Pathological RNA transcripts associated with TDP-43 dysfunction (TDP-43-regulated cryptic transcripts)

Pathological RNA transcripts associated with TDP-43 dysfunction represent a critical class of therapeutic targets in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) [Klim et al., 2019; Melamed et al., 2019]. Under normal conditions, the TAR DNA-binding protein 43 (TDP-43) resides in the nucleus and regulates RNA processing, specifically repressing the inclusion of non-conserved "cryptic" exons [Neumann et al., 2006]. In disease states, TDP-43 undergoes nuclear depletion and cytoplasmic aggregation, leading to the inclusion of these cryptic exons in essential genes such as STMN2 (Stathmin-2) and UNC13A [Ma et al., 2022; Brown et al., 2022]. The resulting transcripts often contain premature stop codons or undergo truncated polyadenylation, leading to a loss of functional protein essential for axonal repair and synaptic integrity. Therapeutic strategies, such as antisense oligonucleotides (ASOs), aim to bind these pathological transcripts to prevent mis-splicing or restore the production of full-length, functional proteins [QurAlis, 2023]. This approach targets the molecular consequences of TDP-43 loss-of-function, which is observed in approximately 97% of ALS cases.

Other names

Cryptic exon-containing transcriptsTDP-43-dependent mis-spliced RNAsSTMN2 cryptic transcriptsUNC13A cryptic transcriptsTDP-43-repressed cryptic exons

Splice-switching antisense oligonucleotides (ASOs) designed to block the inclusion of cryptic exons or restore normal polyadenylation sites, thereby recovering functional protein levels [QurAlis, 2023; Klim et al., 2019].