UC Santa Cruz

While chronic environmental exposure to manganese (Mn) is associated with neurocognitive and fine motor deficits in children, relatively little is understood about cellular responses to Mn spanning the transition between physiologic to toxic levels of exposure. Here, we investigated the specific, sensitive, and temporal response of Golgi Phosphoprotein 4 (GPP130) to Mn in AF5 GABAergic neuronal cells, and whether GPP130 degradation occurs in brain cells in vivo in rats subchronically exposed to Mn. Results show that GPP130 degradation is specific to Mn in AF5 cells, and does not occur following exposure to cobalt, copper, iron, nickel, or zinc. GPP130 degradation occurs without measurable increases in intracellular Mn levels and at Mn exposures as low as 0.54 µM. Furthermore, GPP130 protein was detected in only ~15 - 30 % of striatal and cortical brain cells in control animals, and Mn-exposed animals exhibited a significant reduction in both the number of GPP130-postive cells, and the overall cellular levels of GPP130 protein, demonstrating the in vivo relevance of this Mn-specific response within the primary target organ of Mn toxicity. These results may provide insight into important specific mechanism(s) of cellular Mn regulation and toxicity within the brain, including the selective susceptibility of cells to Mn cytoxicity.