The sigma-1 receptor-zinc finger protein 179 pathway protects against hydrogen peroxide-induced cell injury

Abstract

The accumulation of reactive oxygen species (ROS) have implicated the pathogenesis of several human diseases including neurodegenerative disorders, stroke, and traumatic brain injury, hence protecting neurons against ROS is very important. In this study, we focused on sigma-1 receptor (Sig-1R), a chaperone at endoplasmic reticulum, and investigated its protective functions. Using hydrogen peroxide (H2O2)-induced ROS accumulation model, we verified that apoptosis-signaling pathways were elicited by H2O2 treatment. However, the Sig-1R agonists, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS), reduced the activation of apoptotic pathways significantly. By performing protein-protein interaction assays and shRNA knockdown of Sig-1R, we identified the brain Zinc finger protein 179 (Znf179) as a downstream target of Sig-1R regulation. The neuroprotective effect of Znf179 overexpression was similar to that of DHEAS treatment, and likely mediated by affecting the levels of antioxidant enzymes. We also quantified the levels of peroxiredoxin 3 (Prx3) and superoxide dismutase 2 (SOD2) in the hippocampi of wild-type and Znf179 knockout mice, and found both enzymes to be reduced in the knockout versus the wild-type mice. In summary, these results reveal that Znf179 plays a novel role in neuroprotection, and Sig-1R agonists may be therapeutic candidates to prevent ROS-induced damage in neurodegenerative and neurotraumatic diseases.

Specificity protein 1-zinc finger protein 179 pathway is involved in the attenuation of oxidative stress following brain injury

“…The inhibition of Znf179 expression was shown to significantly suppress neuronal differentiation [5]. Recently, the results of our study indicated that Znf179 acts as a novel neuroprotector mitigating cell death after hydrogen peroxide (H 2 O 2 )-induced oxidative stress, and its accumulation correlates with H 2 O 2 exposure time [6]. However, the mechanism of H 2 O 2 -induced elevation of Znf179 expression remains unclear.…”

“…Previously, we had generated a stable cell line, with cells expressing GFP-Znf179 fusion protein [6]. The endogenous Znf179 levels were shown to be upregulated in these cells as well, in comparison with those in the GFP-expressing control cells (Fig.…”

“…Previous studies showed that Znf179 is a bifunctional transcription regulator capable of activating and inhibiting gene expression [6], [23]. Znf179 overexpression in U373MG human glioma cells led to the significant changes in the expression of 437 genes (98 upregulated and 339 downregulated) [23].…”

“…Recently, several studies revealed that Znf179 is an important regulator of neural development, synaptic plasticity, and cellular survival [5], [6], [22], [23]. During the embryonic development, Znf179 induces cell cycle arrest at the G0/G1 phase, which initiates neuronal differentiation [5].…”

“…In adult brain, Znf179 regulates excitatory synapses and spine density at the cytoplasm through endosomal membrane association [22]. The treatment of brain cells with pro-inflammatory cytokines or the exposure to oxidative stress were shown to lead to an increase in Znf179 levels, which further leads to the downregulation of pro-apoptotic genes and the upregulation of antioxidant gene expression [6], [23]. Therefore, high expression levels of Znf179 are crucial not only in the fetal period during the development of the nervous system, but also in the adult brain, where this protein is involved in the maintenance of neural functions and protection of the nervous tissue cells from stress-induced damage.…”