Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases

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.

Polysulfide exerts a protective effect against cytotoxicity caused by t‐buthylhydroperoxide through Nrf2 signaling in neuroblastoma cells

“…GSH levels within cells are typically in the millimolar range and act as reducing agents to protect cells from oxidative stress [28]. Therefore, we expected that the observed increase in intracellular GSH resulted in protective effects against various oxidative damages.…”

Glutathione in multiple sclerosis: More than just an antioxidant?

“…GSH is also important in the storage and transport of cysteine and the maintenance of protein sulfhydryl groups in a reduced form. 3,18,21 In CNS cells, the GSH concentration is typically around 1-2 mM, several hundred times greater than seen in the cerebrospinal fluid (CSF), which is ~4µM, and in the blood, which is ~2µM. To maintain this rather disparate concentration ratio, active intracellular GSH synthesis is required.…”

“…A crucial component of the non-enzymatic branch of the cellular detoxification of ROS, GSH is ubiquitously distributed in cells throughout the body, 3,18 and impairment of GSH metabolism is involved in the pathogenesis of several neurodegenerative diseases. 3 GSH is synthesized in two sequential ATP-dependent reactions: first, γ-glutamylcysteine is formed from glutamate and cysteine through the action of γ-glutamylcysteine synthetase (γ-GCS); and second, GSH is synthesized by γ-glutamylcysteine binding to glycine, in a reaction catalyzed by GSH-synthetase (GS) 18,21 (Figure1). The synthesis of glutathione is limited by cysteine bioavailability and the γ-GCS-catalyzed reaction is the rate-limiting step.…”

“…2 Oxidative stress and antioxidant mechanisms in MS ROS are highly reactive molecules that play important roles in various physiological cellular processes, such as cell signaling, gene expression and host defense; however, increased ROS levels induce oxidative stress, which is a common pathological feature in several neurological disorders, including MS. 2,3 To protect themselves from ROS-induced damage and cell death, cells are equipped with an elaborate antioxidant machinery and under physiological conditions, the levels of cellular ROS are in equilibrium with this endogenous antioxidant system; however, when this balance is altered by either an increase in ROS production or reduced antioxidant protection, oxidative stress and subsequent damage to proteins, lipids and deoxyribonucleic acid (DNA) occurs. 2,3 The CNS is particularly sensitive to oxidative stress, due to its high cellular metabolic activity and enrichment in polyunsaturated fatty acids. 4 Furthermore, the activities of antioxidant enzymes, such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) are reported to be lower in the brain, compared to other tissues.…”

Supportive or detrimental roles of P2Y receptors in brain pathology?—The two faces of P2Y receptors in stroke and neurodegeneration detected in neural cell and in animal model studies

“…Oxidative stress is regarded as a factor contributing to inducement of the PTP and apoptosis [35,37,38]. Cells have antioxidant tools to degrade ROS, including SOD, catalase, glutathione peroxidase, and thioredoxins [39][40][41][42]. In many cases, it is still under debate whether ROS are the cause or consequence of neurodegenerative diseases.…”