TAR DNA-binding protein 43 mRNA (TDP-43 mRNA)

TAR DNA-binding protein 43 (TDP-43) mRNA is the transcript of the TARDBP gene, which encodes a multifunctional RNA-binding protein essential for RNA processing (UniProt, 2024). It plays a pivotal role in regulating splicing, mRNA transport, and the formation of stress granules. In neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), the protein product of this mRNA mislocalizes and aggregates, leading to both loss of nuclear function and gain of cytoplasmic toxicity (Neumann et al., 2006). Therapeutic strategies targeting the TDP-43 mRNA involve the use of antisense oligonucleotides (ASOs) or RNA interference (RNAi) to reduce the levels of the transcript or to modulate its splicing (Lagier-Tourenne et al., 2010). A major challenge in this approach is the essential nature of TDP-43; because the protein is required for cell survival, therapies must be carefully titrated to avoid total depletion. Current research also focuses on using mRNA-targeting tools to restore the expression of downstream targets like STMN2 and UNC13A, which are disrupted by TDP-43 pathology (Klim et al., 2019; Melamed et al., 2019). Clinical development is ongoing, with several investigational compounds aiming to achieve a safe reduction in toxic TDP-43 species while preserving physiological function.

Other names

TARDBP mRNATDP-43 transcriptTransactive response DNA-binding protein 43 mRNA

Antisense-mediated mRNA degradation via RNase H recruitment or steric hindrance of translation