Iron-responsive element (IRE) sequences in mRNA of neurotoxic proteins (IRE)

Iron-responsive element (IRE) sequences are conserved stem-loop structures located in the untranslated regions (UTRs) of mRNAs that encode proteins involved in iron metabolism and neurodegeneration. In the 5'-UTR of mRNAs for neurotoxic proteins like amyloid precursor protein (APP) and alpha-synuclein, the IRE acts as a translational rheostat that responds to cellular iron levels through the binding of iron regulatory proteins (IRPs). Under conditions of iron overload or oxidative stress, the translation of these neurotoxic proteins is upregulated, contributing to the pathogenesis of Alzheimer's and Parkinson's diseases. Therapeutic strategies target these RNA structures with small molecules to suppress the translation of pathogenic proteins without affecting their steady-state mRNA levels. By stabilizing the IRE-IRP complex or mimicking iron-depleted states, these drugs aim to reduce the accumulation of toxic protein aggregates in the brain. This approach represents a novel post-transcriptional mechanism for treating neurodegenerative disorders by modulating the brain's metal-linked proteotoxicity (Bandyopadhyay et al., 2013; Rogers et al., 2002).

Other names

Iron-responsive elementIRE-mRNA5'-UTR iron-responsive elementAmyloid precursor protein IREAlpha-synuclein IREPrion protein IRE

Small molecules bind to the 5'-untranslated region (UTR) of specific mRNAs containing an iron-responsive element (IRE) to inhibit the translation of neurotoxic proteins such as amyloid precursor protein (APP) and alpha-synuclein. This often involves stabilizing the IRE stem-loop structure or modulating the binding affinity of iron regulatory proteins (IRPs), thereby preventing the recruitment of the ribosome and reducing the production of pathogenic protein aggregates (Cahill et al., 2009; Rogers et al., 2016).