Dopaminergic toxicity of 1-methyl-4-phenylpyridinium (MPP+): Model for Parkinson’s disease

Abstract

Parkinson's disease (PD) is among the most common neurodegenerative diseases. Approximately 60,000 Americans are diagnosed with this disease every year. The cause or cure for PD remains unknown. MPP+ is a dopaminergic neurotoxin that induces symptoms similar to PD and commonly used as a good model to study the molecular causes of PD. The specific dopaminergic toxicity of MPP+ is proposed to be due to the uptake through dopamine transporter (DAT) followed by the inhibition of complex I of the electron transport chain leading to cellular energy starvation. However, this proposal has not been conclusively established. We investigated the mechanism of MPP+ toxicity using MN9D (neuronal) and HepG2 (non-neuronal) cell models. Our studies show that both cells take-up substantial levels of MPP+ under similar experimental conditions, while only MN9D cells are susceptible to MPP+toxicity. MPP+ toxicity is independent of DAT in MN9D cells. Extracellular Ca2+decreases MPP+ uptake into MN9D cells, but has no effect on the toxicity. Voltage-gated Ca2+ channel blockers decrease the MPP+ uptake into MN9D cells, but again do not protect the MN9D cell from MPP+ toxicity. These and other findings suggest a novel mechanism in which MPP+ perturb intracellular Ca2+ leading to neuronal cell death. The understanding of the causes of PD at the molecular level could lead to the development of therapeutic and preventive measures.