NURR1 Deficiency Is Associated to Altered Microglial Phenotype in Male Mice

Montarolo, F et al (2025) in Molecular Neurobiology, 8 March 2025.

This study investigates the role of NURR1 in microglial function within the central nervous system (CNS). Microglia are the resident immune cells of the CNS and their activation and phenotype can significantly impact on neuroinflammatory processes and neurodegenerative diseases.

Advances in NURR1-Regulated Neuroinflammation Associated with Parkinson’s Disease

Al-Nusaif, M. et al (2022) in International Journal of Molecular Sciences, vol.23, no.24, p.16184.

This review discusses how NURR1 modulates neuroinflammation in PD, highlighting its role in suppressing inflammatory gene expression in microglia and astrocytes, and its potential as a therapeutic target.

The Role of NURR1 in Metabolic Abnormalities of Parkinson’s Disease

Al-Nusaif, M. et al (2022) in Molecular Neurodegeneration, Vol. 17, No. 46.

This study explores how Nurr1 influences metabolic processes in dopaminergic neurons, particularly in the context of Parkinson’s Disease, and its potential as a therapeutic target.

Medicinal Chemistry and Chemical Biology of Nurr1 Modulators: An Emerging Strategy of Neurodegeneration

Willems, S. et al (2022) in J Med Chem, Vol. 65, No.14, p9548-9563.

This review discusses the structural and functional characteristics of Nurr1, highlighting its neuroprotective and anti-inflammatory properties. It also summarises known small molecule Nurr1 ligands and their therapeutic potential in neurodegeneration.

Nurr1 (NR4A2) regulates Alzheimer’s disease-related pathogenesis and cognitive function in the 5XFAD mouse model

Moon, M. et al (2019) in Aging Cell, Vol. 18, No.1.

This study demonstrates that NURR1 is predominantly expressed in neurons rather than glial cells in the 5XFAD mouse model of Alzheimer’s disease. Their findings suggest that NURR1 plays a significant role in regulating Alzheimer’s disease-related pathogenesis and cognitive function.

Altered NR4A Subfamily Gene Expression Level in Peripheral Blood of Parkinson’s and Alzheimer’s Disease Patients

Montarolo, F. et al (2016) in Neurotox Res, Vol.30, No. 3, p.338-44.

All three NR4A genes exhibited significantly reduced expression levels in PD patients, which suggests that the whole NR4A subfamily may play a role in the pathogenesis of PD and could serve as potential biomarkers for disease diagnosis or progression. In Alzheimers, only NR4A1 levels were notably decreased.

Nurr1 reduction influences the onset of chronic EAE in mice

Montarolo, F. et al (2015) in Inflamm Res, Vol. 64, no. 11, p 841-4.

This study investigates the role of Nurr1 in the onset and progression of experimental autoimmune encephalomyelitis (EAE) using a mouse model, and found that reducing the expression of NURR1 leads top earlier onset. In these mice, the immune response against myelin, a hallmark of MS, becomes more pronounced, which accelerates the disease progression.

a-Synuclein-Induced Down-Regulation of Nurr1 Disrupts GDNF Signaling in Nigral Dopamine Neurons

Decressac, M. et al (2012) in Sci Transl Med, Vo.4, No.163.

This article explores how alpha-synuclein accumulation leads to decreased NURR1 expression, impairing GDNF signalling and contributing to dopaminergic neuron degeneration.

Nurr1 Transcriptionally Regulates the Expression of Alpha-Synuclein

Yang, Y.X. et al (2008) in Neuroreport, Vol. 19, No.8. p867-71.

This research identifies that reduced NURR1 expression leads to increased alpha-synuclein levels, suggesting a link between NURR1 dysfunction and PD pathogenesis.

A Nurr1 Agonist Causes Neuroprotection in a Parkinson’s Disease Lesion Model Primed with a Toll-Like Receptor 3 dsRNA Inflammatory Stimulant Poly (l:C)

Smith, G.A. et al (2015) in PLOS ONE, vol.10, no.3, e0121072.

This study evaluates the effects of a NURR1 agonist, SA00025, demonstrating its ability to induce dopaminergic gene expression and provide neuroprotection in an inflammation-exacerbated PD model.

Decreased NURR1 gene expression in patients with Parkinson’s Disease

Le, W. et al (2008) in J Neurol Sci, Vol. 273, No. 1-2, p29-33.

NURR1 gene expression was significantly decreased in patients with PD. There was no significant difference in NURR1 gene expression among PD patients with or without anti-PD medication.

Nurr1 in Parkinson’s Disease and related disorders

Chu, Y. et al (2006) in J Comp Neurol, Vol. 494, No.3, p495-514.

These data demonstrate that Nurr1 deficiency in dopaminergic neurons is associated with the intracellular pathology in both synucleinopathies and tauopathies.

Age-related decreases in Nurr1 immunoreactivity in the human substantia nigra

Chu, Y. et al (2002)

Stereologic counts revealed a significant reduction in the number of Nurr1-ir nigral neurons in middle aged (23.13%) and aged (46.33%) relative to young subjects.

Expanding the clinical spectrum of NR4A2-related disorder

Borden, C. et al (2025), in Genetics in Medicine Open, Vol. 3, p103286.

This study presents two patients with NR4A2-related disorders, expanding the clinical spectrum to include reactive hypoglycaemia, cystic kidney disease and joint hyper mobility.

NURR1-deficient mice have age - and sex- specific behavioural phenotypes

Montarolo, F. et al (2022), in J Neurosci Res, Vol. 100, no.9, p1747-1754.

The study concludes that NURR1 plays a critical role in modulating behaviour, and deficiency leads to phenotypes that differ depending on both sex and age and suggests potential implications for understanding dopaminergic dsyfunction in neurodegenerative diseases like Parkinson’s.

Working memory deficits in schizophrenia are associated with the rs34884856 variant and expression levels of NR4A2 gene in a sample Mexican population: a case control study

Ruiz-Sanchez, E. et al (2021) in BMC Psychiatry, Vol. 21, No. 86.

Case Study: Findings suggest that changes in expression levels of the NR4A2 gene could be associated with working memory in schizophrenia depending on the patient’s genotype in a sample from a Mexican population.

Loss-of-Function Mutations in NR4A2 Cause Dopa-Responsive Dystonia Parkinsonism

Wirth, T. et al (2020), in Mov Disord., Vol. 35, No.5, p. 880-885.

Case Study: The two patients reported here both had a history of mild intellectual disability in childhood and subsequently developed dystonia Parkinsonism in early adulthood. Brain magnetic resonance imaging was normal, and DATscan suggested bilateral dopaminergic denervation. Two frameshift mutations (insertions) were identified.

De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy

Singh, S. et al (2020) in Genet Med, Vol. 22, No. 8, p1413-1417.

This research considers nine unrelated patients, showing that mutations in NR4A2 were associated with developmental delay, hypotonia and epilepsy in six cases. The findings suggest the role of NR4A2 as a critical gene in neurodevelopment and seizure regulation.

NURR1 deficiency is associated to ADHD-like phenotypes in mice

Montarolo, F. et al (2019), in Transl Psychiatry, Vol 9, No. 1.

NURR1 is involved in regulating dopamine production, which is a key neurotransmitter implicated in ADHD. The study concludes that NURR1 deficiency plays a significant role in the etiology of ADHD and suggests that understanding NURR1’s role could open up new avenues for personalised treatments.

Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes

Guo, H et al. (2019) in Genetics in Medicine, Vol. 21, p1611-1620.

This study included one patient with a de novo frameshift variant in NR4A2 resulting in autism symptoms, whilst the study concluded that patients with more than one risk variant were more severely affected compared with patients with a single or no-risk variant.

Heterozygous loss of function of NR4A2 is associated with intellectual deficiency, Rolandic epilepsy and language impairment

Ramos, L.L.P et al (2019) in Clin Case Rep, Vol. 7, No.8, p1582-1584.

This case study highlights a patient with a de novo loss-of-function NR4A2 variation and reinforces the role of NR4A2 in neurodevelopmental phenotypes.

NR4A2 haploinsufficiency is associated with intellectual disability and autism spectrum disorder

Levy, J. et al (2018) in Clin Genet, Vol. 94. No.2

This report describes three additional patients with de novo deletions including NR4A2, presenting with language impairment, developmental delay, intellectual disability and / or autism spectrum disorder.

Haploinsufficiency of NR4A2 is associated with neurodevelopment phenotype with prominent language impairment

Reuter, M.S. et al (2017), in Am J Med Genet A, Vol. 173, No.8.

This study reports a female patient with a deletion of NR4A2, leading to mild intellectual disability and significant speech and language impairment. The findings support NR4A2 haploinsuffiency as a cause for neurodevelopmental disorders, particularly affecting language development.

Nurr1 modulators - a patent review (2019-present)

Edgner, M. et al (2025) in Expert Opinion Ther Pat, published online on 7 June 2025.

This paper discusses NURR1 modulation as an emerging new therapeutic concept and considers several promising compounds covered by patent applications.

Adeno-associated virus (AAV) 9-mediated gene delivery of Nurr1 and Foxa2 ameliorates symptoms and pathologies of Alzheimer disease model mice by suppressing euro-inflammation and glial pathology

Yang, Y. et al (2023) in Mol Psychiatry, Vol.28, No. 12, p5359-5374.

A series of functional, histologic and transcriptome analyses revealed that the combined expression of Nurr1 and Foxa2 substantially ameliorated AD-associated amyloid and Tau proteinopathy, cell senescence, synaptic loss and neuro-inflammation.

An optimized Nurr1 agonist provides disease-modifying effects in Parkinson’s disease

Kim, W. et al (2023), in Nat Commun, Vol. 14, No. 1, p4283.

An optimised agonist of Nurr1, 4A7C-301, protects dopamine neurons against environmental and genetic risk factors of Parkinson’s Disease (PD) in vitro, and improves both motor and non-motor deficits in male rodent models of PD.

Development of a Potent Nurr1 Agonist Tool for In Vivo Applications

Vietor, J. et al (2023) in J Med Chem, Vol 66, No. 9, p6391-6402.

The optimized compound induced Nurr1-regulated gene expression in astrocytes and exhibited favourable pharmokinetics in rats, thus emerging as a superior chemical tool to study Nurr1 activation in vitro and in vivo.

Assessment of NR4A Ligands That Directly Bind and Modulate the Orphan Nuclear Reception Nurr1

Aldhafiri, S. et al (2023) in Journal of Medicinal Chemistry, Vol. 66, no.9, p 5312-5329.

This article provides an in-depth analysis of NR4A ligands, including C-DIM12, and their interactions with Nurr1, highlighting their potential in treating neurodegenerative diseases.

The NR4A Orphan Receptor Modulator C-DIM12 Selectively Alters Inflammatory Mediators in Myeloid Cells

Aldhafiri, S. et al (2023) in Receptors, 2023, Vol.2, p264-283.

This article discusses the effects of C-DIM12, a compound that activates NR4 receptors, on inflammatory mediators in myeloid cells. It suggests that C-DIM12 could be a potential therapeutic agent for modulating immune responses via NR4A2.

Lithium’s effects on therapeutic targets and MRI biomarkers in Parkinson’s disease: A pilot clinical trial

Guttuso, T. et al (2023) in IBRO Neuroscience Rep, Vol. 14, p429-434.

The trial provides preliminary evidence supporting lithium’s potential effects, which aligns with previous research suggesting that lithium may influence neuroprotective pathways and disease progression in neurodegenerative conditions.

Activity-Dependent Nr4a2 Induction Modulates Synaptic Expression of AMPA Receptors and Plasticity via a Ca2+/CRTC1/CREB Pathway

Catala-Solsona, J. et at (2023) in J Neurosci, Vol. 43, No. 17, p. 3028-3041.

This study not only provides mechanistic insights into the molecular pathways related to hippocampus synaptic plasticity and learning, but also identifies Nr4a2 as a potential therapeutic target for pathologic conditions associated with dysregulation of glutamtergic synaptic function.

PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function

Rajan, S. et al (2020) in Nat Chem Biol, Vol. 16, No. 8, p876-886.

The paper demonstrates that both PGE1 and PGA1 can bind to Nurr1, using techniques like binding assays and structural analysis. The study opens up possibilities for targeting prostaglandin receptors or manipulating the prostaglandin-Nurr1 interaction to restore or protect dopaminergic neurons.

Pharmacological activation of Nr4a rescues age-associated memory decline

Chatterjee, S. et al (2019), Neurobiology of Aging, Vol. 85, p 140-1444

This study investigates the role of Nr4a2 in memory formation and its potential as a therapeutic target for age-related cognitive decline.

Study of the NR4A family gene expression in patients with multiple sclerosis treated with Fingolimod

Montarolo, F. et al (2019) in Europe J Neurol, Vol. 26, No.4, p667-672.

Patients treated with Fingolimod for >2 years in this preclinical study were characterised by higher levels of NR4A2 compared with the T0 group, approaching those of healthy controls.

Selective brain penetrable Nurr1 transactivator for treating Parkinson’s Disease

Wang, J. et al (2016) in Oncotarget, Vol. 7. no. 7, p7469-7479.

This study suggests that IRX4204 represents a novel, potent and selective pharmacological means to activate cellular RXR-Nurr1 signalling and promote dopaminergic neuron survival in PD prevention and / or treatment.

Nurr1-Based Therapies for Parkinson’s Disease

Dong, J. et al (2016) in CNS Neuroscience Ther, Vol. 22, No. 5, p351-9.

This review highlights the progress in preclinical studies of Nurr1-based therapies and discusses the outlook of this emerging therapy as a promising new generation of PD medication.

Current Pharmaceutical Treatments and Alternative Therapies of Parkinson’s Disease

Dong, J. et al (2016) in Curr Neuropharmacol, Vol. 14, No.4, p339-55.

This review article provides a comprehensive review of established and emerging therapies for PD.

Adenosine Modulates NR4A Orphan Nuclear Receptors to Attenuate Hyperinflammatory Responses in Monocytic Cells

Crean, D. et al (2015) in The Journal of Immunology.

This study explores how adenosine and its receptor agonists can modulate NR4A receptors, including NR4A2, to reduce hyper inflammatory responses in monocytic cells. It suggests that targeting NR4A2 may be beneficial in conditions characterised by excessive inflammation.