Iron-responsive element in the 5'-untranslated region of neurotoxic protein mRNAs (5'-UTR IRE)

The Iron-responsive element (IRE) is a highly conserved RNA stem-loop structure located in the 5'-untranslated region (UTR) of mRNAs for several key neurotoxic proteins, most notably the Amyloid Precursor Protein (APP), alpha-synuclein (SNCA), and the Prion protein (PrP) (Rogers et al., 2002; Friedlich et al., 2007). These elements function as critical post-transcriptional regulators that coordinate protein synthesis with cellular iron availability. In the absence of sufficient iron, Iron Regulatory Proteins (IRP1 and IRP2) bind to the 5'-UTR IRE, creating a steric block that prevents the 43S pre-initiation complex from scanning the mRNA, thus inhibiting translation (Muckenthaler et al., 2017). In neurodegenerative conditions such as Alzheimer's and Parkinson's diseases, iron dyshomeostasis often leads to the pathological upregulation of these proteins. Therapeutic agents like Buntanetap (Posiphen) are designed to target these IRE structures or the IRE-IRP interaction to suppress the translation of neurotoxic species, thereby reducing the accumulation of amyloid plaques and Lewy bodies (Chen-Plotkin et al., 2022). This approach represents a novel strategy for disease modification by intervening at the level of protein production rather than clearance.

Other names

IRE stem-loop5'-UTR iron-responsive elementAPP 5'-UTR IRESNCA 5'-UTR IREPrP 5'-UTR IREIron-regulatory element

Small molecules bind to or stabilize the IRE-IRP complex or otherwise interfere with the 5'-UTR-mediated translation initiation to reduce the synthesis of neurotoxic proteins.