The Role of Non-Coding RNAs in the Neuroprotective Effects of Glutathione

Abstract

The establishment of antioxidative defense systems might have been mandatory for most living beings with aerobic metabolisms, because oxygen consumption produces adverse byproducts known as reactive oxygen species (ROS). The brain is especially vulnerable to the effect of ROS, since the brain has large amounts of unsaturated fatty acids, which are a target of lipid oxidation, as well as comparably high-energy consumption compared to other organs that results in ROS release from mitochondria. Thus, dysregulation of the synthesis and/or metabolism of antioxidants-particularly glutathione (GSH), which is one of the most important antioxidants in the human body-caused oxidative stress states that resulted in critical diseases, including neurodegenerative diseases in the brain. GSH plays crucial roles not only as an antioxidant but also as an enzyme cofactor, cysteine storage form, the major redox buffer, and a neuromodulator in the central nervous system. The levels of GSH are precisely regulated by uptake systems for GSH precursors as well as GSH biosynthesis and metabolism. The rapid advance of RNA sequencing technologies has contributed to the discovery of numerous non-coding RNAs with a wide range of functions. Recent lines of evidence show that several types of non-coding RNAs, including microRNA, long non-coding RNA and circular RNA, are abundantly expressed in the brain, and their activation or inhibition could contribute to neuroprotection through the regulation of GSH synthesis and/or metabolism. Interestingly, these non-coding RNAs play key roles in gene regulation and growing evidence indicates that non-coding RNAs interact with each other and are co-regulated. In this review, we focus on how the non-coding RNAs modulate the level of GSH and modify the oxidative stress states in the brain.

Keywords: antioxidant; central nervous system; circular RNA; glutathione; long non-coding RNA; microRNA; neuroprotection; oxidative stress.

Figure 1

Regulation of the redox system. Among the three amino acids that form GSH—i.e., cysteine (Cys), glutamate (Glu) and glycine (Gly)—Cys is the rate-limiting substrate. Cys is supplied via the Cys transporter EAAC1 or cystine (Cys₂) transporter system xc-. Cys₂ is intracellularly reduced to Cys once imported into the cell, and turns out to be a building block of the antioxidant GSH.GSH synthesis is catalyzed by GCL and GSS. GSR transfers an electron from nicotinamide adenine dinucleotide phosphate (NADPH) to GSSG, and thereby catalyzes the reduction of GSSG to GSH. GPx reduces peroxide (R-OOH) to a harmless compound (R-OH) by gathering the needed reducing equivalents from GSH. SOD converts superoxide anion to less noxious hydrogen peroxide (H₂O₂), and catalase (CAT) reduces H₂O₂ without any activator.

Figure 2

Signal transduction related to transactivation of antioxidative genes regulated by ncRNAs. Nrf2 is a transcriptional factor that enters the nucleus in response to oxidative stress, resulting in increased expression of numerous neuroprotective genes. Nrf2 is regulated through the PI3K/Akt pathway, which plays key roles in regulating neuroprotection against oxidative stress. BDNF is a ligand of TrkB, which promotes neuronal survival and protects against apoptosis mediated through the PI3K/Akt pathway. BDNF can also bind to p75^NTR—which was identified as a low-affinity nerve growth factor receptor—and BDNF can activate the NFκB pathway as well as the p38/JNK pathways. Boxes indicate miRNAs that target the signal transduction molecule, and the rounded rectangle indicates lncRNA.

Figure 3

Interplay of lncRNAs and miRNAs in neuroprotective effect. LncRNAs play a key role in neuroprotection mainly by acting as a miRNA sponge. Boxes indicate miRNAs that target the signal transduction molecule, and the rounded rectangle indicates lncRNAs.

Figure 4

Interplay of circRNAs and miRNAs in cellular protective effect. CircRNAs play a key role in protective function mainly by acting as a miRNA sponge. Boxes indicate miRNAs that target the signal transduction molecule, and the oval indicates circRNAs.