NR1D1 downregulation in astrocytes induces a phenotype that is detrimental to cocultured motor neurons

Abstract

Nuclear receptor subfamily 1 group D member 1 (NR1D1, also known as Rev‐erbα) is a nuclear transcription factor that is part of the molecular clock encoding circadian rhythms and may link daily rhythms with metabolism and inflammation. NR1D1, unlike most nuclear receptors, lacks a ligand‐dependent activation function domain 2 and is a constitutive transcriptional repressor. Amyotrophic lateral sclerosis (ALS) is the most common adult‐onset motor neuron disease, caused by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Approximately 10%–20% of familial ALS is caused by a toxic gain‐of‐function induced by mutations of the Cu/Zn superoxide dismutase (SOD1). Dysregulated clock and clock‐controlled gene expression occur in multiple tissues from mutant hSOD1‐linked ALS mouse models. Here we explore NR1D1 dysregulation in the spinal cord of ALS mouse models and its consequences on astrocyte–motor neuron interaction. NR1D1 protein and mRNA expression are significantly downregulated in the spinal cord of symptomatic mice expressing mutant hSOD1, while no changes were observed in age‐matched animals overexpressing wild‐type hSOD1. In addition, NR1D1 downregulation in primary astrocyte cultures induces a pro‐inflammatory phenotype and decreases the survival of cocultured motor neurons. NR1D1 orchestrates the cross talk between physiological pathways identified to be disrupted in ALS (e.g., metabolism, inflammation, redox homeostasis, and circadian rhythms) and we observed that downregulation of NR1D1 alters astrocyte–motor neuron interaction. Our results suggest that NR1D1 could be a potential therapeutic target to prevent astrocyte‐mediated motor neuron toxicity in ALS.

Circadian rhythm alterations affecting the pathology of neurodegenerative diseases

“…The expression of an important regulator of the molecular clock, Nr1d1, which is known to coordinate communication between circadian rhythm, metabolism, and inflammation (Cho et al, 2012), was reduced in transgenic mice with ALS (Killoy et al, 2021). It is noteworthy that the negative regulation of Nr1d1 in astrocytes induces phenotype that is detrimental to motor neurons and may thus be associated with ALS (Killoy et al, 2022). Besides this, genes for sirtuins (Sirt1, Sirt3 and Sirt6), metabolic enzymes (Pfkfb3, Cpt1 and Nampt) and redox regulators (Nrf2, G6pd, Pgd), which have their expression controlled by clock genes, were also reduced, indicating that besides Nr1d1, other clock genes are reduced in ALS (Killoy et al, 2021).…”

The role of circadian clock in astrocytes: From cellular functions to ischemic stroke therapeutic targets

“…Traf2 conveys proinflammatory signals from the TNF receptor to NF-κB (Griffin et al, 2019). Silencing Rev-erb expression in astrocytes was further confirmed to decrease the survival of co-cultured neurons and lead sensibly to hydrogen peroxide toxicity (Griffin et al, 2019;Killoy et al, 2022). NF-κB-mediated inflammation is also regulated by astrocytic circadian clock Per1, shRNAmiR (a technique known as RNAi, RNA interference)-induced knockdown of Per1 activated NF-κB signaling pathway and increased the expression of monocyte chemoattractant protein 1 (MCP-1) and interleukin 6 in astrocytes (Sugimoto et al, 2014; Figure 3).…”