Impaired Glutathione Synthesis in Neurodegeneration

Abstract

Glutathione (GSH) was discovered in yeast cells in 1888. Studies of GSH in mammalian cells before the 1980s focused exclusively on its function for the detoxication of xenobiotics or for drug metabolism in the liver, in which GSH is present at its highest concentration in the body. Increasing evidence has demonstrated other important roles of GSH in the brain, not only for the detoxication of xenobiotics but also for antioxidant defense and the regulation of intracellular redox homeostasis. GSH also regulates cell signaling, protein function, gene expression, and cell differentiation/proliferation in the brain. Clinically, inborn errors in GSH-related enzymes are very rare, but disorders of GSH metabolism are common in major neurodegenerative diseases showing GSH depletion and increased levels of oxidative stress in the brain. GSH depletion would precipitate oxidative damage in the brain, leading to neurodegenerative diseases. This review focuses on the significance of GSH function, the synthesis of GSH and its metabolism, and clinical disorders of GSH metabolism. A potential approach to increase brain GSH levels against neurodegeneration is also discussed.

Glutathione-Dependent Detoxification Processes in Astrocytes

“…Due to the dependence of many cellular processes on GSH it is not surprising that an impaired GSH metabolism has been connected with human diseases [3][4][5][6]. This appears to be especially the case for neurological disorders as ample evidence connects disturbances in the GSH metabolism of the brain with the progression of neurological disorders [7,8], including Parkinson's disease [9], Alzheimer's disease [10], multiple sclerosis [11] as well as schizophrenia and bipolar disorder [12]. Also alterations of cognitive functions with ageing have been correlated with a decline in GSH content in brain and with impaired GSH-dependent functions [13].…”

“…Astrocytes are also considered to play an important role in the GSH metabolism of the brain [7,16,23,28]. The high cellular GSH content and the strong capacity of astrocytes for GSH-dependent detoxification processes helps to protect these cells but also their neighbours against the toxic potential of oxidants and toxins [28][29][30].…”

Untitled

“…peroxidation) of unsaturated lipid bonds in cell membranes and unbridged SH functional groups in protein amino acids. These include cysteine and methionine as well as peptides such as glutathione, whose depletion has been associated with a variety of neurodegenerative diseases (Aoyama and Nakaki, 2013 Oehr and LeMay (2014). Moreover, the fact that water-derived EZs in vitro have been seen on rabbit muscle (Zheng J and Pollack GH, 2003;and Zheng J et al 2006) suggests that TOSH structures not only grow adjacent to protein structures in vivo, but in doing, provide an antioxidant benefit to all hydrated biologically-active membranes more generally (Oehr and LeMay 2014, page 16).…”

“…For example, in Aoyama and Nakaki (2013), citing the work of many others, their extensive review article referred to the electron-donating role played by NADPH in regenerating both enzymes, as well as GSSG into GSH (see page 21025). While the electrical potential of NADPH of -320 mV exceeds that of TOSH's -208 to -219 mV, the fact that TOSH can help regenerate GSH, means that the limited supply of NADPH is not wasted, thus allowing it to protect vital protein structures from oxidation and potential misfolding.…”

“…If true, this would contradict some currently held views on the topic. For example, according to Aoyama and Nakaki (2013), no known defense has been reported against hydroxyl radicals (page 21026). It appears that TOSH can indirectly and potentially directly destroy hydroxyl and peroxynitrite, as shown below:…”