Neurotoxicology of dietary iron/manganese interactions

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Manganese is an essential nutrient for humans and other mammals, and it functions as a critical cofactor for many key enzymes involved in cellular metabolism. However, exceedingly high brain manganese concentrations are known to cause neurotoxicity with symptoms similar to Parkinson's disease (PD). Recent rodent studies have linked dietary iron deficiency with excessive brain manganese accumulation, specifically in dopamine-rich brain regions. To date, it is still unknown how and why manganese accumulation occurs primarily in these brain regions, although it has been hypothesized that the dopamine transporter may mediate this process. The objective of this project is to specifically determine the mechanism by which manganese accumulation targets dopamine-rich brain regions and establish neurochemical changes associated with manganese neurotoxicity. The first aim of the project is to ascertain the role of the dopamine transporter in the accumulation of manganese into dopamine-rich brain regions. Both in vivo and in vitro studies are proposed which will utilize dietary and pharmacological manipulations to accomplish this aim. The second aim of the project is to identify neurochemical alterations in dopaminergic regions due to both manganese neurotoxicity and manganese accumulation caused by dietary iron deficiency. Recent studies suggest that the extrapyramidal symptoms of manganese neurotoxicity are due to abnormal gamma-aminobutryic acid (GABA) metabolism which may indirectly alter dopamine neurobiology causing PD-like behaviors. Disturbances in GABA metabolism have also been linked to manganese accumulation due to iron deficiency. Proposed in vivo microdialysis studies will determine whether iron status represents a risk factor for neurochemical alterations that are exacerbated by manganese accumulation. If successful, these studies will lay the foundation for the development of a pharmacological therapy aimed at the prevention of manganese-accumulation in vulnerable populations.