TAR DNA-binding protein 43 mRNA iron-responsive element (TDP-43 mRNA IRE)

The TAR DNA-binding protein 43 (TDP-43) mRNA iron-responsive element (IRE) is a highly conserved RNA stem-loop structure located within the 5' untranslated region (UTR) of the TARDBP transcript [1]. This element functions as a post-transcriptional regulatory sensor that binds Iron Regulatory Proteins (IRP1 and IRP2) to control the translation of TDP-43 in response to cellular iron levels [1,2]. Under low-iron conditions, IRPs bind to the IRE and physically block the recruitment of the 43S pre-initiation complex, thereby inhibiting translation; conversely, high iron levels trigger IRP dissociation, leading to increased TDP-43 protein production [2,3]. In neurodegenerative conditions like Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD), the dysregulation of TDP-43 levels and its subsequent aggregation are hallmark features of pathogenesis [3,4]. Therapeutic candidates such as buntanetap (ANVS401) target this IRE to suppress the translation of TDP-43 and other neurotoxic proteins, aiming to restore proteostasis and reduce neurodegeneration [5]. This regulatory element represents a significant target for small molecule intervention in proteinopathies where protein overexpression drives disease progression [4,5]. Sources: [1] PubMed: 30639114; [2] PubMed: 33434134; [3] UniProt: Q13148; [4] NIH/NCBI Gene: 23435; [5] Annovis Bio Pipeline Documentation.

Other names

TARDBP mRNA iron-responsive elementTDP-43 5' UTR IRETDP-43 IRETARDBP 5'-untranslated region iron-responsive element

Modulation of mRNA translation by stabilizing the interaction between Iron Regulatory Proteins (IRPs) and the iron-responsive element (IRE) in the 5' UTR, thereby sterically hindering ribosomal assembly and reducing protein synthesis.