Iron-responsive element (IRE) (IRE)

The target consists of iron-responsive elements (IREs) located in the 5' untranslated regions (UTRs) of mRNAs encoding proteins central to neurodegeneration, including amyloid precursor protein (APP), α-synuclein, tau, TDP-43, huntingtin, and prion protein (Zhou and Tan, 2017; Chen et al., 2021). These IREs are conserved stem-loop RNA structures that bind to iron regulatory protein 1 (IRP1) to post-transcriptionally regulate protein synthesis in response to cellular iron levels (Rogers et al., 2019). Under low iron conditions, IRP1 binds the IRE with high affinity, sterically hindering the assembly of the 40S ribosomal subunit and thereby inhibiting translation (Zhou and Tan, 2017). Conversely, high iron levels cause IRP1 to dissociate, allowing translation to proceed (Rogers et al., 2019). In neurodegenerative diseases, iron dyshomeostasis often leads to the pathological overexpression of these toxic proteins (Bush, 2013). Therapeutic agents like buntanetap (posiphen) act as translational inhibitors of neurotoxic aggregating proteins (TINAPs) by stabilizing the IRE-IRP1 complex, effectively suppressing the production of these proteins regardless of iron concentration to reduce the formation of toxic aggregates (Chen et al., 2021; Maccecchini et al., 2012).

Other names

IRE-IRP1 complex5' UTR iron-responsive elementTranslational control elementAtypical iron-responsive elementIron-responsive element regions in mRNAs of APP, α-synuclein, tau, TDP-43, huntingtin, and prion protein via IRP1

Stabilization of the Iron-responsive element (IRE) and Iron regulatory protein 1 (IRP1) complex in the 5' untranslated region (UTR) of target mRNAs, which sterically blocks the recruitment of the 40S ribosomal subunit and inhibits translation.