Tmem59-KO Mouse

Tmem59, also known as DCF1, is a type I transmembrane protein. It has been implicated in autophagy, as it contains a peptide in its intracellular domain that can interact with ATG16L1, promoting LC3 labelling and lysosomal targeting of its endosomal compartment [6]. It also plays a role in modulating Wnt/β -catenin signaling by promoting the formation of Wnt signalosomes [5].

In mice, complete or microglia-specific Tmem59 knockout leads to autism-like behaviors, along with enhanced excitatory synaptic transmission, increased dendritic spine density, and impaired synapse engulfment by microglia. This occurs likely through the destabilization of the C1q receptor CD93 [1]. TMEM59 ablation in mice results in loss of olfactory sensory neurons, impaired olfactory functions, and disrupted olfactory epithelium maintenance and regeneration, with an associated increase in inflammatory cell infiltration [2]. In the context of cerebral ischemic stroke, TMEM59 knockout in mice exacerbates the damage, as shown by elevated infarction volume, neurological deficit scores, and increased microglial activation and pyroptosis [3]. In the 5xFAD mouse model of Alzheimer's disease, TMEM59 haploinsufficiency reduces insoluble Aβ levels, Aβ plaques, and neurite dystrophy, rescuing synaptic plasticity and memory deficits [4].

In conclusion, Tmem59 is crucial for normal physiological functions in the nervous system, especially in synapse refinement, olfactory function, and protection against cerebral ischemic stroke. Mouse models with Tmem59 knockout or haploinsufficiency have revealed its significant role in diseases such as autism-like disorders, olfactory dysfunction, and Alzheimer's disease, providing insights into potential therapeutic strategies for these conditions.

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/