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Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases
Department of Pharmacology, Case Western Reserve University, 2109 Adelbert Rd., Cleveland, OH 44106, USA
Louis B. Stokes Veterans Affairs Medical Research Center, 10701 East Blvd, Cleveland, OH 44106, USA
* Author to whom correspondence should be addressed.
Received: 1 July 2012; in revised form: 22 August 2012 / Accepted: 24 September 2012 / Published: 9 October 2012
(This article belongs to the Special Issue Glutathione
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.
Keywords: glutathione; N-acetylcysteine; oxidative stress; redox signaling; neurodegenerative diseases; apoptosis; protein aggregation; glutathionylation; nitrosylation
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MDPI and ACS Style
Johnson, W.M.; Wilson-Delfosse, A.L.; Mieyal, J.J. Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases. Nutrients 2012, 4, 1399-1440.
Johnson WM, Wilson-Delfosse AL, Mieyal JJ. Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases. Nutrients. 2012; 4(10):1399-1440.
Johnson, William M.; Wilson-Delfosse, Amy L.; Mieyal, John. J. 2012. "Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases." Nutrients 4, no. 10: 1399-1440.