nestin, Map2, and Nurr1 appear early
- Dopaminergic neurons (TH-positive) are generated in the process
- bHLH genes act as powerful triggers for neural differentiation
- Findings may inform strategies for generating neurons from stem cells
Extended mutation analysis and association studies of Nurr1 (NR4A2) in Parkinson disease.
Hering R, Petrovic S, Mietz EM, Holzmann C, Berg D, Bauer P, Woitalla D, Müller T, Berger K, Krüger R, Riess O
This study examines mutations in the NR4A2 gene, which is linked to Parkinson's disease, and finds that certain variants may increase disease risk. The results suggest that NR4A2 plays a key role in Parkinson's, especially in early-onset cases.
- NR4A2 mutations are associated with Parkinson's disease
- Specific variants increase risk, especially in early-onset cases
- NR4A2 is a key gene in Parkinson's pathology
- Findings support NR4A2 as a potential therapeutic target
Nur77 induction and activation are necessary for interleukin-1 stimulation of proopiomelanocortin in AtT-20 corticotrophs.
Kovalovsky D, Paez Pereda M, Labeur M, Renner U, Holsboer F, Stalla GK, Arzt E
Interleukin-1 stimulates POMC production in corticotroph cells by activating Nur77, a protein encoded by the NR4A2 gene. Without functional Nur77, this stimulation does not occur, showing Nur77 is essential for this process.
- Nur77 (NR4A2) is required for IL-1 to boost POMC production
- IL-1 activates Nur77 via p38 kinase signaling
- Blocking Nur77 stops ACTH release in response to IL-1
- Nur77 activity directly controls stress hormone production
- This pathway may influence inflammation and stress responses
[The research advance of nuclear receptor Nurr1].
Lai YL, Xie ZP
Nurr1, a nuclear receptor encoded by the NR4A2 gene, plays a critical role in brain development and dopamine neuron function. Mutations in NR4A2 cause a rare neurodevelopmental disorder with features like intellectual disability, movement issues, and autism-like behaviors.
- NR4A2 mutations disrupt brain development and dopamine signaling
- Nurr1 is essential for the survival and function of dopamine neurons
- Disorders linked to NR4A2 include intellectual disability and movement problems
- Nurr1 is a potential target for therapies in related neurological conditions
Modulation of nurr1 gene expression in mesencephalic dopaminergic neurones.
Volpicelli F, Perrone-Capano C, Da Pozzo P, Colucci-D'Amato L, di Porzio U
Nurr1, a key gene for developing dopamine-producing brain cells, is highly active during a narrow window in early brain development and can be boosted by electrical activity and the Sonic hedgehog protein. This suggests ways to potentially enhance dopamine neuron formation, which may inform future therapies for NR4A2-related disorders.
- Nurr1 peaks during early brain development in rats
- Nurr1 increases with electrical activity in dopamine neurons
- Sonic hedgehog boosts dopamine neuron growth in lab cultures
- Nurr1 expression is flexible and responsive to signals
- Findings may guide treatments for NR4A2-related conditions
Temporally induced Nurr1 can induce a non-neuronal dopaminergic cell type in embryonic stem cell differentiation.
Sonntag KC, Simantov R, Kim KS, Isacson O
Nurr1 can turn stem cells into dopamine-producing cells that are not neurons, and these cells maintain their dopamine-making ability as long as Nurr1 is present. This shows Nurr1 is powerful enough on its own to create and sustain a midbrain-like dopamine cell type without needing normal brain cell development.
- Nurr1 alone creates dopamine cells from stem cells
- These cells are not neurons but make dopamine
- Nurr1 keeps the dopamine cells functional
- Nurr1 boosts key dopamine support proteins
- No need for normal brain cell development
Transcription factors specifying dopamine phenotype are decreased in cocaine users.
Bannon MJ, Pruetz B, Barfield E, Schmidt CJ
Cocaine use reduces levels of key proteins (Nurr1 and Pitx3) that help maintain dopamine neurons in the brain, leading to a partial loss of their normal function. This suggests long-term cocaine use may harm the brain's dopamine system.
- Cocaine use lowers Nurr1 and Pitx3 in human dopamine neurons
- These proteins are essential for dopamine neuron health
- Loss may impair dopamine function over time
- Findings suggest cocaine harms brain dopamine systems
Regulation of the osteopontin gene by the orphan nuclear receptor NURR1 in osteoblasts.
Lammi J, Huppunen J, Aarnisalo P
Nurr1 directly activates the osteopontin gene in bone-forming cells, suggesting it plays a role in bone development and maintenance. This interaction may influence how bone responds to hormones like PTH and vitamin D.
- Nurr1 boosts osteopontin production in bone cells
- Nurr1 works with vitamin D to enhance osteopontin expression
- Nurr1 is needed for PTH to increase osteopontin
- Estrogen-related receptors block Nurr1's effect on osteopontin
- Nurr1 directly binds to the osteopontin gene promoter
Congenital hypoventilation and impaired hypoxic response in Nurr1 mutant mice.
Nsegbe E, Wallén-Mackenzie A, Dauger S, Roux JC, Shvarev Y, Lagercrantz H, Perlmann T, Herlenius E
Mice without the Nurr1 gene have severe breathing problems at birth, including slow breathing, pauses in breathing, and an inability to respond to low oxygen, which leads to death. Nurr1 is active in key brain areas that control breathing and oxygen response, showing it is essential for newborns to adapt to breathing outside the womb.
- Nurr1 is critical for newborn breathing adaptation
- Nurr1-deficient mice cannot respond to low oxygen
- Nurr1 is found in brain regions controlling breathing
- Breathing failure causes death within 24 hours
- Heterozygous mice also show breathing abnormalities
Differential role of ERK in cAMP-induced Nurr1 expression in N2A and C6 cells.
Lee MK, Nikodem VM
cAMP increases Nurr1 levels in two cell types, but the role of the ERK pathway differs: it helps boost Nurr1 in one cell type but blocks it in the other. This suggests that treatments targeting ERK may have opposite effects depending on the cell context.
- cAMP increases Nurr1 in both cell types
- ERK helps Nurr1 in N2A cells, blocks it in C6 cells
- PKA is required for Nurr1 increase in both
- MEK inhibition boosts Nurr1 in C6 cells
- ERK effects depend on cell type
Defining an N-terminal activation domain of the orphan nuclear receptor Nurr1.
Nordzell M, Aarnisalo P, Benoit G, Castro DS, Perlmann T
Nurr1, a key protein for brain development, has a specific region at its beginning that controls its activity. This region can be boosted by a cellular signaling pathway involving MAPK, which adds phosphate groups to a specific site outside the core activation area.
- A small region near Nurr1's start drives its activity
- MAPK signaling enhances Nurr1 function via phosphorylation
- Phosphorylation at a specific site boosts Nurr1 activity
- This effect varies by cell type, suggesting targeted regulation
Dopaminergic properties and experimental anti-parkinsonian effects of IPX750 in rodent models of Parkinson disease.
Jiang C, Wan X, Jankovic J, Christian ST, Pristupa ZB, Niznik HB, Sundsmo JS, Le W
IPX-750 is a pro-drug designed to deliver dopamine more effectively to the brain by using sugar transporters. It shows strong anti-parkinsonian effects in multiple rodent models of Parkinson’s disease, including those with Nurr1 deficiency, and does not cause toxicity in cells. The drug’s effects last even after stopping treatment, suggesting it may build up in the brain.
- IPX-750 improves brain delivery of dopamine via sugar transporters
- It reduces Parkinson’s-like symptoms in mice and rats
- No toxicity seen in cell studies at effective doses
- Effects persist for weeks after stopping treatment
- May help treat dopamine deficiency, including in Nurr1-related conditions
Dopaminergic differentiation of human embryonic stem cells.
Zeng X, Cai J, Chen J, Luo Y, You ZB, Fotter E, Wang Y, Harvey B, Miura T, Backman C, Chen GJ, Rao MS, Freed WJ
Human embryonic stem cells can be turned into dopamine-producing neurons that function like real brain cells, which may help in studying and treating conditions like Parkinson's disease. These lab-grown neurons survive transplantation and release dopamine, but few remain after being implanted in animals.
- hESCs become dopamine neurons when grown with PA6 cells
- Cells produce dopamine and show key markers of mature neurons
- Transplanted neurons survive and release dopamine in animal brains
- No undifferentiated stem cells remain after transplant
- Results support potential for cell-based therapies
Short interfering RNAs (siRNAs) for reducing dopaminergic phenotypic markers.
Bäckman C, Zhang Y, Hoffer BJ, Tomac AC
This study shows that siRNAs can effectively reduce the levels of key dopamine-related genes, including NR4A2 (NURR1), in mammalian cells, suggesting a potential method to control gene expression for research or future therapies.
- siRNAs successfully reduced NR4A2 and other dopamine-related genes
- The U6 promoter system delivered siRNAs effectively in cells
- Findings may support future gene therapy approaches
- Could help study loss-of-function effects in dopamine pathways
Nurr1-RXR heterodimers mediate RXR ligand-induced signaling in neuronal cells.
Wallen-Mackenzie A, Mata de Urquiza A, Petersson S, Rodriguez FJ, Friling S, Wagner J, Ordentlich P, Lengqvist J, Heyman RA, Arenas E, Perlmann T
RXR ligands activate Nurr1-RXR heterodimers in the developing brain, boosting survival of dopamine-producing and other neurons. This suggests a potential pathway for treating neurodegenerative diseases like Parkinson’s by targeting this receptor complex.
- RXR ligands are present in the embryonic brain
- They activate Nurr1-RXR pairs to protect neurons
- This mechanism supports dopamine neuron survival
- Targeting Nurr1-RXR may treat neurodegenerative diseases
p57(Kip2) cooperates with Nurr1 in developing dopamine cells.
Joseph B, Wallén-Mackenzie A, Benoit G, Murata T, Joodmardi E, Okret S, Perlmann T
p57Kip2 works with Nurr1 to help dopamine brain cells mature properly, independent of its role in stopping cell division. This interaction is essential for the development of midbrain dopamine neurons, which are affected in NR4A2-related syndrome.
- p57Kip2 helps dopamine neurons mature
- It works directly with Nurr1, not just by stopping cell division
- This process is critical for proper brain development
- Disruption may contribute to NR4A2-related neurological issues
Immunohistochemical analysis of protein expression after middle cerebral artery occlusion in mice.
Erdö F, Trapp T, Mies G, Hossmann KA
This study examined how brain injury from a stroke-like event affects protein levels and location in mice, finding that Nurr1, a protein linked to NR4A2, moved from the nucleus to the cytoplasm after injury. The results highlight complex changes in protein behavior that may influence brain damage and recovery, though the findings are in mice, not humans.
- Nurr1 moved from nucleus to cytoplasm after brain injury
- Many proteins changed in level or location after stroke-like injury
- Protein changes varied by brain region and were linked to cell death
- Findings may reveal new pathways in brain injury and repair
Organization and development of corticocortical associative neurons expressing the orphan nuclear receptor Nurr1.
Arimatsu Y, Ishida M, Kaneko T, Ichinose S, Omori A
Nurr1 is a key protein in neurons that connect different parts of the brain's outer layer, helping to form the circuits needed for thinking and behavior. These neurons are active early in development and are likely involved in building and maintaining proper brain wiring.
- Nurr1 marks neurons that link brain regions for higher thinking
- These neurons form early and stay active throughout life
- Nurr1 neurons are excitatory and help build brain circuits
- Nurr1 is found in layers involved in long-distance brain connections
- This suggests Nurr1 helps shape brain wiring critical for function
Molecular mechanisms underlying midbrain dopamine neuron development and function.
Smidt MP, Smits SM, Burbach JP
NR4A2 (NURR1) is a key transcription factor essential for the development and function of midbrain dopamine neurons, which are critical for movement and emotion. Disruptions in NR4A2 or related genes lead to impaired dopamine neuron formation and function, contributing to neurodevelopmental disorders.
- NR4A2 is vital for dopamine neuron development
- Loss of NR4A2 disrupts dopamine system function
- Gene dysfunction affects movement and emotion control
- The system has limited ability to compensate for gene defects
PIASgamma represses the transcriptional activation induced by the nuclear receptor Nurr1.
Galleguillos D, Vecchiola A, Fuentealba JA, Ojeda V, Alvarez K, Gómez A, Andrés ME
PIASgamma suppresses Nurr1's ability to activate genes important for dopamine neuron development, and this interaction occurs in brain cells where both proteins are present. The suppression does not depend on Nurr1 being modified by SUMO, suggesting a different mechanism for how PIASgamma controls Nurr1 activity.
- PIASgamma turns down Nurr1's gene-activating power
- This happens in brain cells that make dopamine neurons
- The effect works even without SUMO modification of Nurr1
- Mutations in Nurr1 affect its activity but not how PIASgamma represses it
- PIASgamma may naturally regulate Nurr1 in the brain
Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a.
Castelo-Branco G, Wagner J, Rodriguez FJ, Kele J, Sousa K, Rawal N, Pasolli HA, Fuchs E, Kitajewski J, Arenas E
Wnt proteins help control the growth and development of dopamine-producing brain cells, with Wnt-1 boosting precursor cell division and Wnt-5a promoting their maturation into functional dopamine neurons. These findings reveal distinct roles for different Wnt signals in building the brain's dopamine system.
- Wnt-1 increases division of dopamine precursor cells
- Wnt-5a helps precursors become mature dopamine neurons
- Wnt-3a boosts precursor growth but not neuron formation
- Blocking Wnt signals stops both proliferation and maturation
- Different Wnts have unique roles in dopamine neuron development
The transcription factor Nurr1 in human NT2 cells and hNT neurons.
Misiuta IE, Anderson L, McGrogan MP, Sanberg PR, Willing AE, Zigova T
Nurr1, a key protein for dopamine neuron development, is present in human NT2 cells and in neurons derived from them, suggesting these cells may help study or treat conditions involving dopamine neurons, including NR4A2-related syndromes.
- Nurr1 is expressed in both NT2 cells and their neuron-like derivatives
- Nurr1 appears early and stays present during neuron development
- Nurr1 co-exists with tyrosine hydroxylase, a marker of dopamine neurons
- These cells may model dopamine neuron development and function