The transcription factor Nurr1 is up-regulated in amyotrophic lateral sclerosis patients and SOD1-G93A mice

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both lower and upper motor neurons (MNs) in the central nervous system (CNS). ALS etiology is highly multifactorial and multifarious, and an effective treatment is still lacking. Neuroinflammation is a hallmark of ALS and could be targeted to develop new therapeutic approaches. Interestingly, the transcription factor Nurr1 has been demonstrated to play an important role in inflammatory process in several neurological disorders, such as Parkinson's disease (PD) and Multiple Sclerosis (MS). In the present paper, we demonstrated for the first time that Nurr1 expression levels were up-regulated in the peripheral blood of ALS patients. Moreover, we investigated Nurr1 function in the SOD1-G93A mouse model of ALS. Interestingly, Nurr1 was strongly upregulated in the spinal cord during the asymptomatic and early symptomatic phases of the disease, where it promoted the up-regulation of the BDNF mRNA and the repression of NF-kB pro-inflammatory targets, such as iNOS. Therefore, we hypothesize that Nurr1 is activated in an early phase of the disease as survival endogenous anti-inflammatory mechanism, although not sufficient to revert disease progression. Based on these observations, Nurr1 could represent a potential biomarker for ALS and a promising target for future therapies for ASL.

Activation of Nurr1 with Amodiaquine Protected Neuron and Alleviated Neuroinflammation after Subarachnoid Hemorrhage in Rats

“…Despite Nurr1 was mainly expressed on neurons, bodies of literature had recently reported the antineuroinflammatory effects of Nurr1 in various disease models [34,40,46]. Meanwhile, taken into account that neuroinflammation was an important pathophysiological process involved in the early brain injury of SAH so that we could not ignore this point.…”

“…A similar phenomenon was observed in the HT22 cells; moreover, the effect of AQ on the expression of nuclear Nurr1 was in a dose-dependent manner (Figure 6(c)). Numerous studies had reported that Nurr1 exerted an anti-inflammatory effect by regulating NF-κB in vitro and in vivo [38][39][40]. The stimulation of Nurr1 with AQ could decrease the expression of nuclear NF-κB in the rat models and HT22 cells (Figures 6(a) and 6(c)).…”

Analogs of the Dopamine Metabolite 5,6-Dihydroxyindole Bind Directly to and Activate the Nuclear Receptor Nurr1

“…The nuclear receptor Nurr1 (NR4A2) plays critical roles in both developing and adult midbrain dopaminergic neurons, controlling the transcription of genes required for the synthesis ( TH ) and vesicular packaging ( VMAT2 ) of dopamine, among other essential biological functions (e.g., management of oxidative stress, responsiveness to inflammatory signals). − Clinical and animal data indicate that disrupted Nurr1 function contributes to inducing the dysregulation of dopaminergic neurons observed in the early stages of Parkinson’s disease (PD), as well as other dopamine-related CNS disorders (e.g., ALS, MS). ,− Unraveling the complex biology of Nurr1 would be facilitated by bona fide Nurr1-targeting synthetic small molecules that can be used to directly modulate the receptor. Phenotypic assays have identified synthetic ligands that reportedly up-regulate transcription and protein levels of Nurr1 target genes, provide some degree of neuroprotection, and improve behavioral deficits in mouse models. − However, there is little evidence that these compounds directly activate endogenous Nurr1, with the exception of the antimalarial drug amodiaquine and related analogs. ,− …”

Genetic and Transcriptomic Biomarkers in Neurodegenerative Diseases: Current Situation and the Road Ahead

“…These include kinesins (e.g., KIF5C and KIFC3) and the dynactin subunit DCTN1 which are involved in axonal transport [ 107 , 108 , 109 ], neurotrophic factors (e.g., Trk-B, BDNF, PI3K, AKT, NFκB, GSK3β, and FASL) involved in cell proliferation and differentiation [ 110 ], apoptotic regulatory proteins CyFIP2 and RbBP9 [ 111 ], the vascular endothelial growth factor-A (VEGF-A) and chemokine ligand (CCL2) which are thought to play a role in neuroprotection [ 112 ], and the transcription factor Nurr1 which is involved in neuroinflammation [ 113 ]. However, most of these mRNAs are similarly dysregulated in other neurodegenerative diseases or have not been tested for ALS specificity, with exceptions for FasL mRNA, which showed a significant increase in the peripheral blood leukocytes (PBL) of ALS patients relative to PD, ataxia, and healthy controls [ 114 ], and Nurr1, which was downregulated in the peripheral blood of PD patients [ 114 ] and upregulated in ALS [ 113 ]. Further, VEGF-A and CCL2 mRNAs showed higher elevation in the PBL of Indian ALS patients with respiratory dysfunction and could therefore be disease progression biomarkers [ 112 ].…”