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. Author manuscript; available in PMC: 2019 Dec 1.
Published in final edited form as: J Neurochem. 2018 Nov 19;147(6):831–848. doi: 10.1111/jnc.14580

Figure 7: Proposed model for Mn-induced neurotoxicity.

Figure 7:

(a) Under physiological conditions, free ferrous iron (Fe2+) causes IRP1 release from iron responsive elements (IRE) that are located within the 5’-untranslated regions (5’-UTRs) of APP and H-Ferritin mRNA inducing enhanced ribosomal protein translation. To counteract toxic redox-active Fe2+ levels, APP facilitates the stabilization of membrane-bound Fe2+-exporter ferroportin (FPN) while H-Ferritin safely sequesters Fe2+ via conversion to redox-inactive Fe3+. (b) Manganese (Mn) decreases APP and H-Ferritin protein translation by increasing the binding of IRP1 to the IRE on the 5’-UTR of APP and H-Ferritin mRNA. Translational blockage of APP and H-Ferritin results in accumulation of toxic Fe2+ that fuels the generation of reactive oxygen species (ROS), ultimately resulting in neurotoxicity.