Glutathione in the Nervous System as a Potential Therapeutic Target to Control the Development and Progression of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a rare neurological disorder that affects the motor neurons responsible for regulating muscle movement. However, the molecular pathogenic mechanisms of ALS remain poorly understood. A deficiency in the antioxidant tripeptide glutathione (GSH) in the nervous system appears to be involved in several neurodegenerative diseases characterized by the loss of neuronal cells. Impaired antioxidant defense systems, and the accumulation of oxidative damage due to increased dysfunction in GSH homeostasis are known to be involved in the development and progression of ALS. Aberrant GSH metabolism and redox status following oxidative damage are also associated with various cellular organelles, including the mitochondria and nucleus, and are crucial factors in neuronal toxicity induced by ALS. In this review, we provide an overview of the implications of imbalanced GSH homeostasis and its molecular characteristics in various experimental models of ALS.

Keywords: amyotrophic lateral sclerosis; glutathione; neurogenerative disease; oxidative stress.

Figure 1

Astrocyte-mediated regulation of GSH biosynthesis and transport to motor neurons. The biosynthesis and release of GSH are associated with the Nrf2 signaling pathway in astrocytes [83]. Astrocytes take up cysteine, glutamate, and glycine through various transporters; thereafter, GSH is released from astrocytes via multidrug resistance protein 1 and transported to the motor neurons [104]. Cysteine and glutamate uptake are mediated by the X_c- transporter and excitatory amino acid transporter in astrocytes [91,105]. Glycine is transported by astrocytic glycine transport type 1 [106]. Intracellular GSH is synthetized from these amino acids in astrocyte [107]. Extracellular GSH may be taken up by motor neurons directly or indirectly [108]. Motor neurons also take up three amino acids for GSH synthesis. Increased GSH synthesis in astrocytes may exert a protective effect against motor neuronal toxicity under oxidative stress and in ALS.