Until recently the mechanism for this intracellular iron accumulation was unknown but new studies point to DMT1 misregulation as a primary cause. DMT1 can directly transport iron into the cell and is also required for iron exit from vesicles containing transferrin-bound iron. Thus, DMT1 plays a critical role in regulating overall iron levels in the cell. In the brain, the Gefitinib abundance of DMT1 has been found to increase with age, suggesting a link between the transporter and metal misregulation in the development of age-based neurodegeneration. Consistent with this interpretation, postmortem PD brains contain more DMT1 compared to age-matched controls. In animal studies, a direct link between DMT1 function and dopaminergic neuronal loss has been found. A spontaneous mutation in DMT1 found in both the mk mouse and Belgrade rat, results in deficits in iron transport. Experiments using both rodent mutants have shown that the animals are protected against experimentally induced PD using neurotoxins MPTP and 6- hydroxydopamine. These results implicate a functional DMT1 gene with susceptibility to PD and a parsimonious interpretation would suggest that PD is linked to the failure of metal homeostasis. The principle aim of this study was to identify changes in Ndfip1 expression in control and PD brains given that we have previously identified regulation of DMT1 by Ndfip1. To pursue this, we first studied the involvement of Ndfip1 in regulating DMT1 levels as well as cell survival during iron toxicity using mouse dopaminergic neurons. Secondly, we examined the levels of Ndfip1 and iron in the substantia nigra of PD brains and compared these with controls using biochemical analysis to identify changes in protein expression and metal concentrations. Thirdly, upregulate Ndfip1 within the substantia nigra. Finally, we studied the expression of Ndfip1 with known markers of PD pathology to correlate the levels of Ndfip1 with neuronal stress. Our overall results show that Ndfip1 is upregulated in dopaminergic neurons and abnormally upregulated in astrocytes within the substantia nigra of PD brains, suggesting that Ndfip1 is responsive to the disease process and even abnormally activated in non-neuronal cells. Given the known role of Ndfip1 in regulating DMT1 and protecting neurons against stress, our results suggest that upregulation of Ndfip1 might represent attempts to regulate metal levels in PD pathogenesis. In PD, dopaminergic neurons of the substantia nigra are preferentially susceptible to the misregulation of iron as the metabolism of dopamine gives rise to various molecules that can act as endogenous toxins in the presence of iron. The resulting oxidative stress can inhibit proteasome function and result in the formation of protein aggregates, a hallmark of PD pathology. It is therefore of interest to determine if dopaminergic neurons have protective pathways against metal toxicity. In this study, we report the upregulation of the E3 ligase adaptor protein Ndfip1 in PD brains.