Missing link: Parkinson's disease and manganese toxicity.

摘要

Although manganese (Mn) plays an essential role for normal metabolic function, chronic exposure to high atmospheric levels in the workplace has been shown to result in a disorder known as manganism which closely resembles the dystonic movements associated with Parkinson's disease. Although the neurologic sites of the two disorders are different, it has been suggested that some people who experience overexposed to Mn are more likely to develop Parkinson's disease (PD) due to genetic defects. In a reciprocal fashion, there is evidence that susceptibility to manganism may be associated with genes that induce early onset of Parkinsonism. Guilarte et al. 1 2 reported that Mn may induce Parkinson-like symptoms by impairing nigrostriatal dopamine transmission. Thus, it would be of interest to examine the relationship between Parkinson's and manganism. Accordingly, my project examined the interaction of dopamine (DA) and Mn on cell viability in the normal HEK-293 cells and those transfected with YFP-DAT (dopamine transporter).;Results of these studies demonstrate that Mn toxicity is equivalent in the two cell lines indicating that the presence of DAT does not interfere with Mn cytotoxicity. In contrast, dopamine was found to be more toxic in the cells possessing DAT. When the two substances were exposed simultaneously to the DAT containing HEK cells, only Mn toxicity was observed in the cell viability assay which suggesting that Mn was interfering with dopamine transport. When dopamine was preincubated prior to the addition of Mn, an additive response was observed between the two neurotoxins. Results from my study suggest that Mn may function to inhibit DAT and prevent the internalization of dopamine.;My work has also established conditions for DJ-1 knockdown with DJ-1 being a gene where mutations lead to early onset PD. DJ-1 is believed to affect antioxidant responses in the cells thus it is of interest of learn how Mn and DA toxicities respond to DJ-1 knockdown.