Redox Signaling Mediated by Thioredoxin and Glutathione Systems in the Central Nervous System

Abstract

Significance: The thioredoxin (Trx) and glutathione (GSH) systems play important roles in maintaining the redox balance in the brain, a tissue that is prone to oxidative stress due to its high-energy demand. These two disulfide reductase systems are active in various areas of the brain and are considered to be critical antioxidant systems in the central nervous system (CNS). Various neuronal disorders have been characterized to have imbalanced redox homeostasis. Recent Advances: In addition to their detrimental effects, recent studies have highlighted that reactive oxygen species/reactive nitrogen species (ROS/RNS) act as critical signaling molecules by modifying thiols in proteins. The Trx and GSH systems, which reversibly regulate thiol modifications, regulate redox signaling involved in various biological events in the CNS.

Critical issues: In this review, we focus on the following: (i) how ROS/RNS are produced and mediate signaling in CNS; (ii) how Trx and GSH systems regulate redox signaling by catalyzing reversible thiol modifications; (iii) how dysfunction of the Trx and GSH systems causes alterations of cellular redox signaling in human neuronal diseases; and (iv) the effects of certain small molecules that target thiol-based signaling pathways in the CNS.

Future directions: Further study on the roles of thiol-dependent redox systems in the CNS will improve our understanding of the pathogenesis of many human neuronal disorders and also help to develop novel protective and therapeutic strategies against neuronal diseases. Antioxid. Redox Signal. 27, 989-1010.

Keywords: CNS; glutaredoxin; glutathione; redox signaling; thiol-targeted compounds; thioredoxin.

FIG. 1.

Two thiol-dependent redox systems. The disulfides in oxidized Trxs/GSH are converted to thiols by consumption of NADPH through redox cycling via TrxRs/GRs. GSH, glutathione; GR, glutathione reductase; Trx, thioredoxin; TrxR, thioredoxin reductase.

FIG. 2.

Production of ROS and redox signaling regulation in the neuronal system by Trx and GSH/Grx systems. ROS are produced via the leaking of electrons from the mitochondrial respiration chain or through some enzymatic reactions under physiological conditions. Trx and GSH/Grx systems are present specifically in different subcellular organelles in neuronal and glial cells and locally control redox signaling. Grx, glutaredoxin; ROS, reactive oxygen species. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

Different thiol modifications regulated by Trx and GSH systems. Cysteines within proteins can be modified by H₂O₂ into sulfenic acid (-SOH), sulfinic acid (-SO₂H), sulfonic acid (-SO₃H), or disulfide (-S-S-). Nitric oxide can react with thiols to form S-nitrosylation (-SNO) and GSSG can form S-glutathionylation (-SSG) with reactive thiols. Trx and GSH systems participate in reduction of many of these thiol modifications. H₂O₂, hydrogen peroxide. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

Trx and Grx systems regulate thiol modifications of GAPDH and the effects on neuronal system. S-nitrosylation of GAPDH promotes its binding to Siah1, which degrades nuclear proteins and causes neuron apoptosis. Trx catalyzes denitrosylation of GAPDH. S-glutathionylation of GAPDH diminishes its activity and contributes to neurodegeneration. Grx can catalyze deglutathionylation of GAPDH. S-sulfhydration of GAPDH also enhances its binding to Siah1 and leads to degradation of PSD95 and synapse loss. Both Trx and Grx systems may play a role in desulfhydrating GAPDH. PSD95, postsynaptic density 95. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 5.

Trx regulated cell death pathways. Trx is a redox regulator for several transcription factors involved in many cellular events in the central nervous system, for example, AP-1, NF-κB, and p53. Trx1 can directly prevent cell death by binding ASK1. Not surprisingly, TXNIP, the endogenous inhibitor of Trx1, can promote ASK1-mediated apoptosis. Different redox statuses of Trx1 exert different effects on caspases. Reduced Trxs can denitrosylate and activate caspase 3, which executes apoptosis, while oxidized Trx1 can be nitrosylated and subsequently transnitrosylate caspase 3 thereby curbs caspase 3-mediated apoptosis. ASK1, apoptosis-signaling kinase 1; TXNIP, thioredoxin-interacting protein. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 6.

Two proposed mechanisms for Grx catalyzed degulathionylation. The dithiol mechanism (upper part) requires both active site cysteines. During reaction, N-terminal active site cysteine forms disulfide with targeted proteins. The monothiol mechanism (lower part) needs only the N-terminal active site cysteine, which takes over the GSH mixed disulfide from targeted proteins. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 7.

X-Interaction between Mercury Compounds and Trx and GSH Systems. Mercury compounds target directly thiols and selenols in the individual components of Trx and GSH systems (step 1) in the cytosol and mitochondria, causing decreased activity. TrxR1 and 2 are major targets. Additionally, generation of ROS (step 2) aggravates the oxidation of sensitive targets (e.g., GSH and Trx1). Oxidation of GSH (step 3) further decreases activity of GSH-dependent enzymes, even when they are not direct targets of Hg (e.g., Grx1; step 4), and increases GSSG that is excreted by the cell. ROS production releases Nrf2, which is translocated to the nucleus (step 5), and induces Phase II enzyme synthesis (e.g., GR) in an attempt to counteract oxidative effects (step 6). Pathways and cellular structures are oversimplified for a matter of clarity. Hg, mercury; Nrf2, nuclear factor E2-related factor 2. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 8.

The toxicity mechanism of PQ in mammalian cells. PQ undergoes redox cycling in cells to generate large amount of ROS, which cause lipid peroxidation, DNA damage, and protein oxidation and heavily disturb Trx and GSH systems. PQ, paraquat.