Glutathione and Related Molecules in Parkinsonism

Int J Mol Sci. 2021 Aug 13;22(16):8689. doi: 10.3390/ijms22168689.

Abstract

Glutathione (GSH) is the most abundant intrinsic antioxidant in the central nervous system, and its substrate cysteine readily becomes the oxidized dimeric cystine. Since neurons lack a cystine transport system, neuronal GSH synthesis depends on cystine uptake via the cystine/glutamate exchange transporter (xCT), GSH synthesis, and release in/from surrounding astrocytes. Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), a detoxifying master transcription factor, is expressed mainly in astrocytes and activates the gene expression of various phase II drug-metabolizing enzymes or antioxidants including GSH-related molecules and metallothionein by binding to the antioxidant response element (ARE) of these genes. Accumulating evidence has shown the involvement of dysfunction of antioxidative molecules including GSH and its related molecules in the pathogenesis of Parkinson's disease (PD) or parkinsonian models. Furthermore, we found several agents targeting GSH synthesis in the astrocytes that protect nigrostriatal dopaminergic neuronal loss in PD models. In this article, the neuroprotective effects of supplementation and enhancement of GSH and its related molecules in PD pathology are reviewed, along with introducing new experimental findings, especially targeting of the xCT-GSH synthetic system and Nrf2-ARE pathway in astrocytes.

Keywords: Nrf2; astrocyte; glutathione; mesencephalon; metallothionein; neuroprotection; oxidative stress; parkinsonism; region specificity; serotonin 5-HT1A receptor; striatum.

Publication types

  • Review

MeSH terms

  • Amino Acid Transport System y+ / metabolism*
  • Animals
  • Astrocytes / metabolism
  • Carboxylic Ester Hydrolases / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation
  • Glutathione / metabolism*
  • Humans
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress
  • Parkinsonian Disorders / metabolism*
  • Signal Transduction*

Substances

  • Amino Acid Transport System y+
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • SLC7A11 protein, human
  • Carboxylic Ester Hydrolases
  • arylesterase
  • Glutathione