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.
Highlights
Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease, is a progressive neurodegenerative disease characterized by the selective loss of motor neurons in the spinal cord and motor cortex [1,2]
GSH deficiency and the dysfunction of GSH metabolism are common to several neurodegenerative diseases, including
Accumulating evidence suggests that aberrant GSH homeostasis is linked to the development and progression of ALS, the precise role and mechanism of redox imbalance in neuronal cells in this disease remains to be determined
Summary
Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease, is a progressive neurodegenerative disease characterized by the selective loss of motor neurons in the spinal cord and motor cortex [1,2]. Mutations in the TAF15 gene have been implicated in the pathogenesis of familial and sporadic ALS, and the TAF15 protein forms prion-like aggregates in the cytoplasm of spinal cord neurons of rats, leading to increased neuronal toxicity [16,23,24]. Uncertainties remain regarding the mechanisms underlying the association between GSH and the dysfunction of neuronal cells and the specific functions of GSH that are critical for inducing neuronal toxicity, such as ROS production and protein aggregation in ALS pathogenesis, dysfunctional GSH metabolism, GSH-related enzymatic systems, such as GR and GST, and an imbalanced redox status are increasingly postulated to be crucial to the development and progression of ALS. This review is the first to focus on the functions of GSH in ALS conditions and its role as a potential therapeutic agent in ALS pathogenesis
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