Unc-13 homolog A (UNC13A) (UNC13A)

Unc-13 homolog A (UNC13A) is a critical presynaptic protein essential for the priming of synaptic vesicles, a process that renders them fusion-competent for neurotransmitter release (UniProt Q9UPW8). It plays a pivotal role in synaptic plasticity and neurotransmission within the central nervous system. In the context of neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), UNC13A has emerged as a major genetic risk factor and therapeutic target. The pathology is driven by the loss of TDP-43 from the nucleus, which normally suppresses the inclusion of a cryptic exon in the UNC13A mRNA (Brown et al., Nature 2022). Without TDP-43, this cryptic exon is incorporated, leading to a frameshift, premature stop codons, and subsequent degradation of the transcript via nonsense-mediated decay, resulting in a loss of UNC13A protein (Ma et al., Nature 2022). Therapeutic strategies, particularly antisense oligonucleotides (ASOs), are being developed to bind the UNC13A mRNA and prevent this cryptic splicing, thereby restoring functional protein levels and potentially slowing disease progression (QurAlis, 2023).

Other names

Munc13-1Protein unc-13 homolog AUNC13Unc-13 homolog A (C. elegans)

Splice-switching antisense oligonucleotide (ASO) mediated prevention of cryptic exon inclusion to restore functional protein levels.