Normal and Pathological NRF2 Signalling in the Central Nervous System

The nuclear factor erythroid 2-related factor 2 (NRF2) was originally described as a master regulator of antioxidant cellular response, but in the time since, numerous important biological functions linked to cell survival, cellular detoxification, metabolism, autophagy, proteostasis, inflammation, immunity, and differentiation have been attributed to this pleiotropic transcription factor that regulates hundreds of genes. After 40 years of in-depth research and key discoveries, NRF2 is now at the center of a vast regulatory network, revealing NRF2 signalling as increasingly complex. It is widely recognized that reactive oxygen species (ROS) play a key role in human physiological and pathological processes such as ageing, obesity, diabetes, cancer, and neurodegenerative diseases. The high oxygen consumption associated with high levels of free iron and oxidizable unsaturated lipids make the brain particularly vulnerable to oxidative stress. A good stability of NRF2 activity is thus crucial to maintain the redox balance and therefore brain homeostasis. In this review, we have gathered recent data about the contribution of the NRF2 pathway in the healthy brain as well as during metabolic diseases, cancer, ageing, and ageing-related neurodegenerative diseases. We also discuss promising therapeutic strategies and the need for better understanding of cell-type-specific functions of NRF2 in these different fields

AGE- AND SEX-SPECIFIC TRANSCRIPTOME CHANGES IN THE MIDBRAIN OF PARK7-DEPLETED MICE

To date, various functions have been reported for DJ-1 protein, encoded by PARK7 gene, mostly associated to maintenance of a balance between the reactive oxygen species (ROS) production and the antioxidant response. Indeed, DJ-1 has been related with several oxidative-stress associated diseases, either by its overexpression or by its absence. Loss-of-function mutations in PARK7 can lead to an early onset PD. PD is the second most common neurodegenerative disease that usually affects the population above the age of 65. PD is characterized by its motor symptoms, although prodromal non-motor symptoms can appear up to 20 years earlier and can have a major impact on quality of life for the patients. One of the most characteristic neuropathological hallmarks of PD is the progressive dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc) of the midbrain, leading to striatal dopamine deficiency. One of the main drivers of the disease is oxidative stress caused by mitochondrial dysfunction. Sex-differences in the incidence, prevalence and severity of the disease are observed in PD, with males affected more than females. In mice, Park7 deletion leads to dopaminergic deficits during aging, and increased sensitivity to oxidative stress. However, the severity of the reported phenotypes varies, and the findings are often not separated by sex. In the present study, gene expression signatures of in vivo midbrain sections from male and female Park7 knock-out mice were investigated at different ages to understand the early, prodromal molecular changes upon loss of DJ-1. Interestingly, while at 3 months the transcriptomes of both male and female mice were unchanged compared to their wild type littermates, an extensive deregulation was observed specifically in 8-month-old males. The affected genes were enriched for processes such as focal adhesion, extracellular matrix (ECM) interaction, and epithelial-to-mesenchymal transition (EMT), while the most enriched transcription factor at the deregulated genes was nuclear factor erythroid 2-related factor 2 (NRF2). Among others, the EMT marker gene Cdh1 as well as antioxidant response genes were altered specifically in the midbrain, but not in the cortex, of male DJ-1 deficient mice. Moreover, many of the misregulated genes are known target genes of estradiol (E2) and all-trans-retinoic acid (ATRA) signaling and show sex-specific expression in wild type mice. In line with this, downregulation of the expression of Cyp1b1, encoding an enzyme involved in the metabolism of both E2 and ATRA was also observed only in the midbrain of male DJ-1 deficient mice. Depletion of DJ-1 or NRF2 in primary male astrocytes recapitulated many of the in vivo changes, including downregulation of Cyp1b1. Interestingly, knock-down of Cyp1b1 led to gene expression changes in focal adhesion and EMT in cultured male astrocytes. Moreover, iPSC-derived astrocytes from PD patient with loss-of-function PARK7 mutation showed changes in genes associated with EMT pathway and NRF2 signaling. Taken together, our data indicate that loss of Park7 leads to sex-specific gene expression changes specifically in males through astrocytic alterations in NRF2-CYP1B1 axis. In addition, since an extensive deregulation occurs in the midbrain of 8-month-old males, the single nuclei chromatin accessibility profile at this age and sex was also investigated, with the aim of identifying the upstream regulatory events that lead to the observed transcriptomic changes and the implication of each cell type on those changes. Despite the low number of recovered nuclei, the major brain cell types were successfully identified. Similar representation in terms of proportion of the total nuclei was observed between the genotypes for all identified cell type populations except for astrocytes, that showed lower numbers in Park7-/- mice in comparison to wild type mice. Moreover, the biggest differences in chromatin accessibility were observed in the astrocyte population that also showed the strongest overlap with the transcriptomic changes. Enrichment analysis performed over the genes showing both epigenomic and transcriptomic changes in astrocytes were consistent with pathways identified in the analysis of the entire midbrain sections. Further indicating the relevance of these changes and their association with astrocytes in the mouse midbrain with Park7 depletion at both chromatin and mRNA level. These findings provide new information about Park7-/- PD mouse model, showing specific changes during aging and suggesting higher sensitivity of males to loss of DJ-1, which might help to better understand variation in the reported phenotypes of Park7-/- mice. These results also point to astrocytes as the main cell population involved in the gene expression changes. Finally, this study gives an insight into the molecular changes that may occur in early stages of PD and help us to understand why males are more affected by PD than females

Normal and Pathological NRF2 Signalling in the Central Nervous System

International audienceThe nuclear factor erythroid 2-related factor 2 (NRF2) was originally described as a master regulator of antioxidant cellular response, but in the time since, numerous important biological functions linked to cell survival, cellular detoxification, metabolism, autophagy, proteostasis, inflammation, immunity, and differentiation have been attributed to this pleiotropic transcription factor that regulates hundreds of genes. After 40 years of in-depth research and key discoveries, NRF2 is now at the center of a vast regulatory network, revealing NRF2 signalling as increasingly complex. It is widely recognized that reactive oxygen species (ROS) play a key role in human physiological and pathological processes such as ageing, obesity, diabetes, cancer, and neurodegenerative diseases. The high oxygen consumption associated with high levels of free iron and oxidizable unsaturated lipids make the brain particularly vulnerable to oxidative stress. A good stability of NRF2 activity is thus crucial to maintain the redox balance and therefore brain homeostasis. In this review, we have gathered recent data about the contribution of the NRF2 pathway in the healthy brain as well as during metabolic diseases, cancer, ageing, and ageing-related neurodegenerative diseases. We also discuss promising therapeutic strategies and the need for better understanding of cell-type-specific functions of NRF2 in these different fields