5'-UTR Iron-responsive element of neurotoxic protein mRNAs (5'UTR-IRE)

The 5'-UTR Iron-responsive element (IRE) is a conserved RNA stem-loop structure located in the 5'-untranslated regions of mRNAs encoding several neurotoxic proteins, including amyloid precursor protein (APP), alpha-synuclein (SNCA), tau, and TDP-43. These elements serve as critical cis-acting regulatory motifs that control protein translation in response to cellular iron levels through interactions with Iron Regulatory Proteins (IRPs). Under low iron conditions, IRPs bind to the IRE, sterically blocking the recruitment of the 43S pre-initiation complex and thus repressing translation. In neurodegenerative diseases, iron accumulation or dysregulated IRP binding leads to the overproduction of these neurotoxic proteins, contributing to the formation of pathological aggregates like amyloid plaques and Lewy bodies. Small molecule drugs such as Posiphen (phenserine enantiomer) target these IRE structures to super-repress translation, effectively lowering the levels of multiple neurotoxic proteins simultaneously. This RNA-targeted approach offers a novel therapeutic strategy for treating a spectrum of neurodegenerative disorders by addressing the common mechanism of translational dysregulation.

Other names

IRE5'-UTR IREIron-responsive element type IIIRE-like stem loop5'-UTR Iron-responsive element

Translational inhibition via stabilization of the IRE-IRP complex or modulation of IRP binding to the 5'-UTR to prevent ribosome assembly.