Unc13a-KO Mouse

Unc13a, without common aliases indicated in the references, is a gene expressed in neuronal tissue. It is involved in maintaining synaptic active zones, enabling the priming and docking of synaptic vesicles, which is crucial for neurotransmission [1,2,3,4].

Genome-wide association studies (GWAS) have shown that a polymorphism (rs12608932) in the UNC13A gene is associated with risk for both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [1]. In the absence of functional TDP-43, risk variants in UNC13A lead to the inclusion of a cryptic exon in its messenger RNA, causing nonsense-mediated decay and loss of functional protein. Depletion of UNC13A leads to impaired neurotransmission [1]. TDP-43 depletion in cultured cells, and in brains and spinal cords from patients with ALS and FTD, induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with these diseases overlap with TDP-43 binding sites and potentiate cryptic exon inclusion [2]. Also, loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells led to the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression [3].

In conclusion, Unc13a is essential for synaptic function, specifically in the processes of vesicle priming and docking for neurotransmission. Studies, especially those related to the loss-of-function scenarios due to TDP-43 depletion and associated polymorphisms, have revealed its crucial role in ALS and FTD. These findings provide potential therapeutic targets for TDP-43 proteinopathies [1,2,3].