PuSH - Publikationsserver des Helmholtz Zentrums München: Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H-Ferritin.

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Venkataramani, V.* ; Doeppner, T.R.* ; Willkommen, D. ; Cahill, C.M.* ; Xin, Y.* ; Ye, G.* ; Liu, Y.* ; Southon, A.* ; Aron, A.* ; Au-Yeung, H.Y.* ; Huang, X.* ; Lahiri, D.K.* ; Wang, F.* ; Bush, A.I.* ; Wulf, G.G.* ; Ströbel, P.* ; Michalke, B. ; Rogers, J.T.*

Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H-Ferritin.

J. Neurochem. 147, 831-848 (2018)

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For more than 150 years, it is known that occupational overexposure of manganese (Mn) causes movement disorders resembling Parkinson's disease (PD) and PD-like syndromes. However, the mechanisms of Mn toxicity are still poorly understood. Here, we demonstrate that Mn dose- and time-dependently blocks the protein translation of amyloid precursor protein (APP) and heavy-chain Ferritin (H-Ferritin), both iron homeostatic proteins with neuroprotective features. APP and H-Ferritin are post-transcriptionally regulated by iron responsive proteins, which bind to homologous iron responsive elements (IREs) located in the 5 '-untranslated regions (5 '-UTRs) within their mRNA transcripts. Using reporter assays, we demonstrate that Mn exposure repressed the 5 '-UTR-activity of APP and H-Ferritin, presumably via increased iron responsive proteins-iron responsive elements binding, ultimately blocking their protein translation. Using two specific Fe2+-specific probes (RhoNox-1 and IP-1) and ion chromatography inductively coupled plasma mass spectrometry (IC-ICP-MS), we show that loss of the protective axis of APP and H-Ferritin resulted in unchecked accumulation of redox-active ferrous iron (Fe2+) fueling neurotoxic oxidative stress. Enforced APP expression partially attenuated Mn-induced generation of cellular and lipid reactive oxygen species and neurotoxicity. Lastly, we could validate the Mn-mediated suppression of APP and H-Ferritin in two rodent in vivo models (C57BL6/N mice and RjHan:SD rats) mimicking acute and chronic Mn exposure. Together, these results suggest that Mn-induced neurotoxicity is partly attributable to the translational inhibition of APP and H-Ferritin resulting in impaired iron metabolism and exacerbated neurotoxic oxidative stress.

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