Neuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2

Abstract

Forebrain neurons have weak intrinsic antioxidant defences compared with astrocytes, but the molecular basis and purpose of this is poorly understood. We show that early in mouse cortical neuronal development in vitro and in vivo, expression of the master-regulator of antioxidant genes, transcription factor NF-E2-related-factor-2 (Nrf2), is repressed by epigenetic inactivation of its promoter. Consequently, in contrast to astrocytes or young neurons, maturing neurons possess negligible Nrf2-dependent antioxidant defences, and exhibit no transcriptional responses to Nrf2 activators, or to ablation of Nrf2's inhibitor Keap1. Neuronal Nrf2 inactivation seems to be required for proper development: in maturing neurons, ectopic Nrf2 expression inhibits neurite outgrowth and aborization, and electrophysiological maturation, including synaptogenesis. These defects arise because Nrf2 activity buffers neuronal redox status, inhibiting maturation processes dependent on redox-sensitive JNK and Wnt pathways. Thus, developmental epigenetic Nrf2 repression weakens neuronal antioxidant defences but is necessary to create an environment that supports neuronal development.

Nrf2 mitigates LRRK2- and α-synuclein–induced neurodegeneration by modulating proteostasis

“…However, growing evidence indicates that Nrf2 can act in neurons via a cell-autonomous manner, leading to transcriptional changes in not only oxidative stress-related genes but also those related to proteostasis and specific neuronal functions (45)(46)(47). Our work demonstrates that Nrf2 can act in a cell-autonomous manner to potently promote neuronal protein homeostasis and reduce neurodegeneration caused by α-synuclein and mutant LRRK2 expression.…”

Adaptive regulation of the brain’s antioxidant defences by neurons and astrocytes

“…This difference was all the more remarkable given that the authors estimated that around 10% of neuronally-enriched cultures were astrocytes. Later qPCR studies by ourselves and others employing near-astrocyte free neuronal cultures corroborated this differential: cortical neurons were found to express approximately 100–1000-fold less Nrf2 than astrocytes [14], [15]. As if this were not enough to limit neuronal Nrf2 activity, neurons also have a greater capacity to promote degradation of what little Nrf2 is expressed, by possessing higher Cul3-dependent Nrf2 degradation capacity than astrocytes [15].…”

“…tBHQ) or to genetic activation of the pathway (Keap1 deficiency). The molecular basis for Nrf2 gene repression in neurons appears to be epigenetic in nature: neurons exhibit far lower levels of Nrf2 promoter histone H3 acetylation than astrocytes [14]. The process of Nrf2 gene repression takes place early in development: while Nrf2 expression and pathway activity are on a par with astrocytes at P0 in vivo and days-in-vitro (DIV) 2 in vitro, repression of expression, and reduction of promoter H3 acetylation has taken place by DIV 9 [14].…”

Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs

“…The elevated production of GSH in astrocytes is sustained by both elevated biosynthesis and regeneration under the control of cellautonomous Nrf2 signaling. Accordingly, astrocytes express basal levels of Nrf2 that can be further increased by several stresses, whereas Nrf2 expression is low in neurons due to epigenetic inactivation of its promoter and/or continuous destabilization of Nrf2 protein [91,92]. Therefore, in astrocytes, Nrf2 regulates the basal expression of genes such as solute carrier family 7 member 11/xCT (SLC7A11/xCT), glutamate-cysteine ligase modifier subunit/gamma-glutamylcysteine synthetase (GCLM/γGCS) and glutathione-disulfide reductase (GSR) required for synthesis and metabolism of GSH, which is essential for redox homeostasis in the brain [45,93].…”