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Protection of intracellular dopamine cytotoxicity by dopamine disposition and metabolism factors
Author(s) -
Weingarten Paul,
Zhou QunYong
Publication year - 2001
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2001.00263.x
Subject(s) - dopamine , dopaminergic , vesicular monoamine transporter , monoamine oxidase , intracellular , dopamine transporter , aromatic l amino acid decarboxylase , biology , pharmacology , cytotoxicity , chemistry , microbiology and biotechnology , biochemistry , monoamine neurotransmitter , endocrinology , enzyme , serotonin , in vitro , receptor
Dopamine has been hypothesized as a contributing factor for the selective degeneration of dopaminergic neurons in Parkinson's disease. However, the cytotoxic mechanisms of dopamine and its metabolites remain poorly understood. Using a stable aromatic amino acid decarboxylase (AADC) expressing a fibroblast cell line, we previously demonstrated a novel, non‐oxidative cytotoxicity of intracellular dopamine. In this study, we further investigate the roles of dopamine metabolism and disposition proteins against intracellular dopamine cytotoxicity by co‐expressing these factors in AADC‐expressing cells. Our results indicate that overexpression of the vesicular monoamine transporter and monoamine oxidase A‐induced protection against intracellular dopamine toxicity, and conversely that pharmacological inhibition of these pathways potentiated l ‐DOPA toxicity in catecholaminergic PC12 cells. Macrophage migration inhibitory factor and glutathione S ‐transferase (GST), factors that have recently been shown to be involved in dopamine metabolism, also exhibited a strong protective role against intracellular dopamine cytotoxicity. Our results support a potential role for non‐oxidative cytoplasmic dopamine toxicity, and imply that disruption in dopamine disposition and/or metabolism could underlie the progressive degeneration of dopaminergic neurons in Parkinson's disease.