Venkataramani V, Doeppner TR, Willkommen D, Cahill CM, Xin Y, Ye G, Liu Y, Southon A, Aron A, Au-Yeung HY, Huang X, Lahiri DK, Wang F, Bush AI, Wulf GG, Ströbel P, Michalke B, Rogers JT. Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H-Ferritin. J Neurochem. 2018 Dec;147(6):831-848. Epub 2018 Nov 19 PubMed.
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The University of Adelaide
This paper and others recently published (see below) illustrate the critical role played by APP in the regulation of cellular iron homeostasis. APP translation is controlled by the binding to its mRNA of Iron Regulatory Protein 1 (IRP1). Using SH-SY5Y cells, Venkararamani et al. demonstrated that the toxic effect of excessive manganese exposure is due, at least in part, to the fact that it increased the suppression of APP translation by IRP1 despite the fact that the Mn exposure simultaneously increased the level of APP mRNA threefold. (These observations are similar to those of a 2016 paper looking at lead toxicity (Rogers et al.). The suppression of APP translation (and translation of other proteins required for iron homeostasis) by Mn led to an increased ratio of ferrous to ferric iron ions and increased oxidative stress. Forced overexpression of APP was able to counter, partially, the toxicity of Mn exposure.
The Venkararamani et al. paper was published almost simultaneously with a paper by Belaidi et al. analyzing iron homeostasis in APP KO mice. As expected, Ferroportin levels were reduced, thus limiting the ability of cells in the brain (presumably neurons) to export iron. Iron accumulated in the brains of aged mice although, intriguingly, not excessively in ferritin. Similar observations of iron accumulation in the brains of APP knockout mice were published in 2014 by Needham et al. and Ciccotosto et al.
Interestingly, the importation of iron into cells, and intracellular recycling of iron from its inactive ferric form to its active ferrous form, is largely dependent on correct endo-lysosomal acidification which Lee et al. and subsequent publications have shown to be deficient in PRESENILIN 1 fAD mutant cells. This has led us to speculate in a recently published hypothesis paper that an effect-in-common of the fAD mutations in APP and the PSEN genes may be disruption of iron homeostasis with subsequent deleterious effects on mitochondrial function, levels of oxidative stress, inflammation and other factors that are central to neurodegenerative disease (Lumsden et al., 2018). While there is an extensive literature supporting the role of iron in late onset neurodegenerative disease including Alzheimer’s disease (e.g. including the recent paper by Bulk et al., the idea that iron dyshomeostasis may play a central role in early onset, familial Alzheimer’s disease has not been studied in depth.
References:
Rogers JT, Venkataramani V, Washburn C, Liu Y, Tummala V, Jiang H, Smith A, Cahill CM. A role for amyloid precursor protein translation to restore iron homeostasis and ameliorate lead (Pb) neurotoxicity. J Neurochem. 2016 Aug;138(3):479-94. PubMed.
Belaidi AA, Gunn AP, Wong BX, Ayton S, Appukuttan AT, Roberts BR, Duce JA, Bush AI. Marked Age-Related Changes in Brain Iron Homeostasis in Amyloid Protein Precursor Knockout Mice. Neurotherapeutics. 2018 Oct;15(4):1055-1062. PubMed.
Needham BE, Ciccotosto GD, Cappai R. Combined deletions of amyloid precursor protein and amyloid precursor-like protein 2 reveal different effects on mouse brain metal homeostasis. Metallomics. 2014 Mar;6(3):598-603. Epub 2014 Jan 21 PubMed.
Ciccotosto GD, James SA, Altissimo M, Paterson D, Vogt S, Lai B, de Jonge MD, Howard DL, Bush AI, Cappai R. Quantitation and localization of intracellular redox active metals by X-ray fluorescence microscopy in cortical neurons derived from APP and APLP2 knockout tissue. Metallomics. 2014 Oct;6(10):1894-904. Epub 2014 Aug 7 PubMed.
Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, Wolfe DM, Martinez-Vicente M, Massey AC, Sovak G, Uchiyama Y, Westaway D, Cuervo AM, Nixon RA. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell. 2010 Jun 25;141(7):1146-58. PubMed.
Lumsden AL, Rogers JT, Majd S, Newman M, Sutherland GT, Verdile G, Lardelli M. Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer's Disease. Front Neurosci. 2018;12:533. Epub 2018 Aug 13 PubMed.
Bulk M, Kenkhuis B, van der Graaf LM, Goeman JJ, Natté R, van der Weerd L. Postmortem T2*- Weighted MRI Imaging of Cortical Iron Reflects Severity of Alzheimer's Disease. J Alzheimers Dis. 2018;65(4):1125-1137. PubMed.
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