Divalent metal transporter 1 up-regulation is involved in the 6-hydroxydopamine-induced ferrous iron influx

The reasons underlying the high iron content found in the substantia nigra (SN) of Parkinson's disease (PD) are largely unknown. We suppose, based on our previous studies, that the newly discovered iron transporter divalent metal transporter 1 (DMT1) might be involved in this SN iron accumulation process. To investigate this, we first observed the cellular expression of DMT1 in rat SN, both with the iron response element (+IRE) and without the IRE (-IRE) forms. The results showed that both forms of DMT1 were expressed on neurons, astrocytes, and microglia but not on oligodendrocytes. We further observed the relationship between the increased iron influx and DMT1 expression in 6-hydroxydopamine (6-OHDA)-treated C6 cells. 6-OHDA (10 μmol/liter) caused a significant increase in ferrous iron influx, with the increased expression of DMT1+IRE, both in protein and in mRNA levels, whereas no change was observed for DMT1-IRE. To clarify further that the increased expression of DMT1 was not due to the increased intracellular iron content, C6 cells were overloaded with ferric ammonium citrate (100 μg/ml). Decreased expression of both forms of DMT1 was observed. Our data suggest that DMT1 is highly expressed in rat SN in a cell-specific manner. Increased DMT1+IRE expression is the mechanism behind ferrous iron influx induced by 6-OHDA treatment in C6 cells. This may give some evidence for the involvement of DMT1 in the iron accumulation in PD.