Iron-responsive element in the 5'-untranslated region of microtubule-associated protein tau mRNA (Tau 5'-UTR IRE)

The iron-responsive element (IRE) in the 5'-untranslated region (5'-UTR) of the microtubule-associated protein tau (MAPT) mRNA is a specialized RNA stem-loop structure that serves as a post-transcriptional regulator of tau protein synthesis. This element functions by binding Iron Regulatory Proteins (IRP1 and IRP2) under conditions of low intracellular iron, which sterically blocks the recruitment of the translation initiation machinery and reduces tau production (Cho et al., 2010; Lei et al., 2012). In states of iron overload, IRPs dissociate from the IRE, allowing for increased translation of tau, a process implicated in the pathogenesis of Alzheimer's disease and other tauopathies where tau protein accumulates and aggregates (Rogers et al., 2011). As a therapeutic target, this RNA structure is unique because it allows for the modulation of tau levels at the translational level rather than targeting the protein after it has already been synthesized or aggregated. Small molecules like Posiphen ((+)-phenserine) have been shown to target this 5'-UTR to lower tau expression, offering a potential disease-modifying strategy for neurodegeneration (Moussa et al., 2020). Understanding the interaction between iron levels and tau translation through this IRE provides a critical link between metabolic dysregulation and neurotoxic protein accumulation.

Other names

Tau IREMAPT 5'-UTR IRETau mRNA 5'-untranslated region stem-loopIron-responsive element of MAPT

Small molecules bind to the 5'-UTR IRE stem-loop to stabilize the structure or enhance Iron Regulatory Protein (IRP) binding, thereby sterically hindering the 43S translation initiation complex and suppressing the translation of tau mRNA into tau protein (Rogers et al., 2011; Cho et al., 2010).