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

Vivek Venkataramani, Thorsten R. Doeppner, Desiree Willkommen, Catherine M. Cahill, Yongjuan Xin, Guilin Ye, Yanyan Liu, Adam Southon, Allegra Aron, Ho Yu Au-Yeung, Xudong Huang, Debomoy Lahiri, Fudi Wang, Ashley I. Bush, Gerald G. Wulf, Philipp Ströbel, Bernhard Michalke, Jack T. Rogers

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 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. Open Data: Materials are available on https://cos.io/our-services/open-science-badges/. https://osf.io/93n6m/. (Figure presented.).

Original languageEnglish (US)
JournalJournal of Neurochemistry
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Apoferritins
Amyloid beta-Protein Precursor
Manganese
Iron
Oxidative stress
5' Untranslated Regions
Protein Biosynthesis
Parkinson Disease
Proteins
Oxidative Stress
Iron-Regulatory Proteins
Ion chromatography
Inductively coupled plasma mass spectrometry
Fueling
Movement Disorders
Metabolism
Oxidation-Reduction
Toxicity
Chromatography
Rats

Keywords

  • amyloid precursor protein (APP)
  • H-ferritin
  • iron responsive element (IRE)
  • manganese (Mn)
  • reactive oxygen species (ROS)
  • SH-SY5Y neural-like cell line

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Venkataramani, V., Doeppner, T. R., Willkommen, D., Cahill, C. M., Xin, Y., Ye, G., ... Rogers, J. T. (Accepted/In press). Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H-Ferritin. Journal of Neurochemistry. https://doi.org/10.1111/jnc.14580

Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H-Ferritin. / Venkataramani, Vivek; Doeppner, Thorsten R.; Willkommen, Desiree; Cahill, Catherine M.; Xin, Yongjuan; Ye, Guilin; Liu, Yanyan; Southon, Adam; Aron, Allegra; Au-Yeung, Ho Yu; Huang, Xudong; Lahiri, Debomoy; Wang, Fudi; Bush, Ashley I.; Wulf, Gerald G.; Ströbel, Philipp; Michalke, Bernhard; Rogers, Jack T.

In: Journal of Neurochemistry, 01.01.2018.

Research output: Contribution to journalArticle

Venkataramani, V, Doeppner, TR, Willkommen, D, Cahill, CM, Xin, Y, Ye, G, Liu, Y, Southon, A, Aron, A, Au-Yeung, HY, Huang, X, Lahiri, D, Wang, F, Bush, AI, Wulf, GG, Ströbel, P, Michalke, B & Rogers, JT 2018, 'Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H-Ferritin', Journal of Neurochemistry. https://doi.org/10.1111/jnc.14580
Venkataramani, Vivek ; Doeppner, Thorsten R. ; Willkommen, Desiree ; Cahill, Catherine M. ; Xin, Yongjuan ; Ye, Guilin ; Liu, Yanyan ; Southon, Adam ; Aron, Allegra ; Au-Yeung, Ho Yu ; Huang, Xudong ; Lahiri, Debomoy ; Wang, Fudi ; Bush, Ashley I. ; Wulf, Gerald G. ; Ströbel, Philipp ; Michalke, Bernhard ; Rogers, Jack T. / Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H-Ferritin. In: Journal of Neurochemistry. 2018.
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AU - Xin, Yongjuan

AU - Ye, Guilin

AU - Liu, Yanyan

AU - Southon, Adam

AU - Aron, Allegra

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AU - Huang, Xudong

AU - Lahiri, Debomoy

AU - Wang, Fudi

AU - Bush, Ashley I.

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N2 - 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. Open Data: Materials are available on https://cos.io/our-services/open-science-badges/. https://osf.io/93n6m/. (Figure presented.).

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