The impact of glutathione metabolism in autism spectrum disorder

Pharmacol Res. 2021 Apr;166:105437. doi: 10.1016/j.phrs.2021.105437. Epub 2021 Jan 22.

Abstract

This paper reviews the potential role of glutathione (GSH) in autism spectrum disorder (ASD). GSH plays a key role in the detoxification of xenobiotics and maintenance of balance in intracellular redox pathways. Recent data showed that imbalances in the GSH redox system are an important factor in the pathophysiology of ASD. Furthermore, ASD is accompanied by decreased concentrations of reduced GSH in part caused by oxidation of GSH into glutathione disulfide (GSSG). GSSG can react with protein sulfhydryl (SH) groups, thereby causing proteotoxic stress and other abnormalities in SH-containing enzymes in the brain and blood. Moreover, alterations in the GSH metabolism via its effects on redox-independent mechanisms are other processes associated with the pathophysiology of ASD. GSH-related regulation of glutamate receptors such as the N-methyl-D-aspartate receptor can contribute to glutamate excitotoxicity. Synergistic and antagonistic interactions between glutamate and GSH can result in neuronal dysfunction. These interactions can involve transcription factors of the immune pathway, such as activator protein 1 and nuclear factor (NF)-κB, thereby interacting with neuroinflammatory mechanisms, ultimately leading to neuronal damage. Neuronal apoptosis and mitochondrial dysfunction are recently outlined as significant factors linking GSH impairments with the pathophysiology of ASD. Moreover, GSH regulates the methylation of DNA and modulates epigenetics. Existing data support a protective role of the GSH system in ASD development. Future research should focus on the effects of GSH redox signaling in ASD and should explore new therapeutic approaches by targeting the GSH system.

Keywords: Acetylcysteine (PubChem CID: 12035); Autism; Folinic acid (PubChem CID: 135403648); Glutathione; Glutathione (PubChem CID: 124886); Glutathione disulfide, oxiglutatione (PubChem CID: 65359); Glutathione redox ratio; L-Cystathionine (PubChem CID: 439258); L-Cysteine (PubChem CID: 5862); L-Methionine (PubChem CID: 6137); Methylcobalamin (PubChem CID: 71306319); NADPH (PubChem CID: 5884); Oxidized glutathione; Sulforaphane (PubChem CID: 5350).

Publication types

  • Review