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Review

Targeting the Iron-Response Elements of the mRNAs for the Alzheimer’s Amyloid Precursor Protein and Ferritin to Treat Acute Lead and Manganese Neurotoxicity

1
Neurochemistry Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
2
Molecular Neurobiology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(4), 994; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20040994
Received: 13 January 2019 / Revised: 8 February 2019 / Accepted: 10 February 2019 / Published: 25 February 2019
(This article belongs to the Special Issue Translational Control)
The therapeutic value of inhibiting translation of the amyloid precursor protein (APP) offers the possibility to reduce neurotoxic amyloid formation, particularly in cases of familial Alzheimer’s disease (AD) caused by APP gene duplications (Dup–APP) and in aging Down syndrome individuals. APP mRNA translation inhibitors such as the anticholinesterase phenserine, and high throughput screened molecules, selectively inhibited the uniquely folded iron-response element (IRE) sequences in the 5’untranslated region (5’UTR) of APP mRNA and this class of drug continues to be tested in a clinical trial as an anti-amyloid treatment for AD. By contrast, in younger age groups, APP expression is not associated with amyloidosis, instead it acts solely as a neuroprotectant while facilitating cellular ferroportin-dependent iron efflux. We have reported that the environmental metallotoxins Lead (Pb) and manganese (Mn) cause neuronal death by interfering with IRE dependent translation of APP and ferritin. The loss of these iron homeostatic neuroprotectants thereby caused an embargo of iron (Fe) export from neurons as associated with excess unstored intracellular iron and the formation of toxic reactive oxidative species (ROS). We propose that APP 5’UTR directed translation activators can be employed therapeutically to protect neurons exposed to high acute Pb and/or Mn exposure. Certainly, high potency APP translation activators, exemplified by the Food and Drug Administration (FDA) pre-approved M1 muscarinic agonist AF102B and high throughput-screened APP 5’UTR translation activators, are available for drug development to treat acute toxicity caused by Pb/Mn exposure to neurons. We conclude that APP translation activators can be predicted to prevent acute metal toxicity to neurons by a mechanism related to the 5’UTR specific yohimbine which binds and targets the canonical IRE RNA stem loop as an H-ferritin translation activator. View Full-Text
Keywords: translational control; 5’untranslated regions (5’UTRs); Lead/manganese; neurotoxicity; iron; small molecule modulators; APP; ferritin translational control; 5’untranslated regions (5’UTRs); Lead/manganese; neurotoxicity; iron; small molecule modulators; APP; ferritin
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MDPI and ACS Style

Rogers, J.T.; Xia, N.; Wong, A.; Bakshi, R.; Cahill, C.M. Targeting the Iron-Response Elements of the mRNAs for the Alzheimer’s Amyloid Precursor Protein and Ferritin to Treat Acute Lead and Manganese Neurotoxicity. Int. J. Mol. Sci. 2019, 20, 994. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20040994

AMA Style

Rogers JT, Xia N, Wong A, Bakshi R, Cahill CM. Targeting the Iron-Response Elements of the mRNAs for the Alzheimer’s Amyloid Precursor Protein and Ferritin to Treat Acute Lead and Manganese Neurotoxicity. International Journal of Molecular Sciences. 2019; 20(4):994. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20040994

Chicago/Turabian Style

Rogers, Jack T., Ning Xia, Angela Wong, Rachit Bakshi, and Catherine M. Cahill 2019. "Targeting the Iron-Response Elements of the mRNAs for the Alzheimer’s Amyloid Precursor Protein and Ferritin to Treat Acute Lead and Manganese Neurotoxicity" International Journal of Molecular Sciences 20, no. 4: 994. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20040994

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