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New articles from Prof. Huaxi Xu, our Associate Editor

Published on: 23 Sep 2021 Viewed: 376

Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.

This week, we would like to share several latest articles from Prof. Huaxi Xu, our Associate Editor.

Title: Proteolytic Shedding of Human Colony-Stimulating Factor 1 Receptor and its implication
Authors: Yue Wei, Menghui Ma, Sheng Lin, Xin Li, Yue Shu, Ziwei Wang, Yuhang Zhou, Banglian Hu, Baoying Cheng, Shengshun Duan, Xiaohua Huang, Huaxi Xu, Yun-Wu Zhang, Honghua Zheng
Type: Short Communication from Journal of Cellular and Molecular Medicine
Both Colony-stimulating factor 1 receptor (CSF1R) and triggering receptor expressed on myeloid cells-2 (TREM2) are trans-membrane receptors and are expressed in the brain primarily by microglia. Mutations in these two microglia-expressed genes associated with neurodegenerative disease have recently been grouped under the term “microgliopathy”. Several literatures have indicated that CSF1R and TREM2 encounters a stepwise shedding and TREM2 variants impair or accelerate the processing. However, whether CSF1R variant affects the shedding of CSF1R remains elusive. Here, plasmids containing human CSF1R or TREM2 were transiently transfected into the human embryonic kidney (HEK) 293T cells. Using Western Blot and/or ELISA assay, we demonstrated that, similar to those of TREM2, an N-terminal fragment (NTF) shedding of CSF1R ectodomain and a subsequent C-terminal fragment (CTF) of CSF1R intra-membrane were generated by a disintegrin and metalloprotease (ADAM) family member and by γ-secretase, respectively. And the shedding was inhibited by treatment with Batimastat, an ADAM inhibitor, or DAPT or compound E, a γ-secretase inhibitor. Importantly, we show that the cleaved fragments, both extracellular domain and intracellular domain of a common disease associated I794T variant, were decreased significantly. Together, our studies demonstrate a stepwise approach of human CSF1R cleavage and contribute to understand the pathogenicity of CSF1R I794T variant in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). These studies also suggest that the cleaved ectodomain fragment released from CSF1R may be proposed as a diagnostic biomarker for ALSP.
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Title: Trisomy 21–induced dysregulation of microglial homeostasis in Alzheimer’s brains is mediated by USP25
Authors: Qiuyang Zheng, Guilin Li, Shihua Wang, Ying Zhou, Ke Liu, Yue Gao, Yulin Zhou, Liangkai Zheng, Lin Zhu, Qingfang Deng, Meiling Wu, Anjie Di, Lishan Zhang, Yingjun Zhao, Hongfeng Zhang, Hao Sun, Chen Dong, Huaxi Xu, Xin Wang
Type: Research Article of Neuroscience
Down syndrome (DS), caused by trisomy of chromosome 21, is the most significant risk factor for early-onset Alzheimer’s disease (AD); however, underlying mechanisms linking DS and AD remain unclear. Here, we show that triplication of homologous chromosome 21 genes aggravates neuroinflammation in combined murine DS-AD models. Overexpression of USP25, a deubiquitinating enzyme encoded by chromosome 21, results in microglial activation and induces synaptic and cognitive deficits, whereas genetic ablation of Usp25 reduces neuroinflammation and rescues synaptic and cognitive function in 5×FAD mice. Mechanistically, USP25 deficiency attenuates microglia-mediated proinflammatory cytokine overproduction and synapse elimination. Inhibition of USP25 reestablishes homeostatic microglial signatures and restores synaptic and cognitive function in 5×FAD mice. In summary, we demonstrate an unprecedented role for trisomy 21 and pathogenic effects associated with microgliosis as a result of the increased USP25 dosage, implicating USP25 as a therapeutic target for neuroinflammation in DS and AD.
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Title: Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) Interacts with Colony-Stimulating Factor 1 Receptor (CSF1R) but Is Not Necessary for CSF1/CSF1R-Mediated Microglial Survival
Authors: Baoying Cheng, Xin Li, Kai Dai, Shengshun Duan, Zhouyi Rong, Yingmin Chen, Liangcheng Lü, Zhaoji Liu, Xiaohua Huang, Huaxi Xu, Yun-Wu Zhang, Honghua Zheng
Type: Original Research Article of Multiple Sclerosis and Neuroimmunology
Triggering receptor expressed on myeloid cells-2 (TREM2) and colony-stimulating factor 1 receptor (CSF1R) are crucial molecules for microgliopathy, which is characterized by microglia dysfunction and has recently been proposed as the neuropathological hallmark of neurological disorders. TREM2 and CSF1R are receptors expressed primarily in microglia in the brain and modulate microglial activation and survival. They are thought to be in close physical proximity. However, whether there is a direct interaction between these receptors remains elusive. Moreover, the physiological role and mechanism of the interaction of TREM2 and CSF1R remain to be determined. Here, we found that TREM2 interacted with CSF1R based on a co-immunoprecipitation assay. Additionally, we found that CSF1R knockdown significantly reduced the survival of primary microglia and increased the Trem2 mRNA level. In contrast, CSF1R expression was increased in Trem2-deficient microglia. Interestingly, administration of CSF1, the ligand of CSF1R, partially restored the survival of Trem2-deficient microglia in vitro and in vivo. Furthermore, CSF1 ameliorated Aβ plaques deposition in Trem2-/-; 5XFAD mouse brain. These findings provide solid evidence that TREM2 and CSF1R have intrinsic abilities to form complexes and mutually modulate their expression. These findings also indicate the potential role of CSF1 in therapeutic intervention in TREM2 variant-bearing patients with a high risk of Alzheimer’s disease (AD).
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Title: TMEM59 interacts with TREM2 and modulates TREM2-dependent microglial activities
Authors: Zhaoji Liu, Jinhuan Ning, Xiaoyuan Zheng, Jian Meng, Linkun Han, Honghua Zheng, Li Zhong, Xiao-Fen Chen, Xian Zhang, Hong Luo, Dan Can, Huaxi Xu, Yun-wu Zhang
Type: Article of Cell Death & Disease
The surface receptor triggering receptor expressed on myeloid cells 2 (TREM2) plays a crucial role in maintaining a multitude of microglial activities, such as survival, proliferation, migration, metabolism, inflammation, and phagocytosis. However, the molecular mechanisms underlying TREM2-mediated microglial activities remain largely elusive. Herein, we found that TREM2 interacted with the type I transmembrane protein TMEM59, whose expression could facilitate autophagic flux through its carboxyl-terminus. TMEM59 expression was decreased upon lipopolysaccharide treatment. While downregulation of TMEM59 promoted anti-inflammatory factor expression and attenuated lipopolysaccharide treatment-induced inflammation. Importantly, we found that overexpression of TREM2 reduced TMEM59 protein levels through promoting its degradation, whereas TMEM59 levels were elevated in Trem2-deficient microglia. Finally, impaired survival, proliferation, migration, and phagocytosis, as well as dysregulated autophagy and metabolism in Trem2-deficient microglia were attenuated upon TMEM59 silencing. Together, our findings reveal a novel function of TREM2 in mediating TMEM59 protein degradation and demonstrate the importance of TMEM59 homeostasis in maintaining TREM2-mediated microglial activities.
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Title: RAB39B Deficiency Impairs Learning and Memory Partially Through Compromising Autophagy
Authors: Mengxi Niu, Naizhen Zheng, Zijie Wang, Yue Gao, Xianghua Luo, Zhicai Chen, Xing Fu, Yanyan Wang, Ting Wang, Manqing Liu, Tingting Yao, Peijie Yao, Jian Meng, Yunqiang Zhou, Yunlong Ge, Zhanxiang Wang, Qilin Ma, Huaxi Xu, Yun-wu Zhang
Type: Original Research Article of Molecular and Cellular Pathology
RAB39B is located on the X chromosome and encodes the RAB39B protein that belongs to the RAB family. Mutations in RAB39B are known to be associated with X-linked intellectual disability (XLID), Parkinson’s disease, and autism. However, the patho/physiological functions of RAB39B remain largely unknown. In the present study, we established Rab39b knockout (KO) mice, which exhibited overall normal birth rate and morphologies as wild type mice. However, Rab39b deficiency led to reduced anxiety and impaired learning and memory in 2 months old mice. Deletion of Rab39b resulted in impairments of synaptic structures and functions, with reductions in NMDA receptors in the postsynaptic density (PSD). RAB39B deficiency also compromised autophagic flux at basal level, which could be overridden by rapamycin-induced autophagy activation. Further, treatment with rapamycin partially rescued impaired memory and synaptic plasticity in Rab39b KO mice, without affecting the PSD distribution of NMDA receptors. Together, these results suggest that RAB39B plays an important role in regulating both autophagy and synapse formation, and that targeting autophagy may have potential for treating XLID caused by RAB39B loss-of-function mutations.
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Title: Overexpression of Human SNX27 Enhances Learning and Memory Through Modulating Synaptic Plasticity in Mice
Authors: Yuanhui Huo, Yue Gao, Qiuyang Zheng, Dongdong Zhao, Tiantian Guo, Shuo Zhang, Yuzhe Zeng, Yiyun Cheng, Huaping Gu, Lishan Zhang, Bin Zhu, Hong Luo, Xian Zhang, Ying Zhou, Yun-wu Zhang, Hao Sun, Huaxi Xu, Xin Wang
Type: Original Research of Membrane Traffic
Abnormal synaptic transmission leads to learning and memory disorders and is the main feature of neurological diseases. Sorting nexin 27 (SNX27) is an endosomal adaptor protein associated with a variety of nervous system diseases, and it is mainly responsible for the trafficking of postsynaptic membrane receptors. However, the roles of SNX27 in regulating synaptic and cognitive function are not fully understood. Here, we first generated a neuron-specific human-SNX27 transgenic mouse model (hSNX27 Tg) that exhibited enhanced excitatory synaptic transmission and long-term potentiation (LTP). In addition, we found that the hSNX27 Tg mice displayed enhanced learning and memory, lower-level anxiety-like behavior, and increased social interaction. Furthermore, we found that SNX27 overexpression upregulated the expression of glutamate receptors in the cortex and hippocampus of hSNX27 Tg mice. Together, these results indicate that SNX27 overexpression promotes synaptic function and cognition through modulating glutamate receptors.
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