Tmem59-KO Mouse

Tmem59, also known as DCF1, is a type I transmembrane protein. It contains a minimal 19-amino-acid peptide in its intracellular domain. Tmem59 is involved in autophagy, interacting with ATG16L1 to promote local activation of LC3 and mediate autophagic degradation of specific membranous compartments [6]. It also potentiates Wnt signaling by promoting the formation of Wnt signalosomes [5].

In microglia, Tmem59 deficiency impairs phagocytosis of synapses, leading to enhanced excitatory synaptic transmission, increased dendritic spine density, and ASD-like behaviors in mice [1]. In the olfactory epithelium, TMEM59 ablation leads to loss of olfactory sensory neurons, impairs olfactory functions, and deteriorates epithelial regeneration after injury, with increased inflammatory cell infiltration [2]. In cerebral ischemic stroke, TMEM59 knockout in mice accelerates cerebral ischemia/reperfusion, exacerbates microglial activation and pyroptosis, while overexpression in microglial cells hinders these processes [3]. In the 5xFAD mouse model of Alzheimer's disease, TMEM59 overexpression exacerbates AD-like pathologies, while haploinsufficiency reduces insoluble Aβ levels, Aβ plaques, and rescues synaptic plasticity and memory deficits [4].

In conclusion, Tmem59 plays crucial roles in multiple biological processes, especially in the nervous system. Studies using gene knockout (KO) and conditional knockout (CKO) mouse models have revealed its significance in autism-like behaviors, olfactory functions, cerebral ischemic stroke, and Alzheimer's disease. These findings contribute to understanding the etiology of these diseases and potentially developing new therapeutic strategies.

References:

1. Meng, Jian, Han, Linkun, Zheng, Naizhen, Xu, Huaxi, Zhang, Yun-Wu. 2022. Microglial Tmem59 Deficiency Impairs Phagocytosis of Synapse and Leads to Autism-Like Behaviors in Mice. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 42, 4958-4979. doi:10.1523/JNEUROSCI.1644-21.2022. https://pubmed.ncbi.nlm.nih.gov/35606143/

2. Ma, Zhenjie, Li, Weihao, Zhuang, Liujing, Liu, Yongliang, Yu, Yiqun. 2023. TMEM59 ablation leads to loss of olfactory sensory neurons and impairs olfactory functions via interaction with inflammation. In Brain, behavior, and immunity, 111, 151-168. doi:10.1016/j.bbi.2023.04.005. https://pubmed.ncbi.nlm.nih.gov/37061103/

3. Zhang, Liang, Wang, Tao, Chen, Xiao-Fang, Cao, Jiang-Bei, Sun, Hu. 2021. TMEM59 protects against cerebral ischemic stroke by suppressing pyroptosis and microglial activation. In Biochemical and biophysical research communications, 543, 72-79. doi:10.1016/j.bbrc.2020.09.013. https://pubmed.ncbi.nlm.nih.gov/33517129/

4. Meng, Jian, Han, Linkun, Zheng, Naizhen, Xu, Huaxi, Zhang, Yun-Wu. 2020. TMEM59 Haploinsufficiency Ameliorates the Pathology and Cognitive Impairment in the 5xFAD Mouse Model of Alzheimer's Disease. In Frontiers in cell and developmental biology, 8, 596030. doi:10.3389/fcell.2020.596030. https://pubmed.ncbi.nlm.nih.gov/33195275/

5. Gerlach, Jan P, Jordens, Ingrid, Tauriello, Daniele V F, Egan, David A, Maurice, Madelon M. 2018. TMEM59 potentiates Wnt signaling by promoting signalosome formation. In Proceedings of the National Academy of Sciences of the United States of America, 115, E3996-E4005. doi:10.1073/pnas.1721321115. https://pubmed.ncbi.nlm.nih.gov/29632210/

6. Boada-Romero, Emilio, Letek, Michal, Fleischer, Aarne, Ramón-Barros, Cristina, Pimentel-Muiños, Felipe X. 2013. TMEM59 defines a novel ATG16L1-binding motif that promotes local activation of LC3. In The EMBO journal, 32, 566-82. doi:10.1038/emboj.2013.8. https://pubmed.ncbi.nlm.nih.gov/23376921/