MAMDC2, a gene encoding a putative extracellular matrix protein, has diverse functions. It is involved in the innate antiviral response in microglia and may play a role in the link between HSV-1 and Alzheimer's disease. It also has potential implications in cell proliferation, skeletal muscle physiology, and may be associated with multiple disease-related pathways [1,2].

In genetic studies, Mamdc2-deficient (Mamdc2-/-) mice are more susceptible to HSV-1 infection, showing an impaired type I interferon-based innate antiviral response. This indicates that MAMDC2 positively regulates the innate antiviral response during neurotropic virus infection. Mechanistically, MAMDC2 interacts with STING via its first MAM domain, enhancing STING polymerization and activating downstream TBK1-IRF3 signaling to promote the expression of I-IFNs [1].

In conclusion, MAMDC2 has essential functions in the innate antiviral response in microglia, as revealed through gene-knockout mouse models. Its role in this process provides insights into the potential mechanism connecting HSV-1 and Alzheimer's disease, highlighting the importance of MAMDC2 in understanding the pathogenesis of such neurological diseases.

References:

1. Wang, Yiliang, Luo, Weisheng, Wang, Xiaohui, Huang, Lianzhou, Wang, Yifei. 2021. MAMDC2, a gene highly expressed in microglia in experimental models of Alzheimers Disease, positively regulates the innate antiviral response during neurotropic virus infection. In The Journal of infection, 84, 187-204. doi:10.1016/j.jinf.2021.12.004. https://pubmed.ncbi.nlm.nih.gov/34902449/

2. Mavillard, Fabiola, Servian-Morilla, Emilia, Dofash, Lein, Ravenscroft, Gianina, Cabrera-Serrano, Macarena. . Ablation of the carboxy-terminal end of MAMDC2 causes a distinct muscular dystrophy. In Brain : a journal of neurology, 146, 5235-5248. doi:10.1093/brain/awad256. https://pubmed.ncbi.nlm.nih.gov/37503746/