huUNC13A Mouse

Synaptic vesicle priming factor UNC13A, also known as Munc13-1, is a member of the UNC13 protein family and a critical component of the presynaptic active zone, playing a central role in neurotransmitter release and synaptic transmission. This protein contains C1, C2, and MUN domains, enabling it to specifically mediate the synaptic vesicle priming process and promote the assembly of the SNARE complex. This renders the vesicles in a fusion-ready state, thereby regulating calcium-dependent neurotransmitter release and participating in critical physiological processes such as short-term synaptic plasticity, learning and memory, and the maintenance of neural network excitability ^[1]. UNC13A is predominantly expressed at high levels in neurons of the central nervous system, with particular enrichment at glutamatergic presynaptic terminals. It can also be detected in certain peripheral nerves and endocrine cells, underscoring its pivotal significance in neural signal transduction and the regulation of synaptic homeostasis ^[2].

Research indicates that genetic variants and aberrant expression of UNC13A are intimately associated with the pathogenesis and progression of multiple neurological diseases, with its implications in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and neurodevelopmental disorders being particularly prominent ^[3]. In ALS, the dysfunction of RNA-binding proteins, notably TDP-43, leads to cryptic exon inclusion in UNC13A mRNA. This causes a reduction in functional protein expression, which consequently impairs synaptic transmission and compromises motor neuron survival ^[4]. In the context of neurodevelopmental disorders, pathogenic UNC13A variants can result in severe epilepsy, intellectual disability, and movement disorders ^[5]. Given its core function in synaptic dynamics, UNC13A has emerged as a crucial molecular target in the therapeutics of neurodegenerative and neurodevelopmental diseases. Pharmacological modulation strategies—such as the use of antisense oligonucleotides (ASOs) or small molecules—aimed at restoring the normal splicing and expression of UNC13A have demonstrated promising therapeutic potential in ALS models ^[6-7].

huUNC13A mice are humanized models constructed using gene editing technology. In this model, the sequences from upstream of exon 1 to the partial 3'UTR of mouse Unc13a were replaced with the sequences from upstream of exon 1 to downstream of exon 44 of human UNC13A. huUNC13A mice can be used for preclinical studies investigating the pathogenesis of neurological and psychiatric diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and neurodevelopmental disorders, as well as for the evaluation of UNC13A-targeted therapeutics.