Iron-responsive element in neurodegenerative protein mRNAs (APP, MAPT, SNCA, TARDBP) (IRE (APP/Tau/SNCA/TDP-43))

The Iron-responsive element (IRE) regions in the mRNAs of Amyloid Precursor Protein (APP), Tau (MAPT), alpha-synuclein (SNCA), and TDP-43 (TARDBP) are conserved RNA stem-loop structures located in the 5' untranslated regions (UTRs) that regulate protein translation in response to cellular iron levels (Rogers et al., 2002; Friedlich et al., 2007). These elements bind Iron Regulatory Proteins (IRP1 and IRP2); under low iron conditions, IRPs bind the IRE to sterically hinder the assembly of the 43S translation initiation complex, thereby suppressing protein synthesis. In neurodegenerative diseases such as Alzheimer's and Parkinson's, iron dysregulation leads to the chronic overproduction of these neurotoxic proteins, which aggregate into pathological plaques and tangles. Therapeutic targeting of these IRE regions, primarily through small molecules like Posiphen (Buntanetap), aims to stabilize the IRE-IRP complex or mimic IRP binding to downregulate the translation of APP, Tau, and alpha-synuclein (Moussa et al., 2020). This translational control mechanism represents a multi-target approach, as a single drug can reduce the levels of several distinct pathogenic proteins by exploiting their shared regulatory motif. Clinical development of such agents focuses on improving cognitive and motor functions by lowering the overall burden of protein aggregation in the brain.

Other names

5'-UTR Iron-responsive elementIRE-type RNA stem-loopAPP 5'-UTR IRESNCA 5'-UTR IREMAPT 5'-UTR IRETARDBP 5'-UTR IREIron-regulatory element

Small molecule-mediated stabilization of the 5'-UTR IRE-IRP complex or direct binding to the IRE stem-loop to sterically inhibit the recruitment of the 40S ribosomal subunit, thereby suppressing the translation of neurotoxic proteins.