Iron-responsive element (IRE)

The iron-responsive element (IRE) is a conserved RNA stem-loop structure located in the untranslated regions (UTRs) of mRNAs that encode proteins critical for iron metabolism and neurodegeneration. In the 5′-UTR of transcripts for amyloid precursor protein (APP), alpha-synuclein (SNCA), tau (MAPT), and TDP-43 (TARDBP), the IRE serves as a translational rheostat by binding to iron regulatory proteins (IRPs), primarily IRP1. Under physiological conditions, the binding of IRP1 to the 5′-UTR IRE sterically blocks the 40S ribosomal subunit from associating with the mRNA, thereby repressing protein translation. However, in states of iron overload or oxidative stress, IRP1 dissociates from the IRE, leading to the overproduction of neurotoxic proteins that aggregate and drive the progression of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Therapeutic agents like buntanetap (posiphen) target this system by increasing the affinity of IRP1 for the IRE, effectively stabilizing the repressor complex and suppressing the translation of multiple pathogenic proteins simultaneously. This RNA-directed approach aims to restore cellular proteostasis and mitigate the toxic cascade of protein aggregation and neurodegeneration.

Other names

Iron response element5′-UTR IREIRE-like motifIron-responsive element-like motifAtypical iron response element

Stabilization of the IRP1-IRE complex to inhibit mRNA translation