Protein unc-13 homolog A (Munc13-1) (Munc13-1)

Protein unc-13 homolog A (Munc13-1) is a large presynaptic scaffolding protein that serves as a master regulator of neurotransmitter release in the mammalian central nervous system [2, 15]. It is essential for the priming of synaptic vesicles, a critical step that renders vesicles fusion-competent by facilitating the assembly of the SNARE complex through the opening of syntaxin-1 [3, 11]. Beyond its fundamental role in synaptic transmission, Munc13-1 is a major genetic modifier and therapeutic target for Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) [4, 6]. In these neurodegenerative diseases, the loss of nuclear TDP-43 leads to the inclusion of a cryptic exon in the UNC13A transcript, resulting in nonsense-mediated decay and a subsequent depletion of the protein that impairs neuronal communication [9, 10]. Current drug development efforts focus on antisense oligonucleotides (ASOs) like TRCN-1023 and QRL-204 designed to restore Munc13-1 levels by preventing this aberrant splicing, as well as small molecule modulators like bryostatin-1 and lithium carbonate [12, 14, 19].

Other names

UNC13AMammalian uncoordinated 13-1KIAA1032Protein unc-13 homolog A

Munc13-1 facilitates the priming of synaptic vesicles by promoting the transition of syntaxin-1 from a closed, autoinhibited state to an open conformation, which is required for the assembly of the SNARE complex [3, 11, 17]. It also acts as a physical bridge between the synaptic vesicle and the presynaptic plasma membrane, ensuring vesicles are positioned for rapid fusion upon calcium influx [1, 5, 11].