Protein unc-13 homolog A pre-mRNA cryptic exon region (UNC13A CE)

The Protein unc-13 homolog A (UNC13A) pre-mRNA cryptic exon region is a specific genomic sequence within the UNC13A gene that is pathologically spliced in neurodegenerative diseases. In healthy cells, the TAR DNA-binding protein 43 (TDP-43) binds to this intronic region to suppress the inclusion of a cryptic exon (Brown et al., Nature, 2022). However, in the majority of Amyotrophic Lateral Sclerosis (ALS) cases and approximately half of Frontotemporal Dementia (FTD) cases, TDP-43 is depleted from the nucleus, leading to the inclusion of this cryptic exon in the mature UNC13A mRNA (Ma et al., Nature, 2022). This inclusion causes a frameshift and a premature stop codon, which triggers nonsense-mediated decay of the transcript and results in a loss of the UNC13A protein. Since UNC13A is essential for synaptic vesicle priming and neurotransmitter release, its loss contributes significantly to neuronal dysfunction and death. Therapeutic strategies like QRL-201 utilize antisense oligonucleotides (ASOs) to target this region and block the inclusion of the cryptic exon, thereby restoring normal UNC13A expression and synaptic function (QurAlis, 2023).

Other names

UNC13A cryptic exonUNC13A intron 20 cryptic exonTDP-43-regulated cryptic exon in UNC13AUNC13A CE region

Splice-switching antisense oligonucleotide (ASO) that binds to the cryptic exon region to sterically block its inclusion in the mature mRNA, thereby preventing nonsense-mediated decay and restoring functional protein levels.