TAR DNA-binding protein 43 pre-messenger RNA (TARDBP pre-mRNA)

TARDBP pre-mRNA is the precursor transcript for the TAR DNA-binding protein 43 (TDP-43), a critical RNA-binding protein involved in RNA processing, splicing, and transport (Polymenidou et al., 2011). A hallmark of TDP-43 biology is its tight autoregulation, where the protein binds to the 3' untranslated region (3' UTR) of its own pre-mRNA to trigger alternative splicing and subsequent nonsense-mediated decay, maintaining homeostatic levels (Lagier-Tourenne et al., 2012). In neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), TDP-43 undergoes nuclear depletion and cytoplasmic aggregation, leading to both loss-of-function and gain-of-toxic-function effects (Neumann et al., 2006). This nuclear loss results in the inclusion of cryptic exons in downstream targets like STMN2 and UNC13A, which serves as a biomarker for disease progression (Ling et al., 2015; Brown et al., 2022). Therapeutic targeting of TARDBP pre-mRNA, primarily using antisense oligonucleotides (ASOs), aims to modulate this autoregulatory mechanism to restore homeostatic protein levels or prevent the accumulation of toxic aggregates (Ionis Pharmaceuticals, 2023). However, precise titration is required, as TDP-43 is essential for cell survival, and excessive depletion can lead to catastrophic loss of RNA homeostasis (Barmada et al., 2010).

Other names

TDP-43 pre-mRNATARDBP transcriptTDP-43 precursor mRNATAR DNA-binding protein 43 transcript

Antisense-mediated modulation of alternative splicing or RNase H-dependent degradation to regulate TDP-43 protein homeostasis.