TAR DNA-binding protein 43-regulated cryptic transcripts (TDP-43 cryptic transcripts)

TAR DNA-binding protein 43 (TDP-43)-regulated cryptic transcripts are messenger RNA (mRNA) species that incorporate non-coding intronic sequences, known as cryptic exons, following the depletion of nuclear TDP-43. In healthy neurons, TDP-43 functions as a splicing repressor by binding to specific intronic regions, preventing the recognition of these cryptic splice sites by the spliceosome (Ling et al., 2015). In diseases such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), TDP-43 undergoes a nuclear-to-cytoplasmic shift and aggregation, leading to a loss of its nuclear regulatory function. This loss-of-function results in the mis-splicing of essential transcripts, most notably Stathmin-2 (STMN2), which is required for axonal maintenance, and Unc-13 homolog A (UNC13A), which is critical for synaptic vesicle priming (Melamed et al., 2019; Brown et al., 2022). The resulting truncated or unstable mRNAs lead to a deficiency in the corresponding proteins, driving neurodegeneration. Therapeutic interventions currently in development, such as antisense oligonucleotides (ASOs), target these specific cryptic splice sites to restore normal splicing and protein expression (Quralis, 2023). Monitoring the levels of these cryptic transcripts in patient biofluids also provides a direct biomarker for TDP-43 nuclear function and therapeutic efficacy (Klim et al., 2019).

Other names

Cryptic exonsTDP-43-dependent mis-spliced RNAStathmin-2 cryptic transcriptUnc-13 homolog A cryptic transcriptDysregulated RNA associated with TDP-43 loss-of-function phenotypes

Splice-switching antisense oligonucleotide-mediated restoration of functional mRNA