Doc2a-KO Mouse

Doc2a, also known as Double C2 domain alpha, is a calcium-sensitive protein involved in vesicle exocytosis, specifically regulating spontaneous synaptic transmission and Ca2+-dependent neurotransmitter release. It is part of the pathways related to synaptic function and has significance in maintaining normal neural communication [1,2]. Genetic models, like the zebrafish model, have been useful in studying its functions [3].

In temporal lobe epilepsy (TLE), the expression of DOC2A is significantly increased in both human patients and rat models of TLE. Its localization is observed in neurons, particularly at presynaptic terminals where it colocalizes with VMAT2, suggesting its abnormal expression may play a role in epilepsy [1]. In zebrafish, doc2a+/- fam57ba+/- double heterozygotes show hyperactivity and increased seizure susceptibility, along with increased body length and head size, indicating its role in regulating brain and body phenotypes related to 16p11.2 deletion-associated symptoms [3]. In STXBP1 encephalopathies, the synaptic levels of Doc2A are unstable in the absence of Munc18-1 and aggregate in the presence of disease-causing Munc18-1 mutants, suggesting its involvement in this neurological disorder [4]. In Hirschsprung's disease, down-regulation of DOC2A promotes the formation of hyperplastic nerve fibers in aganglionic segments, with UNC13B possibly being a downstream molecule [5].

In conclusion, Doc2a plays crucial roles in synaptic function and exocytosis. Studies using gene-modified models, such as those in zebrafish, have revealed its associations with epilepsy, 16p11.2-related phenotypes, STXBP1 encephalopathies, and Hirschsprung's disease. These findings contribute to understanding the molecular mechanisms underlying these diseases and may offer potential therapeutic targets.

References:

1. Hu, Xiao, Tang, Jun, Lan, Xiaofang, Mi, Xiujuan. 2019. Increased expression of DOC2A in human and rat temporal lobe epilepsy. In Epilepsy research, 151, 78-84. doi:10.1016/j.eplepsyres.2019.02.008. https://pubmed.ncbi.nlm.nih.gov/30844661/

2. Groffen, Alexander J A, Friedrich, Reut, Brian, Elisabeth C, Ashery, Uri, Verhage, Matthijs. 2006. DOC2A and DOC2B are sensors for neuronal activity with unique calcium-dependent and kinetic properties. In Journal of neurochemistry, 97, 818-33. doi:. https://pubmed.ncbi.nlm.nih.gov/16515538/

3. McCammon, Jasmine M, Blaker-Lee, Alicia, Chen, Xiao, Sive, Hazel. . The 16p11.2 homologs fam57ba and doc2a generate certain brain and body phenotypes. In Human molecular genetics, 26, 3699-3712. doi:10.1093/hmg/ddx255. https://pubmed.ncbi.nlm.nih.gov/28934389/

4. Guiberson, Noah Guy Lewis, Black, Luca S, Haller, Jillian E, Sharma, Manu, Burré, Jacqueline. . Disease-linked mutations in Munc18-1 deplete synaptic Doc2. In Brain : a journal of neurology, 147, 2185-2202. doi:10.1093/brain/awae019. https://pubmed.ncbi.nlm.nih.gov/38242640/

5. Xiao, Jun, Meng, Xinyao, Chen, Ke, Feng, Jiexiong, Li, Zhi. 2022. Down-Regulation of Double C2 Domain Alpha Promotes the Formation of Hyperplastic Nerve Fibers in Aganglionic Segments of Hirschsprung's Disease. In International journal of molecular sciences, 23, . doi:10.3390/ijms231810204. https://pubmed.ncbi.nlm.nih.gov/36142117/