TMEM59 modulates TREM2-regulated microglial responses in ischemia and serves as a potential therapeutic target

Microglial responses mediated by the triggering receptor expressed on myeloid cells 2 (TREM2) play a crucial role in ischemia, but the underlying mechanism remains unclear. Herein, we found that TREM2 and its interacting protein, transmembrane protein 59 (TMEM59), had opposite expression dynamics in microglia from mice subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and HMC3 cells treated with oxygen–glucose deprivation/reoxygenation (OGD/R), with TREM2 expression gradually increased, whereas TMEM59 expression increased first and then gradually decreased after ischemia modeling. We confirmed that TREM2 deficiency deteriorated neurological function impairments, cell apoptosis, microgliosis, and neuroinflammation in MCAO/R mice.

Notably, TMEM59 haploinsufficiency dramatically attenuated the exacerbated impairments in TREM2-deficient mice with MCAO/R. Mechanistically, TMEM59 deficiency suppressed aberrant autophagy activation and neuroinflammation in microglia following MCAO/R and OGD/R. Moreover, both microglia-specific and systemic deletion of TMEM59 ameliorated neurological function impairments, cell apoptosis, microgliosis, neuroinflammation, and aberrant autophagy in MCAO/R mice.

Finally, we developed a peptide targeting TMEM59 to promote its degradation and showed that treatment with this peptide reduced TMEM59 protein levels and effectively rescued neurological impairments and related pathologies in MCAO/R mice. Our findings establish TMEM59 as a key negative regulator of TREM2 function in microglia and a key driver of maladaptive microglial autophagy and neuroinflammation in ischemia, indicating that TMEM59 reduction represents a promising therapeutic strategy for ischemia treatment. We would like to thank the Core Facility of Biomedical Science, Xiamen University, for technical supports.

This work was supported by grants from National Natural Science Foundation of China (82588301 and U25A2072 to Y.-w.Z.; 82501698 to J.M.; 82371420 to X.Z.) and the Nanqiang Outstanding Young Talents Program from Xiamen University (0070/X2450216 to H.Li). These authors contributed equally: Jinghui Wang, Zihao Zhao, Jian Meng. Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, Fujian, China Jinghui Wang, Zihao Zhao, Jian Meng, Ziqian Tang, Yunxia Lu, Zhongding Li, Jian Zhang, Naizhen Zheng, Jing Cao, Yong Wang, Kun Li, Xian Zhang, Hong Luo, Yingjun Zhao, Huihui Li & Yun-wu Zhang Y.-w.Z., J.M., Y.W., J.W., and Z.Z. are co-applicants of a patent for the TMEM59-targeting peptide related to this study (patent no.

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