Mechanisms of NURR1 Regulation: Consequences for Its Biological Activity and Involvement in Pathology

García-Yagüe, Ángel Juan; Cuadrado, Antonio

doi:10.3390/ijms241512280

Cited by 3 publications

(4 citation statements)

References 124 publications

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“…Recent studies support the role of NR4A2 in hippocampal synaptic plasticity and cognitive functions, although the underlying molecular mechanisms are still poorly understood (revised in [51,60]). Psychiatric, communicative, and cognitive problems may be related to the underlying dysfunction of dopaminergic pathways comprising the mesolimbic system, as these are involved in mood and attention regulation, working memory, and associative learning [60,62]. In addition, since primary language areas receive dopaminergic projections from subcortical regions [63], dysfunction of these pathways may influence the regulation of language processing.…”

Section: Discussionmentioning

confidence: 99%

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NR4A2 as a Novel Target Gene for Developmental and Epileptic Encephalopathy: A Systematic Review of Related Disorders and Therapeutic Strategies

Gabaldon-Albero,

Mayo,

Martinez

2024

IJMS

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The NR4A2 gene encodes an orphan transcription factor of the steroid–thyroid hormone–retinoid receptor superfamily. This review focuses on the clinical findings associated with the pathogenic variants so far reported, including three unreported cases. Also, its role in neurodegenerative diseases, such as Parkinson’s or Alzheimer’s disease, is examined, as well as a brief exploration on recent proposals to develop novel therapies for these neurological diseases based on small molecules that could modulate NR4A2 transcriptional activity. The main characteristic shared by all patients is mild to severe developmental delay/intellectual disability. Moderate to severe disorder of the expressive and receptive language is present in at least 42%, while neuro-psychiatric issues were reported in 53% of patients. Movement disorders, including dystonia, chorea or ataxia, are described in 37% patients, although probably underestimated because of its frequent onset in late adolescence–young adulthood. Finally, epilepsy was surprisingly present in 42% of patients, being drug-resistant in three of them. The age at onset varied widely, from five months to twenty-six years, as did the classification of epilepsy, which ranged from focal epilepsy to infantile spasms or Lennox–Gastaut syndrome. Accordingly, we propose that NR4A2 should be considered as a first-tier target gene for the genetic diagnosis of developmental and epileptic encephalopathy.

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Section: Discussionmentioning

confidence: 99%

“…Other alternative approaches have been proposed to regulate the activity of NR4A2, including post-translational modifications, among which phosphorylation by kinases or SUMOylation are the best characterized (reviewed in [60]).…”

Section: Treatmentsmentioning

confidence: 99%

NR4A2 as a Novel Target Gene for Developmental and Epileptic Encephalopathy: A Systematic Review of Related Disorders and Therapeutic Strategies

Gabaldon-Albero,

Mayo,

Martinez

2024

IJMS

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“…The demise of these neurons occurs as a result of various factors such as oxidative stress, problems with mitochondria, and external toxins (1–4). [ 1 2 3 4 ]…”

Section: Introductionmentioning

confidence: 99%

Simultaneous treatment with cells and rosemary extract ameliorates 6-OHDA-induced toxicity in the hippocampus of mice

Kousha,

Vaezi,

Kashani

et al. 2024

Journal of Advanced Pharmaceutical Technology &Amp; Research

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In this study, we delved into the hippocampal region to understand the effects of adipose stem cells (ADSCs) and rosemary extract (RE). Our main objective was to explore how these substances influence spatial memory, neurotrophins, and changes in antioxidant enzymes. Moreover, we meticulously investigated the impact of dopamine deficiency, a notable characteristic linked with Parkinson’s disease (PD), on memory impairment. This study comprised five groups of Wistar rats – all male, all selected randomly. We labeled two of these gatherings “lesion” (L) and “sham” (SH). Each got injections in the bilateral form with 6 μg – one group getting saline, while another got 6-OHDA. From couple weeks before the neurotoxin injection to 8 weeks later on, our lesion cohort was treated with rosemary at a dosage rate of 50 mg/kg body weight – let’s call it RE for simplicity sake. Moreover, there is also this other lot, designated as cell-transplanted lesion group or catchy exercise (CE) as we prefer to interpret them; they had cell transplants conducted exactly 7 days after receiving their respective injections. Bringing up the rear, we got a group treated with both cell transplant and rosemary (CE+R). We performed spatial memory tests at 4 weeks, then again at 8. At the end of eighth week, the brains were extracted for q-PCR, enzymatic and immunohistochemical studies. Turning our gaze toward a comparison between the CE+R and CE groups versus the L group, we spot an intriguing drop in escape latency time. There is also more time spent in quadrants. Digging deeper into this matter, the CE+R bunch unveiled a clear surge when it comes to the expression of four genes, namely NGF, BDNF, NT3, and NT4! This was notable especially while comparing with both R and even other fellows from its very own broader group – CE. In a bit complex bit related to enzyme activity now, there is some good news as well for those in favor of potent antioxidants such as GPx or SOD. CE + R group, showed a significant increase of GPX and SOD enzymes, compared to the SH and L groups, and a significant decrease of MDA activity as compared to other treated groups. A significant decrease of escape latency and increase of time in quadrant were observed in the CE+R and CE groups compared to L group. What’s more, the levels of MDA in the CE+R group plummeted significantly when set up against the SH group. Wrapping things up, a definite downscale was observed in the density of GFAP-positive cells throughout different regions located within the hippocampus; this decline presented itself not solely in treatment groups but gripped onto those falling under SH as well, especially when compared to its comrade – the L group. Using ADSCs and taking RE orally have shown promising results in improving memory issues linked with PD.

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“…Disruptions in circadian rhythms have been linked to various neurodevelopmental disorders such as hyperactivity, anxiety, attention-deficit/hyperactivity disorder (ADHD), and autism (Ashton & Jagannath, 2020;Coogan et al, 2019;Martinez-Cayuelas et al, 2023), all of which are associated with altered dopamine (DA) neurotransmission. The transcription factor Nurr1 (NR4A2/nuclear receptor related-1) plays a critical role in the development and preservation of DAergic phenotype (García-Yagüe & Cuadrado, 2023). Interestingly, the function of Nurr1 is subjected to regulation by circadian clock proteins.…”

Section: Introductionmentioning

confidence: 99%

Impact of food additives on neurodevelopmental processes in zebrafish (Danio rerio): Exploring circadian clock genes and dopamine system

Christy,

Vignesh,

Nellore

et al. 2024

Developmental Neurobiology

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Assessing the impact of food additives on neurodevelopmental processes extends beyond traditional acute toxicity evaluations to address subtler, long‐term effects. This study investigates the impact of common food additives (tartrazine, sunset yellow, sodium benzoate, and aspartame) on neurodevelopment in zebrafish embryos, observed from 18 hours postfertilization (hpf) to 91 days postfertilization (dpf). Results show reduced 96 hpf locomotor activity after aspartame exposure, with elevated additives correlating with decreased heart rates and induced neurodegenerative phenotypes, including bent tails and abnormal pigmentation. Although locomotor activity decreases at 7 days postexposure, a gradual recovery is observed. Transcriptome analysis indicates alterations in clock genes (Cry2 and Per2) and dopamine‐related genes (NURR1 and tyrosine hydroxylase) in zebrafish larvae. Dietary additive exposure during embryonic development impacts clock genes, influencing dopamine activity and resulting in neurobehavioral changes. This study underscores potential risks associated with dietary additive exposure during critical developmental stages, warranting reconsideration of consumption guidelines, especially for expectant mothers. Observed neurodevelopmental toxicity, even below recommended levels, emphasizes the importance of safeguarding neurodevelopmental health in early life. Our findings contribute to understanding the neurotoxic effects of dietary additives, emphasizing the necessity of protecting neurodevelopment during vulnerable periods. This study is the first to demonstrate a direct correlation between food additives and the dysregulation of key circadian rhythm and dopaminergic genes in zebrafish, providing new insights into the neurodevelopmental impacts of dietary additives. These findings pave the way for further research into the molecular mechanisms and potential implications for human health.

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Mechanisms of NURR1 Regulation: Consequences for Its Biological Activity and Involvement in Pathology

Cited by 3 publications

References 124 publications

NR4A2 as a Novel Target Gene for Developmental and Epileptic Encephalopathy: A Systematic Review of Related Disorders and Therapeutic Strategies

NR4A2 as a Novel Target Gene for Developmental and Epileptic Encephalopathy: A Systematic Review of Related Disorders and Therapeutic Strategies

Simultaneous treatment with cells and rosemary extract ameliorates 6-OHDA-induced toxicity in the hippocampus of mice

Impact of food additives on neurodevelopmental processes in zebrafish (Danio rerio): Exploring circadian clock genes and dopamine system

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