A Sensitive and Selective Cellular Target of Manganese Exposure

March 13, 2013

Manganese (Mn) exposure in rats reduces brain GPP130 levels in vivo.  Figure shows representative IHC photomicrographs of brain cortex labeled with GPP130 (green) and Draq5 nuclear DNA stain (red).  Upper panels are from a control animal; lower panels from a Mn-exposed animal (for both, left panel x20 magnification, right panel x63 magnification).

Little is known about how cells respond to manganese (Mn) over the transition from physiologic to toxicologic exposure, though how cells respond may shed light on the mechanism(s) of Mn neurotoxicity.  The role of cellular Mn regulation and the selective susceptibility of some cells to Mn cytotoxicity in the brain have been explored in a recent study by researchers at the University of California, Santa Cruz.  

In a recent study published in Synapse (Early View, December 26, 2012; Issue 67, Volume 5), lead author Melisa Masuda investigated the cellular responses to Mn at very low exposure levels spanning the transition between physiologic to toxic levels.  The study focused on a recently reported effect of Mn to cause the degradation of Golgi Phosphoprotein 4 (GPP130), a cis-Golgi associated protein that is responsible for the cellular trafficking of protein cargo from the endosome to the Golgi.   

In Masuda’s study, the nature of the GPP130 response was investigated in detail in AF5 GABAergic neuronal cells, and in vivo in a rodent model.  The findings show that GPP130 degradation in AF5 cells was specific to Mn, and did not occur following exposure to other metals such as cobalt, copper, iron, nickel, or zinc.  Moreover, GPP130 degradation was highly sensitive to Mn exposure, occurring at supra-physiologic exposure levels, below those that produced measureable increases in intracellular Mn. Masuda also observed a close temporal association between changes in intracellular Mn levels and GPP130 degradation, suggesting a possible role for GPP130 in cellular Mn homeostasis (e.g., loss of GPP130 favors cellular Mn efflux).

Masuda then confirmed that a similar GPP130 degradation response to Mn occurred in brain cells in vivo in rats subchronically exposed to Mn.  This study was the first to show GPP130 localization in brain cells in vivo, and showed that the protein was detectable by immunofluorescence in only ∼15–30% of cells in striatal and cortical rat brain slices.  Additionally, Mn-exposed animals exhibited a significant reduction in both the number of GPP130-positive cells, and the overall levels of GPP130 protein, demonstrating the in vivo relevance of this Mn-specific response within the primary target organ of Mn toxicity.

Melisa Masuda, a graduate student in the Microbiology and Environmental Toxicology program at UC Santa Cruz, is the first author of the Synapse paper.  Co-authors Michelle Braun-Sommargren and Dan Crooks are former members of the laboratory of senior author Donald Smith.  This work was supported by a grant from the National Institutes of Health.