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NURR1 (Nuclear receptor-related 1 protein or NR4A2) is a nuclear protein receptor transcription factor with an essential role in the development, regulation, and maintenance of dopaminergic neurons and mediates the response to stressful stimuli during the perinatal period in mammalian brain development. The dysregulation of NURR1 activity may play a role in various diseases, including the onset and progression of neurodegenerative diseases, and several other pathologies. NURR1 is regulated by multiple mechanisms, among which phosphorylation by kinases or SUMOylation are the best characterized. Both post-translational modifications can regulate the activity of NURR1, affecting its stability and transcriptional activity. Other non-post-translational regulatory mechanisms include changes in its subcellular distribution or interaction with other protein partners by heterodimerization, also affecting its transcription activity. Here, we summarize the currently known regulatory mechanisms of NURR1 and provide a brief overview of its participation in pathological alterations.

New multi-target indole and naphthalene derivatives containing the oxadiazolone scaffold as a bioisostere of the melatonin acetamido group have been developed. The novel compounds were characterized at melatonin receptors MTR and MTR, quinone reductase 2 (QR2), lipoxygenase-5 (LOX-5), and monoamine oxidases (MAO-A and MAO-B), and also as radical scavengers. We found that selectivity within the oxadiazolone series can be modulated by modifying the side chain functionality and co-planarity with the indole or naphthalene ring. In phenotypic assays, several oxadiazolone-based derivatives induced signalling mediated by the transcription factor NRF2 and promoted the maturation of neural stem-cells into a neuronal phenotype. Activation of NRF2 could be due to the binding of indole derivatives to KEAP1, as deduced from surface plasmon resonance (SPR) experiments. Molecular modelling studies using the crystal structures of QR2 and the KEAP1 Kelch-domain, as well as the recently described X-ray free-electron laser (XFEL) structures of chimeric MTR and MTR, provided a rationale for the experimental data and afforded valuable insights for future drug design endeavours.

Acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2 is largely the result of a dysregulated host response, followed by damage to alveolar cells and lung fibrosis. Exacerbated pro-inflammatory cytokines release (cytokine storm) and loss of T-lymphocytes (leucopenia) characterize the most aggressive presentation. Here we propose that a multi-faceted anti-inflammatory strategy based on pharmacological activation of nuclear factor erythroid 2 p45-related factor 2 (NRF2), can be deployed against the virus. The strategy provides robust cytoprotection by restoring the redox and protein homeostasis, promoting resolution of inflammation, and facilitating repair. NRF2 activators such as sulforaphane and bardoxolone methyl are already in clinical trials. The safety and efficacy information of these modulators in humans, together with their well-documented cytoprotective and anti-inflammatory effects in preclinical models, highlight the potential of this armamentarium for deployment to the battlefield against COVID-19.

In recent years the nuclear transcription factor (erythroid-derived 2)¿like 2 (Nrf2) has been identified as the key factor in the cell auto-protection mechanisms. Under no pathological conditions, Nrf2 is mainly located in the cytosol, bound to the Kelch like ECH associated protein 1 (Keap1). In contrast, under oxidative conditions, Keap1 changes its conformation and breaks the binding with Nrf2 allowing its accumulation and translocation to the nucleus where it induces the transcription of key antioxidant enzymes. Nrf2 dysregulation is involved in different pathologies such as cancer, cardiovascular diseases or neurodegenerative diseases, among others [1]. In recent years, a great amount of new molecules able to disrupt the interaction between Nrf2 and Keap1, have been studied, however most of them are electrophilic molecules and are prone to interact with several non-desired targets. In our group we are applying the surface plasmon resonance (SPR) technique for the identification of new non-electrophilic inhibitors of the Nrf2 - Keap1 protein-protein interaction (PPI). This kind of molecules could exhibit a more specific mechanism for the induction of Nrf2 activity. Thus, the ability of several molecules from our library to interact with the purified Kelch domain of Keap1 attached to a CM5 sensor chip has been evaluated in a SPR assay [2]. With this technique, a new hit with affinity for Keap1 was identified. The affinity value was comparable to that of the positive control ML-334, a well-known inhibitor of the Nrf2 - Keap1 PPI. Starting from this new hit, a larger family with improved potency have been obtained [3]. This new family of bis-heterocyclic compounds do not present any electrophilic character, are able to reach the central nervous system and exhibit other complementary activities such as radical scavenging and neurogenic properties, which make them potential candidates for the treatment of neurodegenerative diseases such as Alzheimer¿s disease.

TAU protein aggregation is the main characteristic of neurodegenerative diseases known as tauopathies. Low-grade chronic inflammation is also another hallmark that indicates crosstalk between damaged neurons and glial cells. Previously, we have demonstrated that neurons overexpressing TAUP301L release CX3CL1, which activates the transcription factor NRF2 signalling to limit over-activation in microglial cells in vitro and in vivo. However, the connection between CX3CL1/CX3CR1 and NRF2 system and its functional implications in microglia are poorly described. We evaluated CX3CR1/NRF2 axis in the context of tauopathies and its implication in neuroinflammation. Regarding the molecular mechanisms that connect CX3CL1/CX3CR1 and NRF2 systems, we observed that in primary microglia from Cx3cr1-/- mice the mRNA levels of Nrf2 and its related genes were significantly decreased, establishing a direct linking between both systems. To determine functional relevance of CX3CR1, migration and phagocytosis assays were evaluated. CX3CR1-deficient microglia showed impaired cell migration and deficiency of phagocytosis, as previously described for NRF2-deficient microglia, reinforcing the idea of the relevance of the CX3CL1/CX3CR1 axis in these events. The importance of these findings was evident in a tauopathy mouse model where the effects of sulforaphane (SFN), an NRF2 inducer, were examined on neuroinflammation in Cx3cr1+/+ and Cx3cr1-/- mice. Interestingly, the treatment with SFN was able to modulate astrogliosis but failed to reduce microgliosis in Cx3cr1-/- mice. These findings suggest an essential role of the CX3CR1/NRF2 axis in microglial function and in tauopathies. Therefore, polymorphisms with loss of function in CX3CR1 or NRF2 have to be taken into account for the development of therapeutic strategies.

Chronic neuroinflammation is a hallmark of the onset and progression of brain proteinopathies such as Alzheimer disease (AD) and it is suspected to participate in the neurodegenerative process. Transcription factor NRF2, a master regulator of redox homeostasis, controls acute inflammation but its relevance in low-grade chronic inflammation of AD is inconclusive due to lack of good mouse models. We have addressed this question in a transgenic mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-WT mice died prematurely, at around 14 months of age, due to motor deficits and a terminal spinal deformity but AT-NRF2-KO mice died roughly 2 months earlier. NRF2-deficiency correlated with exacerbated astrogliosis and microgliosis, as determined by an increase in GFAP, IBA1 and CD11b levels. The immunomodulatory molecule dimethyl fumarate (DMF), a drug already used for the treatment of multiple sclerosis whose main target is accepted to be NRF2, was tested in this preclinical model. Daily oral gavage of DMF during six weeks reduced glial and inflammatory markers and improved cognition and motor complications in the AT-NRF2-WT mice compared with the vehicle-treated animals. This study demonstrates the relevance of the inflammatory response in experimental AD, tightly regulated by NRF2 activity, and provides a new strategy to fight AD.

[Introduction]: TAU protein aggregation is the main characteristic of a group of age-related neurodegenerative diseases called tauopathies. One of the key hallmarks associated with neurodegeneration is the presence of low-grade chronic inflammation, indicating a crosstalk between damaged neuron and glial cells. Previously we have shown that TAUP301L overexpressing neurons released CX3CL1 that activates anti-inflammatory NRF2 signalling in microglial cells in vitro and in vivo. However, the potential role of CX3CR1 in the context of TAU pathology and its implication neuroinflammation are poorly described., [Material and Methods]: Pro-inflammatory markers in immortalized microglia cells (IMG) treated with CX3CL1 were analysed. We also studied mRNA expression levels of NF-ƘB, anti-inflammatory Nrf2 signalling and TAM receptors (TYRO3, AXL and MER) in CX3CR1-deficient primary microglia cells. Finally, the effect of sulforaphane (SFN), a NRF2 inducer, was examined on neuroinflammation in Cx3cr1+/+ and Cx3cr1-/- mice stereotaxically injected in the right hippocampus with an adeno-associated vector expressing human TAUP301L and treated daily with SFN (50mg/kg, i.p) during three weeks., [Results]: In this study we show that CX3CL1 treatment induced NF-ƘB-p65 and pro-inflammatory cytokines expression. On the other hand, CX3CR1-deficient primary microglia cells present impaired NF-ƘB mRNA expression levels and decreased anti-inflammatory NRF2 signalling, suggesting a dual role of CX3CL1/CX3CR1 axis in neuroinflammation. Lack of CX3CR1 microglia exhibit decreased mRNA expression levels of TAM receptors (TYRO3, AXL and MER) that functionally results in a deficiency in phagocytosis. SFN treatment reverses astrogliosis in Cx3cr1+/+ and Cx3cr1-/-, whereas at microglial level we did not see any improvement in the Cx3cr1-/- mice., [Conclusions]: These findings suggest that CX3CR1-NRF2 axis activation is essential in the modulation of microglial activation associated with tauopathy, and that the associated polymorphisms of CX3CR1 must be taken into account in the design of pharmacological strategies for the treatment of taupathies.

Chronic neuroinflammation is a hallmark of the onset and progression of brain proteinopathies such as Alzheimer disease (AD) and it is suspected to participate in the neurodegenerative process. Transcription factor NRF2, a master regulator of redox homeostasis, controls acute inflammation but its relevance in low-grade chronic inflammation of AD is inconclusive due to lack of good mouse models. We have addressed this question in a transgenic mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-WT mice died prematurely, at around 14 months of age, due to motor deficits and a terminal spinal deformity but AT-NRF2-KO mice died roughly 2 months earlier. NRF2-deficiency correlated with exacerbated astrogliosis and microgliosis, as determined by an increase in GFAP, IBA1 and CD11b levels. The immunomodulatory molecule dimethyl fumarate (DMF), a drug already used for the treatment of multiple sclerosis whose main target is accepted to be NRF2, was tested in this preclinical model. Daily oral gavage of DMF during six weeks reduced glial and inflammatory markers and improved cognition and motor complications in the AT-NRF2-WT mice compared with the vehicle-treated animals. This study demonstrates the relevance of the inflammatory response in experimental AD, tightly regulated by NRF2 activity, and provides a new strategy to fight AD.

[Background]: Little is known about the regulation of transcription factor Nurr1. [Results]: We identified a bipartite NLS and two NES signals implicated in its subcellular trafficking, and we report that oxidative stress induces nuclear export of Nurr1. [Conclusion]: Nurr1 shuttles between the cytoplasm and nucleus, and its subcellular localization is modified by stress. [Significance]: Nurr1 subcellular localization will help understand its function under physiopathological conditions. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.