Journal article
Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H-Ferritin
V Venkataramani, TR Doeppner, D Willkommen, CM Cahill, Y Xin, G Ye, Y Liu, A Southon, A Aron, HY Au-Yeung, X Huang, DK Lahiri, F Wang, AI Bush, GG Wulf, P Ströbel, B Michalke, JT Rogers
Journal of Neurochemistry | WILEY | Published : 2018
DOI: 10.1111/jnc.14580
Abstract
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 a..
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Awarded by National Institutes of Health
Funding Acknowledgements
The authors gratefully thank Katharina Fernsebner (Helmholtz Zentrum Munchen) for providing rat brains and IC-ICP-OES data, Sabrina Becker (FACS core facility, University Medical Center Gottingen), Wong Fongying and Rachit Bakshi (Massachusetts General Hospital and Harvard Medical School) for excellent technical assistance, Susann Diegmann (Department of Neuropediatrics, University Medical Center Gottingen) for ALK Sanger sequencing of SH-SY5Y cells, Ulrike Muller (University Heidelberg) for providing APP<SUP>+/+</SUP> and APP<SUP>-/-</SUP> MEFs and Christopher J. Chang (University of California, Berkeley) for critical discussion and data analysis of IP-1 and Rho-Nox1 experiments, and Jens C. Hamann (Weil Cornell Medicine) for critical reading and editing of the manuscript. VV was supported by the intramural research grant (Forschungsforderung) of the University Medical Center Gottingen and the Else-Kroner-Fresenius Foundation. XH and JTR are partially supported by a NIH grant (R01AG056614 to XH). DKL is supported by a NIHR01 grant (AG051086 and P30AG010133). FW is supported by the National Natural Science Foundation of China (31530034, and 31330036). The authors have no conflict of interest to declare. The authors declare no conflict of interest whatsoever