Treatment of Parkinson disease with C17.2 neural stem cells overexpressing NURR1 with a recombined republic-deficit adenovirus containing the NURR1 gene.
Mutations in Nurr1 are associated with Parkinson's disease (PD) and there is a correlation between Nurr1 and tyrosine hydroxylase (TH) expression in PD brain.
The observed reduction in PBL NURR1 gene expression indicates possible systemic involvement in PD, and the finding may help identify individuals with PD and other disorders associated with impaired central DAergic system.
These results indicate that Ser125 is critical for basal and ERK1/2-induced NURR1 activity and suggest a role for this and other NURR1 mutations in the regulation of dopamine synthesis and predisposition to Parkinson's disease.
Nurr1 was shown to be involved in the regulation of alpha-synuclein, as decreased expression of Nurr1, which has been found in Parkinson's disease patients with Nurr1 mutations, was shown to transcriptionally increase alpha-synuclein expression.
Nurr1 was shown to be involved in the regulation of alpha-synuclein, as decreased expression of Nurr1, which has been found in Parkinson's disease patients with Nurr1 mutations, was shown to transcriptionally increase alpha-synuclein expression.
These downregulated pathways contained genes known to be transactivated by NR4A2 and were not disrupted in idiopathic PD brain suggesting causality of the mutation.
Gene-based candidates for Parkinson's disease (PD) include the ubiquitin-proteosome system, scavengers of reactive oxygen species, brain-derived neurotrophic factor (BDNF), its receptor, TrkB, and downstream target early growth response 1, Nurr-1, and signaling through protein kinase C and RAS pathways.
Given the absence of a known lipophilic small molecule regulator and established transcriptional role in the formation of the definitive dopaminergic phenotype, Nurr1 represents an intriguing molecule to explore in the context of sporadic PD as a developmental disorder.
Our results provide useful information that the NURR1 and PITX3 gene expression is decreased in the PBL of Chinese patients with PD, indicating their possible systemic involvement in PD.
Given that Nurr1 plays an essential role in maintaining the normal function and survival of mDA neurons, our studies suggest that the α-syn-mediated suppression of Nurr1 protein expression may contribute to the preferential vulnerability of mDA neurons in the pathogenesis of PD.
The protective effect against dopamine-induced cell death was examined, and the subsequent effects on the levels of expression of Parkinson's disease-associated nurr1 and α-synuclein were evaluated in a dopamine-induced system.
The likely involvement of NURR1 in the development and progression of PD makes this protein a potentially interesting target for therapeutic intervention.
These data highlight the role of the Nurr1-Ret signaling pathway as a target of α-synuclein toxicity and suggest that retinoid X receptor ligands with appropriate pharmacological properties could have therapeutic potential in Parkinson's disease.
"Classic" models are based on neurotoxins that selectively target catecholaminergic neurons (such as 6-hydroxydopamine, 1-methyl-1,2,3,6-tetrahydropiridine, agricultural pesticides, etc.), while more recent models employ genetic manipulations that either introduce mutations similar to those find in familial cases of PD (α-synuclein, DJ-1, PINK1, Parkin, etc.) or selectively disrupt nigrostriatal neurons (MitoPark, Pitx3, Nurr1, etc.).
Interestingly, analyzing the regulatory network and mouse knockout expression data for NR4A2, a transcription factor previously associated with rare mutations in PD and here found as the most significantly under-expressed gene in PD among the jointly altered genes, suggests that aging-related NR4A2 expression changes may increase PD risk via downstream effects similar to disease-linked mutations and to expression changes in sporadic PD.
This review highlights the recent progress in preclinical studies of Nurr1-based therapies and discusses the outlook of this emerging therapy as a promising new generation of PD medication.
Nuclear receptor related 1 (NURR1) is an essential protein for maintenance of dopaminergic neurons in adult midbrain of which deficiency leads to Parkinson's disease.
Nurr1 is a member of the nuclear receptor 4 family of orphan nuclear receptors that is decreased in inflammatory responses and leads to neurons death in Parkinson's disease.
In conclusion, Nurr1 overexpression exerts neuroprotective and anti-inflammatory roles via down-regulating CCL2 in both in vivo and in vitro PD models, contributing to developing mechanism-based and neuroprotective strategies against PD.