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Targeting the Iron-Response Elements of the mRNAs for the Alzheimer’s Amyloid Precursor Protein and Ferritin to Treat Acute Lead and Manganese Neurotoxicity
- Source :
- International Journal of Molecular Sciences, Vol 20, Iss 4, p 994 (2019), International Journal of Molecular Sciences
- Publication Year :
- 2019
- Publisher :
- MDPI AG, 2019.
-
Abstract
- 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.
- Subjects :
- small molecule modulators
Quinuclidines
Review
Pharmacology
5’untranslated regions (5’UTRs)
lcsh:Chemistry
Amyloid beta-Protein Precursor
Mice
iron
neurotoxicity
Amyloid precursor protein
lcsh:QH301-705.5
Spectroscopy
Lead/manganese
Neurons
biology
Chemistry
Manganese Poisoning
Iron-Regulatory Proteins
translational control
Translation (biology)
General Medicine
Computer Science Applications
Lead Poisoning, Nervous System
Acute Disease
Intracellular
Thiophenes
Muscarinic Agonists
Response Elements
Muscarinic agonist
Catalysis
Inorganic Chemistry
Alzheimer Disease
mental disorders
medicine
Animals
Humans
RNA, Messenger
Physical and Theoretical Chemistry
Molecular Biology
Messenger RNA
Activator (genetics)
Organic Chemistry
ferritin
Neurotoxicity
medicine.disease
Rats
Ferritin
lcsh:Biology (General)
lcsh:QD1-999
Protein Biosynthesis
Ferritins
biology.protein
Down Syndrome
5' Untranslated Regions
APP
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Volume :
- 20
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....bc820eb15ada2e63823b8ee2aee68542