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TREM2与TDP-43相互作用并介导小胶质细胞对TDP-43相关神经变性的神经保护作用
2021-12-19 23:53
来源：小柯机器人

美国梅奥诊所Long-Jun Wu、Yong U. Liu等研究人员合作发现，TREM2与TDP-43相互作用，并介导小胶质细胞对TDP-43相关神经变性的神经保护作用。2021年12月16日，国际知名学术期刊《自然—神经科学》在线发表了这一成果。

研究人员利用病毒介导和转基因小鼠模型研究了小胶质细胞TREM2在TDP-43相关神经退行性疾病中的作用。研究人员发现，TREM2的缺乏损害了小胶质细胞对病理性TDP-43的吞噬性清除，并增强了神经元的损伤和运动障碍。质谱分析显示，人TDP-43（hTDP-43）诱导了一个TREM2依赖的小胶质细胞亚群，具有高CD11c表达和吞噬能力。利用质谱（MS）和表面等离子体共振（SPR）分析，研究人员进一步证明了TDP-43和TREM2在体外和体内以及肌萎缩侧索硬化症（ALS）患者的人体组织中的相互作用。研究人员通过计算确定了hTDP-43中与TREM2相互作用的区域。这些数据强调，TDP-43可能是小胶质细胞TREM2的配体，这种相互作用在TDP-43相关的神经变性中介导小胶质细胞的神经保护。
 
据介绍，TREM2与神经退行性疾病的风险有关。然而，TREM2在神经退行性疾病中的功能仍未被完全了解。
 
附：英文原文
 
Title: TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration

Author: Xie, Manling, Liu, Yong U., Zhao, Shunyi, Zhang, Lingxin, Bosco, Dale B., Pang, Yuan-Ping, Zhong, Jun, Sheth, Udit, Martens, Yuka A., Zhao, Na, Liu, Chia-Chen, Zhuang, Yongxian, Wang, Liewei, Dickson, Dennis W., Mattson, Mark P., Bu, Guojun, Wu, Long-Jun

Issue&Volume: 2021-12-16

Abstract: Triggering receptor expressed on myeloid cell 2 (TREM2) is linked to risk of neurodegenerative disease. However, the function of TREM2 in neurodegeneration is still not fully understood. Here, we investigated the role of microglial TREM2 in TAR DNA-binding protein 43 (TDP-43)-related neurodegeneration using virus-mediated and transgenic mouse models. We found that TREM2 deficiency impaired phagocytic clearance of pathological TDP-43 by microglia and enhanced neuronal damage and motor impairments. Mass cytometry analysis revealed that human TDP-43 (hTDP-43) induced a TREM2-dependent subpopulation of microglia with high CD11c expression and phagocytic ability. Using mass spectrometry (MS) and surface plasmon resonance (SPR) analysis, we further demonstrated an interaction between TDP-43 and TREM2 in vitro and in vivo as well as in human tissues from individuals with amyotrophic lateral sclerosis (ALS). We computationally identified regions within hTDP-43 that interact with TREM2. Our data highlight that TDP-43 is a possible ligand for microglial TREM2 and that this interaction mediates neuroprotection of microglia in TDP-43-related neurodegeneration. Using mouse models of TDP-43 neurodegeneration, this study demonstrates that microglial TREM2 binds TDP-43 and thus mediates its phagocytic clearance. TDP-43 may serve as a possible ligand for microglial TREM2 in TDP-43-related neurodegeneration.

DOI: 10.1038/s41593-021-00975-6

Source: https://www.nature.com/articles/s41593-021-00975-6

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex


本期文章：《自然—神经科学》：Online/在线发表

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