Glutathione metabolism and Parkinson's disease

Abstract

It has been established that oxidative stress, defined as the condition in which the sum of free radicals in a cell exceeds the antioxidant capacity of the cell, contributes to the pathogenesis of Parkinson disease. Glutathione is a ubiquitous thiol tripeptide that acts alone or in concert with enzymes within cells to reduce superoxide radicals, hydroxyl radicals, and peroxynitrites. In this review, we examine the synthesis, metabolism, and functional interactions of glutathione and discuss how these relate to the protection of dopaminergic neurons from oxidative damage and its therapeutic potential in Parkinson disease.

Keywords: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 1-methyl-4-phenylpyridinium; 2-oxothiadolazine-4-carboxylate; 3,4-dihydroxyphenylacetic acid; 3-morpholinosydnonimine; 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine 3-carboxylic acid; ABC; ASK1; ATP-binding cassette transporter; BBB; BSO; COMT; DA; DAT; DHBT-1; DOPAC; GCL; GPX; GSH; GSSG; GST; Glutathione; Glutathione S-transferase; HVA; JNK; LDH; LPS; MDRP; MPP(+); MPTP; N-acetylcysteine; NAC; OTC; Oxidative Stress; P-glycoprotein; PD; Parkinson disease; Parkinson's disease; Pgp; ROS; SIN1; SNpc; Substantia nigra; TH; VMAT2; apoptosis signal-regulating kinase 1; blood–brain barrier; c-Jun N-terminal kinase; catechol-O-methyltransferase; dopamine; dopamine transporter; glutamylcysteine ligase; glutathione; glutathione S-transferase; glutathione disulfide; glutathione peroxidase; homovanillic acid; l-buthionine-(S,R)-sulfoximine; lactate dehydrogenase; lipopolysaccharide; multidrug resistance protein; reactive oxygen species; substantia nigra pars compacta; tyrosine hydroxylase; vesicular monoamine transporter 2; γ-glutamyl-N-transpeptidase; γGT.

Figure 1

Glutathione synthesis pathway. Glutathione is synthesized from L-glutamate and L-cysteine in a 2-step reaction catalyzed in an ATP dependent manner by γ-glutamylcysteine ligase (GCL) (also referred to as γ-glutamylcysteine synthetase) and the addition of glycine by glutathione synthase. Glutathione can be recycled to its constitutive amino acids by γ-glutamyl-n-transferase and dipeptidase.

Figure 2

Schematic representation of glutathione synthesis and catabolism in the substantia nigra. Glutathione (GSH) synthesis occurs in astrocytes (green) and dopaminergic (DA) neurons (blue). GSH is synthesized from L-glutamate (Glu) and L-cysteine (Cys) by γ-glutamylcysteine ligase (GCL) and the addition of glycine by glutathione synthase. Once generated, the oxidized form of GSH (GSSG) can be recycled to reduced GSH by glutathione reductase (GR) and NADPH. Additionally, GSH and/or its conjugates can be recycled by γ-glutamyl transpeptidase (γGT). GSH reduces ROS generated by a number of agents that are transported through the dopamine transporter (DAT), including MPTP, MPP⁺, and rotenone, that block mitochondrial Complex I. GSH can also reduce direct redox agents such as paraquat (PQ) or DA adducts (DA quinone) and inflammatory cytokines released from microglia (pink). GSH maintenance and clearance of conjugated electrophiles requires energy in the form of ATP and NADPH. Hydrogen peroxide (H₂O₂) is reduced by glutathione peroxidase (GPx) to water using GSH. In DA neurons, the reduction of free radicals is catalyzed by conjugation of GSH to an electrophile by glutathione S-transferase pi (GSTp). Conjugated adducts are transported from the brain parenchyma through MDRPs, including Mrp1 and Mrp5 through the basolateral membrane into capillary endothelial cells. Once in these cells, other MDRPs, including P-gp and Mrp2 transport these to the bloodstream for excretion.