Abstract
Dysregulation of glutathione homeostasis and alterations in glutathione-dependent enzyme activities are increasingly implicated in the induction and progression of neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, and Friedreich’s ataxia. In this review background is provided on the steady-state synthesis, regulation, and transport of glutathione, with primary focus on the brain. A brief overview is presented on the distinct but vital roles of glutathione in cellular maintenance and survival, and on the functions of key glutathione-dependent enzymes. Major contributors to initiation and progression of neurodegenerative diseases are considered, including oxidative stress, protein misfolding, and protein aggregation. In each case examples of key regulatory mechanisms are identified that are sensitive to changes in glutathione redox status and/or in the activities of glutathione-dependent enzymes. Mechanisms of dysregulation of glutathione and/or glutathione-dependent enzymes are discussed that are implicated in pathogenesis of each neurodegenerative disease. Limitations in information or interpretation are identified, and possible avenues for further research are described with an aim to elucidating novel targets for therapeutic interventions. The pros and cons of administration of N-acetylcysteine or glutathione as therapeutic agents for neurodegenerative diseases, as well as the potential utility of serum glutathione as a biomarker, are critically evaluated.
Highlights
Glutathione (GSH) is a vital constituent of cells throughout the body, acting as a redox buffer, and as cofactor for signal transduction, antioxidant defense, and electrophile defense, especially in the brain
Oxidative stress has been implicated as a factor mediating initiation and progression of many neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS/Lou Gehrig’s disease), and Friedreich’s ataxia (FA) [59,60,61,62,63,64]
The perturbation due to changes in protein level/modifications is often caused by dysfunction of protein degradation complexes, leading to abnormal protein turnover, which has been implicated in many neurodegenerative diseases [82]
Summary
Glutathione (GSH) is a vital constituent of cells throughout the body, acting as a redox buffer, and as cofactor for signal transduction, antioxidant defense, and electrophile defense, especially in the brain. Dysregulation of GSH homeostasis and deactivation of GSH-dependent enzymes are believed to contribute to initiation and progression of neurodegenerative diseases, the focus of this review. The review presents a critical overview of the ways that alterations in GSH-dependent biochemistry and cell biology may contribute to neurodegenerative diseases, considering limitations in available information and suggesting future studies. The functions of GSH as redox buffer, nucleophilic scavenger of electrophilic compounds, and signal transduction agent are presented. Building on this foundation, the potential role of impairment of GSH-dependent functions is evaluated in the context of major contributing mechanisms of initiation and progression of the neurodegenerative diseases, including oxidative stress, deactivation of key enzymes, disruption of thiol homeostasis and signaling pathways, protein misfolding, and protein aggregation. The potential utility of GSH as a therapeutic agent and/or biomarker is evaluated
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