Protection of intracellular dopamine cytotoxicity by dopamine disposition and metabolism factors.
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.
Weingarten
P
P
Department of Pharmacology, University of California, Irvine 92697, USA.
Zhou
Q Y
QY
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D053938:DNA Fragmentation; D004298:Dopamine / Q000378:metabolism* / Q000633:toxicity*; D015870:Gene Expression; D005982:Glutathione Transferase / Q000235:genetics / Q000502:physiology; D007980:Levodopa / Q000633:toxicity; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000502:physiology; D008543:Melanins / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D026901:Membrane Transport Proteins; D008995:Monoamine Oxidase / Q000235:genetics / Q000502:physiology; D009479:Neuropeptides; D010084:Oxidation-Reduction; D014162:Transfection; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D008263:Macrophage Migration-Inhibitory Factors; D008543:Melanins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D007980:Levodopa; D008995:Monoamine Oxidase; D005982:Glutathione Transferase; D004298:Dopamine