Potential Roles of Accelerated Dopamine Oxidation, Altered Glutathione Metabolism, 5-S-Cysteinyl-Dopamine and its Oxidative Metabolites in the Pathogenesis of Parkinson’s Disease

Abstract

Many factors appear to be involved in the neurotoxic mechanism that underlies the degeneration of neuromelanin-pigmented dopaminergic neurons in the substantia nigra pars compacta (SNpc) in Parkinson's disease (PD). These include: (1) a massive loss of glutathione (GSH) without corresponding increases of glutathione disulfide, a very early change in the parkinsonian SNpc; (2) increased intraneuronal superoxide (O-2(-.)) generation; (3) mobilization of low molecular weight iron from storage proteins, part of which is scavenged by neuromelanin; (4) increased activity of gamma -glutamyl transpeptidase; (5) an accelerated rate of dopamine (DA) oxidation that does not lead to increased neuromelanin deposition but rather increased formation of 5-S-cysteinyldopamine (5-S-CyS-DA); and (6) decreased activities of mitochondrial complex I and a-ketoglutarate dehydrogenase (alpha -KGDH). Based on these changes and information derived from studies of the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and methamphetamine, a new pathological mechanism is proposed that might contribute to an understanding of SNpc cell death in PD. This neurotoxic mechanism is suggested to be initiated by a transient dopaminergic neuron energy impairment that triggers a cascade of processes which ultimately result in the intraneuronal oxidation of DA by O-2(-.) in the presence of cysteine to form 5-S-CyS-DA. Further O-2(-.)-mediated oxidation of 5-S-CyS-DA is proposed to lead to aberrant dihydrobenzothiazine and benzothiazine metabolites responsible for complex I and alpha -KGDH inhibition.