Acute Manganese Exposure Modifies the Translation Machinery via PI3K/Akt Signaling in Glial Cells

Manganese (Mn) exerts serious neurotoxic effects, among which, the disruption of the glutamate/glutamine (Glu/Gln) cycle, leads to an excitotoxic insult. The molecular mechanisms mediating Mn-induced neurotoxicity, have not yet been fully understood. Glu, the major excitatory neurotransmitter in the nervous system, activates a variety of signal transduction cascades involved in protein synthesis regulation. Although protein translation is an exquisitely regulated process, translational dysregulation has been observed in many neurodegenerative disorders. Hence, we investigated the effect of a short-term Mn exposure in signaling pathways critically involved in protein synthesis, such as the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) cascade. To this end, we used the well-characterized chick cerebellar Bergmann glial cells (BGC) primary culture. Confluent BGC monolayers were exposed to different MnCl(2) concentrations (50–500 μM) for different time periods. The phosphorylation patterns of Akt, the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) as well as the adenosine monophosphate-dependent protein kinase (AMPK) were measured. A time and dose-dependent increase in the phosphorylation status of these proteins was found, thus the involvement of a Ca(2+)/ PI3K/mTOR pathway could be demonstrated. Accordingly, a modulation of [(35)S]-methionine incorporation into newly synthesized polypeptides was found upon Mn acute exposure. These results demonstrate that Mn exerts triggers a change in the protein repertoire of glia cells that support their involvement in Mn neurotoxicity. SUMMARY STATEMENT: We demonstrate herein that short-term exposure of radial glia cells to Manganese, a neurotoxic metal, induces an effect on protein synthesis, altering the protein repertoire of these cells.