Protein UNC13 homolog A (UNC13A)

Protein UNC13 homolog A (UNC13A), also known as Munc13-1, is a master regulator of neurotransmitter release at the presynaptic active zone. It functions as a critical molecular scaffold that facilitates the priming of synaptic vesicles by promoting the assembly of the SNARE complex, specifically by transitioning syntaxin-1 from a closed to an 'open' conformation [10, 15, 17]. In neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), the loss of the nuclear RNA-binding protein TDP-43 leads to the aberrant inclusion of a 'cryptic' exon in UNC13A pre-mRNA [3, 11]. This mis-splicing event triggers nonsense-mediated decay, causing a drastic reduction in functional UNC13A protein levels and subsequent synaptic failure [1, 2, 7]. Therapeutic strategies are currently focused on the development of antisense oligonucleotides (ASOs) that act as splice-modulators to block cryptic exon inclusion and restore functional protein expression [5, 13]. Such interventions represent a precision medicine approach for the majority of ALS patients and approximately half of FTLD patients who exhibit TDP-43 pathology [16, 18].

Other names

Munc13-1Unc-13 homolog AMammalian uncoordinated-13-1UN13A_HUMAN

Splice modulation (splice-switching) to prevent the inclusion of a cryptic exon in pre-mRNA, thereby preventing nonsense-mediated decay and restoring functional protein levels