Are Astrocytes the Predominant Cell Type for Activation of Nrf2 in Aging and Neurodegeneration?

Liddell, Jeffrey R.

doi:10.3390/antiox6030065

Cited by 140 publications

(129 citation statements)

References 271 publications

(437 reference statements)

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“…An important question is which aging brain cells lose their Nrf2 activation responses? Markers of Nrf2 activity can be observed in neurons in postmortem brain tissue and animal models of disease; however, recent evidence demonstrates that Nrf2 activity is low in iPS‐derived human neurons , and that during mouse cortical neuronal development in vitro and in vivo , the expression of Nrf2 is repressed by epigenetic inactivation of its promoter . In contrast, non‐neuronal cells such as astrocytes demonstrate consistent in vitro and in vivo Nrf2 activation responses .…”

Section: Nrf2 Signaling In Agingmentioning

confidence: 99%

The role of Nrf2 signaling in counteracting neurodegenerative diseases

2018

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The transcription factor Nrf2 (nuclear factor‐erythroid 2 p45‐related factor 2) functions at the interface of cellular redox and intermediary metabolism. Nrf2 target genes encode antioxidant enzymes, and proteins involved in xenobiotic detoxification, repair and removal of damaged proteins and organelles, inflammation, and mitochondrial bioenergetics. The function of Nrf2 is altered in many neurodegenerative disorders, such as Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Friedreich's ataxia. Nrf2 activation mitigates multiple pathogenic processes involved in these neurodegenerative disorders through upregulation of antioxidant defenses, inhibition of inflammation, improvement of mitochondrial function, and maintenance of protein homeostasis. Small molecule pharmacological activators of Nrf2 have shown protective effects in numerous animal models of neurodegenerative diseases, and in cultures of human cells expressing mutant proteins. Targeting Nrf2 signaling may provide a therapeutic option to delay onset, slow progression, and ameliorate symptoms of neurodegenerative disorders.

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Section: Nrf2 Signaling In Agingmentioning

confidence: 99%

The role of Nrf2 signaling in counteracting neurodegenerative diseases

2018

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“…Indeed, through interaction with downstream transcription factors and coactivators, PPARs-γ regulate the expression of genes involved in glucose metabolism in mitochondria and fatty acid oxidation (Monsalve, Pyarasani, Delgado-Lopez, & Moore-Carrasco, 2013;Willson, Lambert, & Kliewer, 2001). Specifically, when activated by the full agonist pioglitazone, PPARs-γ increase mitochondrial biogenesis, mitochondrial DNA content and oxygen consumption through interaction with the PPAR-γ coactivator 1-alpha (PGC1α), the nuclear factor erythroid 2-related factor 1-2 (Nrf1-2), and mitochondrial transcription factors (mtTF)A (Gleyzer, Vercauteren, & Scarpulla, 2005), regulating antioxidant gene expression (Liddell, 2017) (Figure 2). In addition, PPAR-γ activation increases mithocondrial fission, which mediates removal of damaged mitochondria and plays an important role in the assembly of mitochondrial electron transport chain (Corona & Duchen, 2016).…”

Section: Nuclear Ppars-γmentioning

confidence: 99%

“…Dimethylfumarate (DMF) is an approved drug for MS, known to switch pro-inflammatory microglia to a neuroprotective state (Parodi et al, 2015) and to reduce disease progression via activation of (erythroid-derived 2)-related factor-2 (Nrf2), a transcription factor with antioxidant properties (Liddell, 2017). DMF has been proposed to exert its therapeutic effects modulating oxidative phosphorylation, through increased levels of the TCA cycle intermediate fumarate in microglia (Tannahill, Iraci, Gaude, Frezza, & Pluchino, 2015); (Figure 3).…”

Section: Mir200b Reduces Inos Expression and No Production And Limitsmentioning

confidence: 99%

How to reprogram microglia toward beneficial functions

Fumagalli

Lombardi

Gressèns

et al. 2018

Glia

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Microglia, brain cells of nonneural origin, orchestrate the inflammatory response to diverse insults, including hypoxia/ischemia or maternal/fetal infection in the perinatal brain. Experimental studies have demonstrated the capacity of microglia to recognize pathogens or damaged cells activating a cytotoxic response that can exacerbate brain damage. However, microglia display an enormous plasticity in their responses to injury and may also promote resolution stages of inflammation and tissue regeneration. Despite the critical role of microglia in brain pathologies, the cellular mechanisms that govern the diverse phenotypes of microglia are just beginning to be defined. Here we review emerging strategies to drive microglia toward beneficial functions, selectively reporting the studies which provide insights into molecular mechanisms underlying the phenotypic switch. A variety of approaches have been proposed which rely on microglia treatment with pharmacological agents, cytokines, lipid messengers, or microRNAs, as well on nutritional approaches or therapies with immunomodulatory cells. Analysis of the molecular mechanisms relevant for microglia reprogramming toward pro-regenerative functions points to a central role of energy metabolism in shaping microglial functions. Manipulation of metabolic pathways may thus provide new therapeutic opportunities to prevent the deleterious effects of inflammatory microglia and to control excessive inflammation in brain disorders.

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“…Motif enrichment is not always accompanied by expression of the corresponding TFs, potentially reflecting synergistic interactions between different cell types in the CNS. For example, NRF2 is a key regulator of the oxidative stress response, and its activity has been shown to be repressed in neurons while inducing a strong response in astrocytes 33 . Therefore, its shared expression may reflect the neuroprotective role that astrocytes provide for other cell types.…”

Section: Resultsmentioning

confidence: 99%

cis-Regulatory Chromatin Contacts in Neural Cells Reveal Contributions of Genetic Variants to Complex Neurological Disorders

Song

Yang

Ren

et al. 2018

Preprint

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47Mutations in gene regulatory elements have been associated with a wide range of complex neurological 48 disorders. However, due to their inherent cell type-specificity and difficulties in characterizing their 49 regulatory targets, our ability to identify causal genetic variants has remained limited. To address these 50 constraints, we perform integrative analysis of chromatin interactions using promoter capture Hi-C 51(pcHi-C), open chromatin regions using ATAC-seq, and transcriptomes using RNA-seq in four 52 functionally distinct neural cell types: iPSC-induced excitatory neurons and lower motor neurons, iPSC-53 derived hippocampal dentate gyrus (DG)-like neurons, and primary astrocytes. We identify hundreds of 54 thousands of long-range cis interactions between promoters and distal promoter-interacting regions 55 (PIRs), enabling us to link regulatory elements to their target genes and reveal putative pathways that are 56 dysregulated in disease. We validate several novel PIRs using CRISPR techniques in human excitatory 57 neurons, demonstrating that CDK5RAP3, STRAP, and DRD2 are transcriptionally regulated by 58 physically linked enhancers. Finally, we show that physical chromatin interactions mediate genetic 59 interactions in autism spectrum disorder (ASD). Our study illustrates how characterizing the 3D 60 epigenome elucidates novel regulatory relationships in the central nervous system (CNS), shedding light 61 on previously unknown functions for noncoding variants in complex neurological disorders. 62 63 the FTO gene have been shown not to regulate FTO, but IRX3 in the brain and both IRX3 and IRX5 in 75 adipocytes, respectively 3,4 . The FTO locus in obesity illustrates the potentially intricate and cell type-76 specific manner in which noncoding variants contribute to disease. However, such well-annotated cases 77 are rare, and we still lack systematic mappings of GWAS SNPs to their regulatory targets, especially in 78 the context of complex neurological disorders. 79 80 Previous epigenomic annotations of the germinal zone (GZ) and cortical and subcortical plates (CP) in 81 the human brain revealed the importance of 3D chromatin structure in gene regulation and disease 5,6 . 82However, these studies utilized complex, heterogeneous tissues, limiting their abilities to interpret gene 83 regulation in a cell type-specific manner. Therefore, charting the landscape of epigenomic regulation in 84 well-characterized, physiologically relevant cell types should offer significant advantages for identifying 85 causal variants, deciphering their functions, and enabling novel therapies for previously intractable 86 diseases. Towards this goal, we used wild type human induced pluripotent stem cells (iPSCs) from the 87 WTC11 line 7 to generate three neuronal cell types: excitatory neurons 8 , hippocampal dentate gyrus 88 (DG)-like neurons 9 , and lower motor neurons 10 . GFAP-positive astrocytes from the gastrulating brains 89 of two individuals were also included for their relevance to human brain development and di...

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Are Astrocytes the Predominant Cell Type for Activation of Nrf2 in Aging and Neurodegeneration?

Cited by 140 publications

References 271 publications

The role of Nrf2 signaling in counteracting neurodegenerative diseases

The role of Nrf2 signaling in counteracting neurodegenerative diseases

How to reprogram microglia toward beneficial functions

cis-Regulatory Chromatin Contacts in Neural Cells Reveal Contributions of Genetic Variants to Complex Neurological Disorders

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