Abstract
Protein glutathionylation is a redox-mediated posttranslational modification that regulates the function of target proteins by conjugating glutathione with a cysteine thiol group on the target proteins. Protein glutathionylation has several biological functions such as regulation of metabolic pathways, calcium homeostasis, signal transduction, remodeling of cytoskeleton, inflammation, and protein folding. However, the exact role and mechanism of glutathionylation during irreversible oxidative stress has not been completely defined. Irreversible oxidative damage is implicated in a number of neurological disorders. Here, we discuss and highlight the most recent findings and several evidences for the association of glutathionylation with neurodegenerative diseases and the role of glutathionylation of specific proteins in the pathogenesis of neurodegenerative diseases. Understanding the important role of glutathionylation in the pathogenesis of neurodegenerative diseases may provide insights into novel therapeutic interventions.
Highlights
Glutathione (GSH) is abundant in all cells as a low molecular weight thiol with intracellular concentrations usually ranging from approximately 1 to 10 mM in vivo [1, 2]
Glutathione peroxidase (Prx), glutaredoxin (Grx), and thioredoxin (Trx), participate in GSH redox homeostasis, which is defined by the GSH concentration divided by the GSSG concentration, while glutathione reductase ensures that GSH remains in a reduced form and maintains a high GSH/GSSG ratio in the cytosol
Numerous pieces of evidence suggest that glutathionylation of specific proteins is associated with a number of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD)
Summary
Glutathione (GSH) is abundant in all cells as a low molecular weight thiol with intracellular concentrations usually ranging from approximately 1 to 10 mM in vivo [1, 2]. The intracellular redox state, including the level of GSH and GSSG, and the GSH/GSSG ratio are an important marker of oxidative stress and cellular health [7, 8]. GSH is synthesized in the cytoplasm; it is translocated to different organelle-specific functions. The major functions of GSH are acting as the indicator of the cellular redox state, antioxidant defense, and the storage and transport of cysteine [16, 17]. Lymphocytes and intestinal epithelial cells require a sufficient intracellular GSH concentration to maintain a reduced redox potential for proliferation [21]. A therapeutic strategy to recover neuronal GSH contents in the brain is a critical treatment for GSH depletion-related neurodegenerative diseases. No therapeutic drugs are available for increasing GSH contents in the brain at present
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