Iron-responsive element in the 5'-untranslated region of TARDBP mRNA (TARDBP 5'-UTR IRE)

The iron-responsive element (IRE) in the 5'-untranslated region (UTR) of the TARDBP mRNA is a conserved RNA stem-loop structure that serves as a critical regulator of TDP-43 protein synthesis. This element functions by binding to iron regulatory proteins (IRPs) under conditions of low cellular iron, which sterically blocks the assembly of the translation initiation complex and suppresses the production of TDP-43. In neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), the pathological accumulation and aggregation of TDP-43 are central to disease progression. Therapeutic targeting of this IRE aims to modulate TDP-43 levels at the translational level rather than the transcriptional level. Small molecules like Buntanetap (Posiphen) are being investigated for their ability to bind these IRE structures and reduce the translation of neurotoxic proteins, including TDP-43, thereby potentially slowing neurodegeneration. This approach represents a novel strategy to restore proteostasis by leveraging the cell's endogenous iron-sensing machinery.

Other names

TDP-43 IRETARDBP IREIron-responsive element of TDP-435'-UTR IRE of TARDBPTDP-43 mRNA iron-responsive element

Small molecule binding to the IRE structure in the 5'-UTR of the mRNA to sterically hinder the recruitment of the ribosomal translation initiation complex, thereby suppressing the translation of the TARDBP mRNA into TDP-43 protein.