Protein unc-13 homolog A (UNC13A)

UNC13A, also known as Protein unc-13 homolog A or Munc13-1, is a critical presynaptic scaffolding protein essential for the priming of synaptic vesicles for neurotransmitter release [9, 16]. It acts by bridging synaptic vesicles to the plasma membrane, facilitating the transition of vesicles into a fusion-ready state [2, 9]. In neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the nuclear depletion of the RNA-binding protein TDP-43 leads to the inclusion of a 'cryptic exon' in UNC13A mRNA, causing nonsense-mediated decay and a severe loss of the functional protein [1, 7, 13]. This loss of UNC13A impairs synaptic transmission and is a major driver of neuronal dysfunction [2, 7]. Therapeutic strategies currently under development include splice-switching antisense oligonucleotides (ASOs) designed to repress cryptic exon inclusion and restore protein levels [5, 12, 15]. Additionally, the UNC13A genotype (e.g., rs12608932) has emerged as a predictive biomarker for lithium carbonate treatment efficacy in ALS patients [2, 22].

Other names

Munc13-1Unc-13 homolog AUNC13KIAA1032

Splice-switching to repress cryptic exon inclusion and restore protein expression