The Role of the Thioredoxin System in Brain Diseases

Abstract

The thioredoxin system, consisting of thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH, plays a fundamental role in the control of antioxidant defenses, cell proliferation, redox states, and apoptosis. Aberrations in the Trx system may lead to increased oxidative stress toxicity and neurodegenerative processes. This study reviews the role of the Trx system in the pathophysiology and treatment of Alzheimer's, Parkinson's and Huntington's diseases, brain stroke, and multiple sclerosis. Trx system plays an important role in the pathophysiology of those disorders via multiple interactions through oxidative stress, apoptotic, neuro-immune, and pro-survival pathways. Multiple aberrations in Trx and TrxR systems related to other redox systems and their multiple reciprocal relationships with the neurodegenerative, neuro-inflammatory, and neuro-oxidative pathways are here analyzed. Genetic and environmental factors (nutrition, metals, and toxins) may impact the function of the Trx system, thereby contributing to neuropsychiatric disease. Aberrations in the Trx and TrxR systems could be a promising drug target to prevent and treat neurodegenerative, neuro-inflammatory, neuro-oxidative stress processes, and related brain disorders.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; antioxidants; metals; multiple sclerosis; oxidative stress; stroke.

Figure 1

PRISMA 2009 Flow Diagram for the review detailing the database searches, the number of abstracts screened and the full texts retrieved.

Figure 2

The role of the Trx system in the pathophysiology of Alzheimer’s disease (AD). The combination of Trx with ASK1 may play a role in the neurodegeneration and survival of cerebellar cells. The increased expression of TrxR, Trx1 and Trx80 decreases the accumulation of Aβ in AD patients. Prx and Trx can be used to diagnose AD in lab instead of clinical application. Trx: thioredoxin; TrxR: thioredoxin reductase; Prx: peroxiredoxin; ASK1: apoptosis signal-regulating kinase 1; Aβ: amyloid β.

Figure 3

The involvement of Trx1 in pathophysiological signal pathways of Parkinson’s disease (PD). Trx1 participates in a variety of biological pathways of PD. During oxidative conditions, Trx1 stimulates apoptosis signaling caspase 12, which antagonizes the activity of mitochondrial complex I. Trx1 might also suppress MPTP in cytoprotective and neuroprotective mechanisms. When exposed to H₂O₂ and dissociated from Trx1, ASK1 can co-immunoprecipitate with DJ-1. Meanwhile, DJ-1 induces expression of Trx1 via transcription factor Nrf-2 to protect cells against oxidative stress. Also, Prx has a protective role via Trx1-ASK1 against dopaminergic neuron cell death. Nrf-2: nuclear factor erythroid 2-related factor 2; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Trx: thioredoxin; TrxR: thioredoxin reductase; Prx: peroxiredoxin; ASK1: apoptosis signal-regulating kinase 1; Aβ: amyloid β.

Figure 4

The role of Trx1 and Gpx in the pathophysiology of Huntington’s disease (HD). Trx1 and GPx participate in various biological pathways in relation to HD. The neuron protection activity of Trx1 is achieved via a decrease of both mHTT and ASK1. Moreover, high expression levels of GPx1/6 also play a crucial role against oxidative stress in HD patients. Trx: thioredoxin reductase; TMX3: thioredoxin-related transmembrane protein 3; ASK1: apoptosis signal-regulating kinase 1; GPx: glutathione peroxidase; mHTT: mutant Huntington protein.

Figure 5

The role of Trx1 in the pathophysiology of ischemic stroke. Trx1 participates in the pathophysiology of brain stroke. Although Trx1 could directly combine with ASK1 to decrease its activity, TXNIP may inhibit Trx1 activity from inducing brain ischemic stroke under oxidative stress conditions. Inhibition of Trx1 with siRNA induces neuronal apoptosis by stimulating the brain ASK1-JNK/p38 signaling pathway.Trx: thioredoxin; TXNIP: Trx1 interacting protein; ASK1: apoptosis signal-regulating kinase 1.

Figure 6

The role of Trx in the pathophysiology of multiple sclerosis (MS). In MS, Trx and sirt1 were upregulated, and TrxR was downregulated. Meanwhile, the activation of the Nrf2 pathway might play a protecting role against oxidative stress by upregulating the expression levels of GSH and Trx. Trx: thioredoxin; TrxR: thioredoxin reductase; Sirt1: sirtuin 1; Nrf2: Nuclear factor (erythroid-derived 2)-like 2.