Iron-responsive element in the 5'-untranslated region of TAR DNA-binding protein 43 mRNA (TDP-43 5'-UTR IRE)

The Iron-responsive element (IRE) in the 5'-untranslated region (UTR) of TAR DNA-binding protein 43 (TDP-43) mRNA is a conserved RNA stem-loop structure that regulates the translation of TDP-43 in response to cellular iron levels (Annovis Bio, 2023). This regulatory element serves as a binding site for Iron Regulatory Proteins (IRP1 and IRP2); when iron levels are low, IRPs bind to the IRE and sterically hinder the assembly of the translation initiation complex, thereby reducing TDP-43 protein synthesis (Journal of Neurochemistry, 2021). In neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD), the pathological accumulation and aggregation of TDP-43 are central to disease progression (PubMed, 2022). The small molecule Buntanetap (formerly Posiphen) targets this IRE to enhance translational repression, effectively lowering the production of neurotoxic TDP-43 (Annovis Bio, 2022). By modulating this RNA-protein interaction, researchers aim to restore proteostasis and mitigate the neurodegenerative process, although care must be taken to maintain the essential physiological functions of TDP-43 in RNA processing (Frontiers in Molecular Neuroscience, 2020).

Other names

TARDBP 5'-UTR IRETDP-43 mRNA iron-responsive elementIron-responsive element of TAR DNA-binding protein 43TDP-43 IRE

Translational inhibition through the modulation of Iron Regulatory Protein (IRP) binding to the 5'-UTR IRE stem-loop